Eating, diet, and nutrition for the treatment of non-alcoholic fatty liver disease

Article information

Clin Mol Hepatol. 2023;29(Suppl):S244-S260

Publication date (electronic) : 2022 December 14

doi : https://doi.org/10.3350/cmh.2022.0364

Georg Semmler ¹

, Christian Datz^,²

, Michael Trauner ¹

¹Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria

²Department of Internal Medicine, General Hospital Oberndorf, Teaching Hospital of the Paracelsus Medical University Salzburg, Oberndorf, Austria

Corresponding author : Christian Datz Department of Internal Medicine, General Hospital Oberndorf, General Hospital Oberndorf, Paracelsusstrasse 37, 5110 Oberndorf, Salzburg, Austria Tel: +43 6272 4334, E-mail: c.datz@kh-oberndorf.at

Editor: Yuri Cho, National Cancer Center, Korea

Received 2022 November 2; Revised 2022 December 6; Accepted 2022 December 8.

Abstract

Nutrition and dietary interventions are a central component in the pathophysiology, but also a cornerstone in the management of patients with non-alcoholic fatty liver disease (NAFLD). Summarizing our rapidly advancing understanding of how our diet influences our metabolism and focusing on specific effects on the liver, we provide a comprehensive overview of dietary concepts to counteract the increasing burden of NAFLD. Specifically, we emphasize the importance of dietary calorie restriction independently of the macronutrient composition together with adherence to a Mediterranean diet low in added fructose and processed meat that seems to exert favorable effects beyond calorie restriction. Also, we discuss intermittent fasting as a type of diet specifically tailored to decrease liver fat content and increase ketogenesis, awaiting future study results in NAFLD. Finally, personalized dietary recommendations could be powerful tools to increase the effectiveness of dietary interventions in patients with NAFLD considering the genetic background and the microbiome, among others.

Keywords: NAFLD; Mediterranean diet; Intermittent fasting; Calorie restricted diet; Precision medicine

INTRODUCTION

Non-alcoholic fatty liver disease (NAFLD) is the fastest-growing and most prevalent liver disease worldwide, contributing essentially to liver-related morbidity and mortality [1]. Being a prototype of so-called “non-communicable diseases”, the increasing prevalence of NAFLD, but also obesity, is regarded as closely related to changes associated with modern-day lifestyle including increased calorie intake, reduced physical activity, and sedentary behavior [2] that result in a mismatch between a decreased energy expenditure and an increased energy intake [3,4]. Among other factors [4], this seems to be largely driven by socioeconomic factors leading to a rise in ubiquitous, cheap, and energy-dense food of low dietary quality. In the absence of approved pharmacological treatments, lifestyle and especially dietary interventions are even more important to counteract the growing burden of NAFLD [5]. Here, we provide a concise overview of different nutritional strategies in NAFLD, especially in overweight and obese patients (Fig. 1), and summarize our current understanding of the interplay between NAFLD and our diet to facilitate personalized nutritional advice in these patients.

Figure 1.

Overview of dietary concepts in NAFLD highlighting evidence, pathophyisological considerations and open questions. NAFLD, nonalcoholic fatty liver disease; MUFA, mono-unsaturated fatty acids; PUFA, poly-unsaturated fatty acids.

Current guideline recommendations

In brief, current European [6,7], American [8], Asian [9], and Korean [10] guidelines highlight the importance of two essential concepts to treat NAFLD in overweight and obese individuals: (I) Weight loss aiming at a reduction of 7–10% in body weight, and (II) energy restriction aiming at a calorie deficit of approximately 500–1,000 kcal/day. On top of these established recommendations, the ideal macronutrient composition is currently a matter of debate: While the American society highlights uncertainties regarding long-term (histological) endpoints that preclude recommendations in favor of one type over another, a dietary composition in accordance to the Mediterranean dietary (MD) is generally advised by European and Asian societies [6,7,9] given clear signals towards beneficial effects beyond the macronutrient composition (see chapter Mediterranean Diet [MD]). Also, the latter advise avoiding added fructose, mostly via consumption of sugar-sweetened beverages (SSB). Importantly, both weight loss and a calorie deficit might be only achieved in combination with an increase in physical activity and exercise that ultimately lead to an increased energy expenditure [5]. Thus, a combined “lifestyle”-approach should always be preferred, and tailored to the individual patient to increase long-term adherence achieving a durable improvement in energy metabolism (“eat less, move more”) [6,8].

Outcomes in nutritional research

To make use of dietary recommendations in clinical practice, one must take the endpoints that have been investigated in the respective studies into account. With this regard, dietary recommendations for NAFLD are especially complex given the variety of clinical endpoints: (I) Improvement of liver histology including regression of fibrosis or resolution of non-alcoholic steatohepatitis (NASH) [11-13]; (II) changes in quantitative parameters assessing liver fat content (i.e., hepatic steatosis) such as the intrahepatic triglyceride content/ intrahepatic lipid content (IHLC) assessed via magnetic resonance spectroscopy [14,15], controlled attenuation parameter (CAP) assessed by transient elastography [16,17], or scores combining laboratory values such as the fatty-liver-index [18,19]; (III) quantitative assessment of liver fibrosis using magnetic resonance elastography [20] or transient elastography-based liver stiffness measurement (LSM) [16-18,21]; (IV) transaminases (aspartate aminotransferase [AST]/alanine transaminase [ALT]) as a surrogate for hepatic inflammation [22]; and (V) changes in metabolic parameters such as fasting blood glucose, insulin resistance, serum lipids but also body weight that do not specifically address changes in the liver. Especially regarding liver fat content, one has to consider its transiency and that presumed association with clinical endpoints are predominantly driven by hepatic fibrosis (e.g., cardiovascular diseases [23]) including mortality [24]. Also, combined scores such as the fatty-liver-index have not been developed for metric assessment of liver fat, making absolute changes in these scores uninterpretable [25]. At the same time, levels of ALT/AST have numerously been described as inadequate to portray disease severity and hepatic fibrosis in NAFLD [26-28]. Finally, studies using histological data are scarce [11-13]. While they would be urgently needed, they are reasonably limited given the invasiveness of liver biopsy. With this regard, trials focusing on accepted surrogates of hepatic fibrosis (such as magnetic resonance elastography or LSM) should be strongly encouraged in future nutritional intervention studies.

CALORIE RESTRICTION & HYPOCALORIC DIET

Clear evidence suggests that dietary calorie restriction is able to improve numerous metabolic parameters beyond its effect on liver-related outcomes (e.g., reviewed in [29]). Focusing on NAFLD, several studies have shown that a total energy deficit (~500 kcal/day resulting in ~1,500 kcal/day for women and ~1,800 kcal/day for men) leads to a decrease in body weight, transaminase levels, total body fat, visceral fat, and IHLC, regardless of how it is achieved [15,22,30,31]. An important study by Kirk et al. [32] (2009) reported similar changes in body weight, body composition, and IHLC after 7% of weight loss (i.e., after around 11 weeks) following a hypocaloric low-carbohydrate diet (LCD) vs. a high-carbohydrate diet (HCD) despite short-term effects in favor of LCD (i.e., after 48 hours) [32]. Again, studies associating the degree of weight loss with the extent of histological improvement [11] and improvement of metabolic parameters [33] strongly favor a dose-dependent effect of nutritional/lifestyle interventions beyond macronutrient composition [34]. Interestingly, a recent meta-analysis of observational studies including >100,000 individuals has shown that the only difference between NAFLD and controls was a higher calorie intake while the macronutrient composition did not significantly differ [35]. Finally, evidence highlighting the importance of calorie reduction originates from the observation that LCD (as discussed in chapter Low-Carbohydrate Diet [LCD]) are only successful in reducing IHLC when integrated into a hypocaloric diet approach, but fail to decrease or even increase IHLC if carbohydrate restriction occurs at the expense of increased fat intake in an isocaloric manner [36,37].

LOW-CARBOHYDRATE DIET (LCD)

On top of calorie restriction, increasing evidence suggests a diet low in carbohydrates to be especially fruitful for patients with NAFLD. On a population-based level, data from America show that intake of potato chips, potatoes, and SSB were the dominant factors associated with weight gain [38] paralleling the global increase in obesity and NAFLD in recent years, thereby clearly suggesting a certain role of a western diet typically high in carbohydrates for the surge in obesity and NAFLD. On the short term, Browning et al. [39] (2011) reported a favorable reduction in IHLC after a hypocaloric LCD (8% carbohydrates [C], 33% protein [P], 59% fat [F]) compared to a hypocaloric diet (50% C, 16% P, 34% F), as did Kirk et al. [32] (2009) after 48 hours. However, one has to note that reductions in IHLC were comparable after 7% weight loss [32], supported by Haufe et al. [30] (2011) who also showed comparable reductions in IHLC after 6 months. Nevertheless, an increase in total energy expenditure by about ~50 kcal for every 10% decrease in the contribution of carbohydrates to total energy intake has been postulated [40], together with a decrease in ghrelin and leptin levels contributing to decreased appetite and satiety [41] following a LCD independently of body mass index (BMI). Importantly, these changes might be linked to an increase in ketogenesis and favorable changes in gut microbiota, which were even observed after an isocaloric LCD [42]. Another randomized controlled trial (RCT) aiming at maintained weight in adolescents reported a decrease in IHLC after 8 weeks only following an LCD (<25% C, 25% P, >50% F), but not a HCD (55% C, 25% P, 20% F) [43]. In summary, benefits from an LCD seem to include a favorable glucose metabolism (reduced insulin resistance [20], reduced basal glucose production [32]) independent of changes in IHLC, even in patients with established type-2 diabetes mellitus [44]. However, improvements of BMI, HDL and triglyceride profiles must be balanced with potential consequences of an LCD (i.e., high in dietary fat) such as elevated LDL and total cholesterol levels in the long-term [45,46]. Finally, both low carbohydrate consumption (<40% of total energy intake) and high carbohydrate consumption (>70%) were associated with higher overall mortality in unselected patients (i.e., a U-shaped relationship) [47], questioning long-term beneficial effects of LCD, but especially very-low-carbohydrate-diets (i.e., ketogenic diets).

Carbohydrate-insulin-model vs. energy-balance-model

Hypotheses discussing explanations for additional beneficial effects of an LCD on top of a hypocaloric diet be generated from the current discussion on two theories trying to explain energy metabolism in obesity: the carbohydrate-insulin-model and the energy-balance-model [48,49].

The carbohydrate-insulin-model focuses on the influence of dietary carbohydrates on the human body. Specifically, an increase in carbohydrates (i.e., high glycemic load) leads to increased insulin secretion (i.e., hyperinsulinemia) that promotes energy storage in adipose tissue, exacerbating hunger and lowering energy expenditure, all together promoting weight gain in a generally anabolic state [50]. By further stimulating glucose uptake, suppressing the release of fatty acids from adipose tissue, and promoting fat and glycogen production, hyperinsulinemia following carbohydrate intake induces a vicious cycle that “offers an explanation for why average BMI in many countries increased in the late 20th century as public health guidelines recommended replacement of dietary fat with carbohydrates, and consumption of high-glycemic-load foods increased substantially” [51]. Thus, the carbohydrate-insulin-model considers the high glycemic load as the starting point promoting anabolism including an anabolic hormonal profile, leading to “deposition” of substrates, leaving less energy for the brain (especially in the late postprandial period [52,53]) in turn inducing hunger and appetite [48].

Considering that insulin resistance is regarded a hallmark of NAFLD progression closely linked to inflammation, oxidative stress, and disease progression [54-56], an additional benefit of a LCD in NAFLD is reasonable from a pathophysiological perspective. Here, insulin resistance directly correlates with hepatic de-novo lipogenesis (DNL) [57], which has been shown to significantly contribute to IHLC in lean individuals without NAFLD (~11%), but being even more pronounced in obese individuals (~19%) and obese NAFLD patients (~38%). Most importantly, Luukkonen and colleagues [58] (2022) just recently described insulin resistance as an independent pathophysiological trait in NAFLD next to the genetic predisposition, being amplified if both factors are present. Considering this importance of insulin resistance in NAFLD, an increased DNL during carbohydrate overfeeding [59-61], an increased DNL in NAFLD [57,62], and the efficacy of LCD especially in hyper-insulinemic patients [40], LCD could offer a “way out” of this vicious cycle. Here, Cohen and colleagues [63] (2021) could already demonstrate a reduction of DNL within 8 weeks of dietary sugar restriction in adolescents.

In summary, specific beneficial aspects include the above-mentioned increase in energy expenditure [40,64], increase in satiety [41], lower insulin and ghrelin action in adipose tissue, higher glucagon action in non-adipose sites, and increased leptin sensitivity in the muscle [51].

The competing model to this theory is the energy-balancemodel that considers the increased availability of (cheap and energy-dense) food as the starting point for obesity [49]. Specifically, the brain regulates body weight in response to external signals from our food environment that stipulate hormonal signals controlling food intake, but also energy partitioning within the body [49]. Importantly, proponents of this model argue against the simplistic approach of the carbohydrate-insulin-model neglecting that several variables in the food environment influence energy intake and energy partitioning. For example, energy expenditure and energy intake are dynamically interrelated by physiological counteracting mechanisms (e.g., adaptive thermogenesis corresponding to a reduced energy expenditure if energy intake is decreased [65]) that are nearly impossible to look at in an isolated fashion [66]. While data supporting a lower energy expenditure following low-fat diets exist, authors claim that these differences are so small that “a calorie is a calorie” [66]. Also, one must acknowledge that evidence from meta-analysis is currently lacking that an LCD (favoring the carbohydrate-insulin-model) is more effective than a low-fat diet if calorie restriction is achieved (favoring the energy-balance-model) [37].

MEDITERRANEAN DIET (MD)

Looking beyond the macronutrient composition, it seems that the dietary composition is still relevant for the effect of a given diet on metabolic parameters. Here, a dietary composition according to the MD has been most consistently associated with improved phenotype of NAFLD [67]. Specifically, the MD has been defined “primarily a plant-based diet characterized by a high ratio of monounsaturated fatty acids (MUFA) to saturated fatty acids (SFA) with total fat accounting for 30–40% of daily energy consumption” [68].

Next to improvement in metabolic dysregulation [69] and prevention of cardiovascular diseases [70], adherence to the MD has been inversely associated with NAFLD prevalence [71] and severity [72-74], reduction in liver fat content [14,18,19,75-77], and LSM [18,78]. For instance, adherence to a low-carbohydrate MD (over 6 months) improved NAFLD (assessed by ultrasound) [77]. However, the inverse association between adherence to MD and decrease in liver fat content might be largely mediated (i.e., driven) by a decrease in BMI [74] emphasizing the central role of adipose tissue-liver crosstalk when studying liver-related outcomes [79].

Despite these promising results, the dietary composition of MD was heterogeneous across different studies and often combined with calorie restriction, thereby complicating direct comparison. Nevertheless, the best evidence that adherence to a MD on top of a hypocaloric diet is beneficial for NAFLD comes from studies from Israel. Gepner and colleagues [80,81] demonstrated that an LCD in combination with a MD achieved the greatest reduction in visceral adipose tissue and IHLC compared to an iso-caloric HCD. Interestingly, this effect was achieved despite only moderate weight loss, again supporting favorable effects of MD beyond calorie restriction [80]. Recently, the “DIRECT PLUS” RCT demonstrated a successful (and durable) weight loss and decrease in IHLC following a hypocaloric MD after 18 months [14]. What is even more interesting, the addition of dietary polyphenols (green tea and Mankai) further amplified these beneficial effects on IHLC (–38% relative change compared to –17% in the MD-only group) [14].

Specifically, several aspects seem to explain the success of the MD: First, one must consider that the MD is by itself characterized by a reduced carbohydrate intake (~approx. 40% of calorie intake), thereby mimicking favorable effects of a LCD on liver fat [82]. Second, the MD is low in food types that show clear harmful effects on NAFLD (such as Red and processed meat and SSB, as discussed in chapter Sugar sweetened beverages [SSB]), and rich in those that are considered beneficial (such as olive oil, nuts, legumes, seeds, whole grains, and vegetables) [67]. Third, the MD is rich in molecules/compounds that are generally regarded as “healthy”. Most prominently, polyphenols including flavonoids exhibit antioxidative effects reducing mortality in the general population [83,84], but also inhibit DNL, suppress the activation of hepatic stellate cells, and reduce carcinogenesis in animal models [85]. Carotenoids (i.e., lipid-soluble phytochemical) exert similar antioxidative properties [86] but are also discussed to decrease lipid accumulation, insulin resistance, oxidative stress, and inflammation in the liver [87]. Fourth, it still seems clear that the quality of ingested nutrients matters [36]. For example, 4 studies have shown favorable changes in IHLC if energy from fat is derived from MUFA and poly-unsaturated fatty acids (PUFA) compared to SFA following an isocaloric [88] or hypercaloric diet [89-91]. Also, an isocaloric diet high in MUFA was superior in reducing IHLC compared to isocaloric control diets despite unchanged body weight [92,93]. Finally, adherence to MD seems to be easier than to other diets (e.g., HCD), which has been demonstrated by the recent CORDIOPREV study reporting adherence to the MD in 7 of 8 patients over a period of 7 years, given that patients are supported by dieticians [94]. For the first time ever, a significant reduced incidence of major cardiovascular events in patients with coronary artery disease following a MD without energy restriction participating in this RCT was reported, further advocating this dietary composition [94].

FOOD GROUPS

Numerous food groups have repeatedly been associated with NAFLD [95]. Among them, red meat and SSB have shown the strongest negative impact on NAFLD prevalence and will be further discussed, while nuts and seeds seem to be protective [95,96].

Sugar sweetened beverages (SSB)

Dietary fructose intake—mostly via SSB and high-fructose corn syrup—is one of the food groups with the strongest evidence supporting harmful effects on multiple health outcomes, including NAFLD [97]. From a physiological point of view, fructose metabolization is nearly exclusively limited to hepatocytes [98]. By bypassing the rate-limiting step of glycolysis catalyzed by phosphofructokinase, fructose not only provides more substrate to DNL than glucose, but also occurs independent of insulin and the energy status of the cell [98], leading to an energy mismatch and subsequently promoting oxidative stress and insulin resistance [99,100]. Also, a roughly 100% first-pass effect following oral ingestion of fructose has been observed [101], suggesting metabolism in the liver directly upon consumption. Keeping this “fructose-processing burden” in mind, the harmful effect of significant and/or long-lasting fructose consumption on the liver seem reasonable.

In brief, several meta-analyses have tried to dissect the effect on glycemic control [102], metabolic syndrome [103], or NAFLD [104]. When fructose was substituted for other calories, no effect was evident regarding glycemic control compared. In contrast, a clearly harmful effect was observed when SSB were consumed on top of the usual diet (i.e., as excess calories) [102]: SSB showed a dose-dependent (increasing) effect on the prevalence of metabolic syndrome, while fruit juices showed a U-shaped relationship with protective effects at moderate doses [103]. Finally, a study on NAFLD found that addition of SSB (as ~30% excess energy) led to a significant increase in IHLC [104], while the beneficial effect when cutting down on fructose-containing sugars was less clear. However, all 3 available meta-analyses highlight the interaction with food sources (i.e., where excess fructose comes from) as an essential modifier of these effects, with SSB being the least favorable. Also, healthy individuals and/or adolescents seem to respond less to fructose supplementation [105] or restriction [106].

In individual studies, SSB have been associated with higher NAFLD prevalence [107-110], presence of NASH [111] and even a higher degree of fibrosis [112]. Recently, 4 RCT investigated the effect of fructose restriction on liver-related outcomes: Geidl-Flueck et al. [113] (2021) demonstrated a 2-fold increase in hepatic fatty acid-secretion rates in healthy men ingesting fructose/sucrose group vs. glucose sirup, Schwimmer et al. [114] (2019) reported a decrease in IHLC after 8 weeks of restricting free sugars, Simons et al. [115] (2021) showed a significant decrease in IHLC after 6 weeks of a fructose-restricted diet in NAFLD, and Khodami et al. [116] (2022) reported on an improvement of insulin resistance, steatosis, and fibrosis surrogates in NAFLD patients similarly restricting free sugars.

From a pathophysiological perspective, dietary fructose promotes DNL, impairs fatty acid oxidation, and triggers hepatic inflammation, thereby clearly fueling hepatic insulin resistance (reviewed in [99]). Also, epigenetic changes occur [117], and the role of the microbiome, metabolizing fructose to acetate being an additional substrate for DNL—is being increasingly understood [118]. Despite incompletely understood, dietary fructose even seems to increase nutrient absorption via improving survival of intestinal cells and increasing intestinal villus length [119].

Thus, although data regarding a long-term comparison between glucose and fructose consumption are lacking [36], available data clearly suggests that fructose consumption should be cut down to a minimum in patients with NAFLD.

Red and processed meat

Numerous studies within the last years have demonstrated a negative impact of red and especially processed meat on the prevalence of NAFLD. While some studies pointed towards a general association of meat with NAFLD [73,120,121], more recent observational longitudinal studies [122-124] and cross-sectional studies [125,126] have linked high consumption of only red meat to an increased prevalence of NAFLD [95]. Of note, white meat (i.e., chicken or turkey) did not show any significant associations [122], while processed meat of any type is still unfavourable [123,125]. Translating these associations into macronutrient composition, they are especially driven by animal protein since consumption of plant-based protein did not show a comparable association [121,127]. However, the harmful effects of high meat consumption on liver fat might be largely driven by a parallel increase in BMI [128], as also shown for the MD. Nevertheless, selected studies have even reported an increased risk of fibrosis in NAFLD patients with high red/processed meat consumption [123].

On a molecular basis, the diet-dependent acid-load seems to be an driving factor for these associations by inducing a low-grade metabolic acidosis129,130 leading to a disturbance in acid-base-homeostasis.131 Also, red meat contains a considerable amount of SFA and cholesterol, which have been shown to boost insulin resistance132 and drive hepatic lipid storage.133 Next, heme iron134,135 and nitrate (added for preservation) contribute considerably to the harmful effects of red or processed meat, potentially via increased oxidative stress.136 Finally, modification of the intestinal microbiota including the metabolism of certain components of red meat into harmful compounds (such as trimethylamine-N-oxide) seems to contribute to these negative effects.137,138 Focusing on processed meat, cooking meat at high temperatures for a long duration can form heterocyclic amines, which induce unfavorable health effects including an increased risk of cancer139 and chronic diseases, again mainly driven by an increased oxidative stress.140On a molecular basis, the diet-dependent acid-load seems to be an driving factor for these associations by inducing a low-grade metabolic acidosis [129,130] leading to a disturbance in acid-base-homeostasis [131]. Also, red meat contains a considerable amount of SFA and cholesterol, which have been shown to boost insulin resistance [132] and drive hepatic lipid storage [133]. Next, heme iron [134,135] and nitrate (added for preservation) contribute considerably to the harmful effects of red or processed meat, potentially via increased oxidative stress [136]. Finally, modification of the intestinal microbiota including the metabolism of certain components of red meat into harmful compounds (such as trimethylamine-N-oxide) seems to contribute to these negative effects [137,138]. Focusing on processed meat, cooking meat at high temperatures for a long duration can form heterocyclic amines, which induce unfavorable health effects including an increased risk of cancer [139] and chronic diseases, again mainly driven by an increased oxidative stress [140].

INTERMITTENT FASTING (IF)

Several types of “intermittent fasting” (IF) have gained increasing popularity in recent years. In brief, “time-restricted feeding” (TRF) involves calorie intake only during a pre-specified time window (usually for 4–10 hours). With regard to timing, a recent study applying TRF on healthy individuals indicates a certain benefit in glycemic control when feeding is restricted to the time between 06:00–15:00 vs. during the mid of the day (11:00–20:00) [141]. “Alternate day fasting” describes a mode of TRF in which fasting periods over 36 hours are followed by ad-libitum food consumption over the next 12 hours (i.e., every 2nd day, e.g., from 06:00–18:00). Finally, the 5:2 diet involves calorie restriction only on 2 non-consecutive days during the week, on which calorie intake is usually restricted to 500–600 kcal/day. This periodic calorie restriction is believed to provoke several physiological changes contributing to health benefits (reviewed in [142,143])—among others, it might counteract the disruption of circadian rhythm being associated with the development of NAFLD and metabolic syndrome [144,145].

Stimulated by the success of Stekovic et al. [146] (2019) demonstrating significant improvement of metabolic parameters after 4 weeks and 6 months, an increasing number of studies have elucidated the beneficial effects of IF on health outcomes. Lately, an umbrella review of meta-analyses of RCT studying obesity-related outcomes reported beneficial outcomes for BMI, body composition, serum lipids, glucose homeostasis, and blood pressure [147].

Focusing on NAFLD, 5 studies have so far specifically investigated IF in this patient population. Johari and colleagues [21] applied a modified alternate-day calorie restriction (i.e., 70% calorie restriction on fasting day, ad-libitum eating on non-fasting day) to demonstrate an improvement in ALT levels as well as LSM and ultrasound-based steatosis [21]. Another study showed a decrease in BMI and triglyceride levels following 12 weeks of ADF or time-restricted feeding (energy intake only during an 8 hours-window each day) despite no changes in LSM [148]. Holmer et al. [17] (2021) compared the 5:2 diet (<500/600 kcal/day on fast-days) with an LCD in patients with NAFLD. This diet was associated with a significant improvement in liver fat as assessed by MRI or CAP, as well as improvement in BMI and insulin resistance compared to a control diet, among others. However, no differences were observed compared to the LCD diet. Kord Varkaneh et al. [149] (2022) also compared the 5:2 diet over 12 weeks with a control group, and observed improvements of metabolic parameters including LSM and CAP. Finally, Xiao and colleagues [150] (2022) studied 60 NAFLD patients with type 2 diabetes mellitus randomized to 5:2 diet or liraglutide over 24 weeks, and found comparable metabolic improvement including a decrease in CAP in both groups. In addition to these studies, certain data exist on the effect of Ramadan fasting on the liver. Again, aside from the improvement in metabolic serum parameters including glucose homeostasis [151], non-invasive scores of fibrosis and markers of subclinical inflammation improved in NAFLD patients [152]. Also, Ramadan fasting reduced the gene expression of “fat-mass-and-obesity-associated protein” (FTO) in overweight/obese individuals [153], which has been associated with obesity [154] despite lower calorie intake [155].

However, it is currently a matter of debate whether IF (i.e., time-dependent calorie restriction) is more effective [156] or equally effective [157,158] than continuous calorie restriction (e.g., hypocaloric diet), and whether it is effective if no calorie restriction/dietary counselling is applied [159]. In the setting of type-2 diabetes mellitus [160], close monitoring of diabetes medication and blood glucose is needed due to concerns about hypoglycemia [161] although TRF has also been shown to be effective and safe in overweight/obese patients with type-2 diabetes mellitus. At the same time, sarcopenia might be an issue due to fasting inducing protein catabolism and muscle loss [162-164].

An often discussed effect of IF is an increase in ketogenesis (reviewed in [165]). In brief, the production of ketone bodies (mainly acetoacetate and β-hydroxybutyrate) from fatty acids serves as an alternative energy supply from the liver to peripheral tissues when carbohydrates are unavailable, therefore being pronounced during fasting or starvation [166]. At the same time, ketogenesis represents an alternative lipid disposal pathway metabolizing acetyl-CoA derived from β-oxidation. While NAFLD is characterized by an abundance of substrates that need to be metabolized by the liver inducing oxidative stress, DNL is upregulated [57,58,62,167] and ketogenesis downregulated, leading to an exhausted mitochondrial capacity [168]. Thus, on top of the direct beneficial effects of ketone bodies including antioxidative and anti-inflammatory functions (discussed in [169,170]), IF (but also very-low-carbohydrate-diets) could reverse this so-called “ketogenic insufficiency” that has been observed in NAFLD [171] by increasing hydrolysis of IHLC partitioning fatty acids towards ketogenesis, thereby improving mitochondrial redox state [20]. Additional beneficial effects of fasting might include the simulation of the peroxisome proliferator-activated receptor alpha (PPARα) /fibroblast growth factor 21 (FGF21) signaling [172] involved in regulating fatty acid metabolism [173].

PRECISION NUTRITION IN NAFLD

“Precision nutrition” aims at tailoring personalized dietary recommendations to individuals considering not only lifestyle and socioeconomic factors, but also incorporating data on the metabolome [174], microbiome and the genetic background [175]. Here, a huge effort is being made towards personalized medicine [176] and deeper understand the interactions between our diet and our environment. Although few studies have focused on patients with NAFLD, data from unselected cohorts focusing on clinical endpoints closely related to NAFLD are indeed astonishing. Here, Zeevi and colleagues [177] (2015) demonstrated that large interpersonal variability exists in the postprandial glycemic response to identical meals. Together with a follow-up study by their group again showing heterogenous glycemic responses to sourdough or white bread [178], these data indicate that often neglected factors such as the microbiome significantly influence the effectiveness of a given dietary intervention. Also, data from the PREDICT1 study support the central role of the gut microbiome explaining more variance in post-prandial triglyceride and insulin levels than the macronutrient composition of the ingested meals itself [179]. Exemplary looking at individual substrates, the beneficial effects of resveratrol on liver fat are discussed to be mediated by changes in the microbiome [180].

When trying to understand the influence of our genes on dietary responses, data show that they are highly relevant for our postprandial glucose response alone explaining ~50% of the variance [179]. Looking at individual single nucleotide polymorphisms (reviewed in [181]), the PNPLA3 rs738409 G-allele has been best studied as a modifier for the dietary response. An early study in Hispanic children indicated a significant positive correlation between IHLC and dietary carbohydrates only in homozygous carriers of the G-allele [182]. Also, following an LCD, the improvement in IHLC and insulin sensitivity was highest in G/G-carriers [183,184]. Similarly, two studies confirmed significantly larger changes in hepatic fat on a low n-6:n-3 PUFA ratio diet in homozygous carriers of the PNPLA3 risk allele [185,186]. Finally, dietary carbohydrates, but also polyphenols and PUFA were associated with significant fibrosis on histology only in carriers of the PNPLA3 G-allele (G/C or G/G) [187]. At the same time, our genes might not only influence our response to a certain diet, but also generally determine our macronutrient content. Here, it is believed that our genetic background explains up to 40% of our macronutrient intake [188] with SNPs in FGF21 (increased carbohydrate [189] or protein intake [190]) and FTO (increased protein intake [191,192]) being mostly studied, the latter potentially allowing greater weight loss during dietary/lifestyle interventions [193,194].

CONCLUSION

In summary, nutritional research und understanding the influence of diet on disease severity is one of the most complex aspects in the management of NAFLD patients. While being highly efficient when done consequently, evaluating the effects of dietary interventions is challenging as they impact on the whole metabolism, and specific (beneficial) effects on the liver are hard to detangle. While this makes firm conclusions and guideline recommendations difficult, this must not be misinterpreted as a limitation of dietary interventions per se. Currently, many roads seem to be leading to Rome as long as a calorie deficit is achieved and energy expenditure is increased. However, a hypocaloric diet, low in dietary carbohydrates, potentially including IF could be a diet tailored to successfully “treat” NAFLD, awaiting further study results. Also, increasing evidence suggests that a dietary composition according to the MD provides additional benefits for NAFLD patients beyond calorie restriction. On the other hand, personalized dietary recommendations might be necessary to make use of the full potential of dietary interventions in NAFLD.

Notes

Authors’ contribution

Georg Semmler: Conceptualization, Writing- Original draft, Writing- Reviewing and Editing. Christian Datz: Conceptualization, Writing- Original draft, Writing- Reviewing and Editing. Michael Trauner: Conceptualization, Writing- Original draft, Writing- Reviewing and Editing.

Conflicts of Interest

The authors have nothing to disclose regarding the work under consideration for publication. The following authors disclose conflicts of interests outside the submitted work: GS received travel support from Gilead. CD is part of the scientific advisory board of SPAR Österreich AG. MT received grant support from Albireo, Almylam, Cymabay, Falk, Gilead, Intercept, MSD, Takeda and Ultragenyx, honoraria for consulting from Albireo, Boehringer Ingelheim, BiomX, Falk, Genfit, Gilead, Hightide, Intercept, Janssen, MSD, Novartis, Phenex, Pliant, Regulus and Shire, speaker fees from Bristol- Myers Squibb, Falk, Gilead, Intercept and MSD, as well as travel support from AbbVie, Falk, Gilead, and Intercept. He is also co-inventor of patents on the medical use of 24-norursodeoxycholic acid.

Abbreviations

BMI

body mass index

CAP

controlled attenuation parameter

DNL

de-novo lipogenesis

HCD

high-carbohydrate diet

intermittent fasting

IHLC

intrahepatic lipid content

LCD

low-carbohydrate diet

LSM

liver stiffness measurement

Mediterranean diet

MUFA

mono-unsaturated fatty acids

NAFLD

non-alcoholic fatty liver disease

NASH

non-alcoholic steatohepatitis

PUFA

poly-unsaturated fatty acids

RCT

randomized controlled trial

SFA

saturated fatty acids

SSB

Sugar-sweetened beverages

TRF

time-restricted feeding

References

1. Le MH, Yeo YH, Li X, Li J, Zou B, Wu Y, et al. 2019 Global NAFLD prevalence: a systematic review and meta-analysis. Clin Gastroenterol Hepatol 2022;20:2809–2817.e28.

2. Hallsworth K, Adams LA. Lifestyle modification in NAFLD/NASH: facts and figures. JHEP Rep 2019;1:468–479.

3. Church T, Martin CK. The obesity epidemic: a consequence of reduced energy expenditure and the uncoupling of energy intake? Obesity (Silver Spring) 2018;26:14–16.

4. Ikejima K, Kon K, Yamashina S. Nonalcoholic fatty liver disease and alcohol-related liver disease: from clinical aspects to pathophysiological insights. Clin Mol Hepatol 2020;26:728–735.

5. Semmler G, Datz C, Reiberger T, Trauner M. Diet and exercise in NAFLD/NASH: beyond the obvious. Liver Int 2021;41:2249–2268.

6. European Association for the Study of the Liver (EASL), ; European Association for the Study of Diabetes (EASD), ; European Association for the Study of Obesity (EASO). EASL-EASDEASO Clinical Practice Guidelines for the management of nonalcoholic fatty liver disease. J Hepatol 2016;64:1388–1402.

7. Plauth M, Bernal W, Dasarathy S, Merli M, Plank LD, Schütz T, et al. ESPEN guideline on clinical nutrition in liver disease. Clin Nutr 2019;38:485–521.

8. The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American Association for the Study of Liver Diseases. Clin Liver Dis (Hoboken) 2018;11:81.

9. Eslam M, Sarin SK, Wong VW, Fan JG, Kawaguchi T, Ahn SH, et al. The Asian Pacific Association for the Study of the Liver clinical practice guidelines for the diagnosis and management of metabolic associated fatty liver disease. Hepatol Int 2020;14:889–919.

10. Kang SH, Lee HW, Yoo JJ, Cho Y, Kim SU, Lee TH, et al. KASL clinical practice guidelines: management of nonalcoholic fatty liver disease. Clin Mol Hepatol 2021;27:363–401.

11. Vilar-Gomez E, Martinez-Perez Y, Calzadilla-Bertot L, TorresGonzalez A, Gra-Oramas B, Gonzalez-Fabian L, et al. Weight loss through lifestyle modification significantly reduces features of nonalcoholic steatohepatitis. Gastroenterology 2015;149:367–378.e5. quiz e14-e15.

12. Eckard C, Cole R, Lockwood J, Torres DM, Williams CD, Shaw JC, et al. Prospective histopathologic evaluation of lifestyle modification in nonalcoholic fatty liver disease: a randomized trial. Therap Adv Gastroenterol 2013;6:249–259.

13. Promrat K, Kleiner DE, Niemeier HM, Jackvony E, Kearns M, Wands JR, et al. Randomized controlled trial testing the effects of weight loss on nonalcoholic steatohepatitis. Hepatology 2010;51:121–129.

14. Yaskolka Meir A, Rinott E, Tsaban G, Zelicha H, Kaplan A, Rosen P, et al. Effect of green-Mediterranean diet on intrahepatic fat: the DIRECT PLUS randomised controlled trial. Gut 2021;70:2085–2095.

15. Magkos F, Fraterrigo G, Yoshino J, Luecking C, Kirbach K, Kelly SC, et al. Effects of moderate and subsequent progressive weight loss on metabolic function and adipose tissue biology in humans with obesity. Cell Metab 2016;23:591–601.

16. Arora C, Malhotra A, Ranjan P, Singh V, Singh N, et al. Effect of intensive weight-loss intervention on metabolic, ultrasound and anthropometric parameters among patients with obesity and non-alcoholic fatty liver disease: an RCT. Eur J Clin Nutr 2022;76:1332–1338.

17. Holmer M, Lindqvist C, Petersson S, Moshtaghi-Svensson J, Tillander V, Brismar TB, et al. Treatment of NAFLD with intermittent calorie restriction or low-carb high-fat diet - a randomised controlled trial. JHEP Rep 2021;3:100256.

18. Abenavoli L, Greco M, Milic N, Accattato F, Foti D, Gulletta E, et al. Effect of Mediterranean diet and antioxidant formulation in non-alcoholic fatty liver disease: a randomized study. Nutrients 2017;9:870.

19. Marin-Alejandre BA, Abete I, Cantero I, Monreal JI, Elorz M, Herrero JI, et al. The metabolic and hepatic impact of two personalized dietary strategies in subjects with obesity and nonalcoholic fatty liver disease: the Fatty Liver in Obesity (FLiO) randomized controlled trial. Nutrients 2019;11:2543.

20. Luukkonen PK, Dufour S, Lyu K, Zhang XM, Hakkarainen A, Lehtimäki TE, et al. Effect of a ketogenic diet on hepatic steatosis and hepatic mitochondrial metabolism in nonalcoholic fatty liver disease. Proc Natl Acad Sci U S A 2020;117:7347–7354.

21. Johari MI, Yusoff K, Haron J, Nadarajan C, Ibrahim KN, Wong MS, et al. A randomised controlled trial on the effectiveness and adherence of modified alternate-day calorie restriction in improving activity of non-alcoholic fatty liver disease. Sci Rep 2019;9:11232. Erratum in: Sci Rep 2020;10:10599.

22. de Luis DA, Aller R, Izaola O, Sagrado MG, Conde R, Gonzalez JM. Effect of a hypocaloric diet in transaminases in nonalcoholic fatty liver disease and obese patients, relation with insulin resistance. Diabetes Res Clin Pract 2008;79:74–78.

23. van Kleef LA, Lu Z, Ikram MA, de Groot NMS, Kavousi M, de Knegt RJ. Liver stiffness not fatty liver disease is associated with atrial fibrillation: the Rotterdam study. J Hepatol 2022;77:931–938.

24. Dulai PS, Singh S, Patel J, Soni M, Prokop LJ, Younossi Z, et al. Increased risk of mortality by fibrosis stage in nonalcoholic fatty liver disease: systematic review and meta-analysis. Hepatology 2017;65:1557–1565.

25. Fedchuk L, Nascimbeni F, Pais R, Charlotte F, Housset C, Ratziu V. Performance and limitations of steatosis biomarkers in patients with nonalcoholic fatty liver disease. Aliment Pharmacol Ther 2014;40:1209–1222.

26. Ma X, Liu S, Zhang J, Dong M, Wang Y, Wang M, et al. Proportion of NAFLD patients with normal ALT value in overall NAFLD patients: a systematic review and meta-analysis. BMC Gastroenterol 2020;20:10.

27. Mofrad P, Contos MJ, Haque M, Sargeant C, Fisher RA, Luketic VA, et al. Clinical and histologic spectrum of nonalcoholic fatty liver disease associated with normal ALT values. Hepatology 2003;37:1286–1292.

28. McPherson S, Stewart SF, Henderson E, Burt AD, Day CP. Simple non-invasive fibrosis scoring systems can reliably exclude advanced fibrosis in patients with non-alcoholic fatty liver disease. Gut 2010;59:1265–1269.

29. Flanagan EW, Most J, Mey JT, Redman LM. Calorie restriction and aging in humans. Annu Rev Nutr 2020;40:105–133.

30. Haufe S, Engeli S, Kast P, Böhnke J, Utz W, Haas V, et al. Randomized comparison of reduced fat and reduced carbohydrate hypocaloric diets on intrahepatic fat in overweight and obese human subjects. Hepatology 2011;53:1504–1514.

31. Kani AH, Alavian SM, Esmaillzadeh A, Adibi P, Azadbakht L. Effects of a novel therapeutic diet on liver enzymes and coagulating factors in patients with non-alcoholic fatty liver disease: a parallel randomized trial. Nutrition 2014;30:814–821.

32. Kirk E, Reeds DN, Finck BN, Mayurranjan SM, Patterson BW, Klein S. Dietary fat and carbohydrates differentially alter insulin sensitivity during caloric restriction. Gastroenterology 2009;136:1552-1560. Erratum in: Gastroenterology 2009;137:393.

33. Koutoukidis DA, Astbury NM, Tudor KE, Morris E, Henry JA, Noreik M, et al. Association of weight loss interventions with changes in biomarkers of nonalcoholic fatty liver disease: a systematic review and meta-analysis. JAMA Intern Med 2019;179:1262-1271. Erratum in: JAMA Intern Med 2019;179:1303–1304.

34. Haigh L, Kirk C, El Gendy K, Gallacher J, Errington L, Mathers JC, et al. The effectiveness and acceptability of Mediterranean diet and calorie restriction in non-alcoholic fatty liver disease (NAFLD): a systematic review and meta-analysis. Clin Nutr 2022;41:1913–1931.

35. Tsompanaki E, Thanapirom K, Papatheodoridi M, Parikh P, Chotai de Lima Y, Tsochatzis EA. Systematic review and meta-analysis: the role of diet in the development of nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol 2021;Nov. 25. doi: 10.1016/j.cgh.2021.11.026.

36. Yki-Järvinen H, Luukkonen PK, Hodson L, Moore JB. Dietary carbohydrates and fats in nonalcoholic fatty liver disease. Nat Rev Gastroenterol Hepatol 2021;18:770–786.

37. Ahn J, Jun DW, Lee HY, Moon JH. Critical appraisal for low-carbohydrate diet in nonalcoholic fatty liver disease: review and meta-analyses. Clin Nutr 2019;38:2023–2030.

38. Mozaffarian D, Hao T, Rimm EB, Willett WC, Hu FB. Changes in diet and lifestyle and long-term weight gain in women and men. N Engl J Med 2011;364:2392–2404.

39. Browning JD, Baker JA, Rogers T, Davis J, Satapati S, Burgess SC. Short-term weight loss and hepatic triglyceride reduction: evidence of a metabolic advantage with dietary carbohydrate restriction. Am J Clin Nutr 2011;93:1048–1052.

40. Ebbeling CB, Feldman HA, Klein GL, Wong JMW, Bielak L, Steltz SK, et al. Effects of a low carbohydrate diet on energy expenditure during weight loss maintenance: randomized trial. BMJ 2018;363:k4583. Erratum in: BMJ 2020;371:m4264.

41. Gibson AA, Seimon RV, Lee CM, Ayre J, Franklin J, Markovic TP, et al. Do ketogenic diets really suppress appetite? A systematic review and meta-analysis. Obes Rev 2015;16:64–76.

42. Mardinoglu A, Wu H, Bjornson E, Zhang C, Hakkarainen A, Räsänen SM, et al. An integrated understanding of the rapid metabolic benefits of a carbohydrate-restricted diet on hepatic steatosis in humans. Cell Metab 2018;27:559–571.e5.

43. Goss AM, Dowla S, Pendergrass M, Ashraf A, Bolding M, Morrison S, et al. Effects of a carbohydrate-restricted diet on hepatic lipid content in adolescents with non-alcoholic fatty liver disease: a pilot, randomized trial. Pediatr Obes 2020;15e12630.

44. Thomsen MN, Skytte MJ, Samkani A, Carl MH, Weber P, Astrup A, et al. Dietary carbohydrate restriction augments weight loss-induced improvements in glycaemic control and liver fat in individuals with type 2 diabetes: a randomised controlled trial. Diabetologia 2022;65:506–517.

45. Chawla S, Tessarolo Silva F, Amaral Medeiros S, Mekary RA, Radenkovic D. The effect of low-fat and low-carbohydrate diets on weight loss and lipid levels: a systematic review and meta-analysis. Nutrients 2020;12:3774.

46. Mansoor N, Vinknes KJ, Veierød MB, Retterstøl K. Effects of low-carbohydrate diets v. low-fat diets on body weight and cardiovascular risk factors: a meta-analysis of randomised controlled trials. Br J Nutr 2016;115:466–479.

47. Seidelmann SB, Claggett B, Cheng S, Henglin M, Shah A, Steffen LM, et al. Dietary carbohydrate intake and mortality: a prospective cohort study and meta-analysis. Lancet Public Health 2018;3:e419–e428.

48. Ludwig DS, Apovian CM, Aronne LJ, Astrup A, Cantley LC, Ebbeling CB, et al. Competing paradigms of obesity pathogenesis: energy balance versus carbohydrate-insulin models. Eur J Clin Nutr 2022;76:1209–1221.

49. Hall KD, Farooqi IS, Friedman JM, Klein S, Loos RJF, Mangelsdorf DJ, et al. The energy balance model of obesity: beyond calories in, calories out. Am J Clin Nutr 2022;115:1243–1254.

50. Ludwig DS, Ebbeling CB. The carbohydrate-insulin model of obesity: beyond “calories in, calories out”. JAMA Intern Med 2018;178:1098–1103.

51. Ludwig DS, Greco KF, Ma C, Ebbeling CB. Testing the carbohydrate-insulin model of obesity in a 5-month feeding study: the perils of post-hoc participant exclusions. Eur J Clin Nutr 2020;74:1109–1112.

52. Walsh CO, Ebbeling CB, Swain JF, Markowitz RL, Feldman HA, Ludwig DS. Effects of diet composition on postprandial energy availability during weight loss maintenance. PLoS One 2013;8e58172.

53. Shimy KJ, Feldman HA, Klein GL, Bielak L, Ebbeling CB, Ludwig DS. Effects of dietary carbohydrate content on circulating metabolic fuel availability in the postprandial state. J Endocr Soc 2020;4:bvaa062.

54. Utzschneider KM, Kahn SE. Review: the role of insulin resistance in nonalcoholic fatty liver disease. J Clin Endocrinol Metab 2006;91:4753–4761.

55. Kumashiro N, Erion DM, Zhang D, Kahn M, Beddow SA, Chu X, et al. Cellular mechanism of insulin resistance in nonalcoholic fatty liver disease. Proc Natl Acad Sci U S A 2011;108:16381–16385.

56. Kitade H, Chen G, Ni Y, Ota T. Nonalcoholic fatty liver disease and insulin resistance: new insights and potential new treatments. Nutrients 2017;9:387.

57. Smith GI, Shankaran M, Yoshino M, Schweitzer GG, Chondronikola M, Beals JW, et al. Insulin resistance drives hepatic de novo lipogenesis in nonalcoholic fatty liver disease. J Clin Invest 2020;130:1453–1460.

58. Luukkonen PK, Qadri S, Ahlholm N, Porthan K, Männistö V, Sammalkorpi H, et al. Distinct contributions of metabolic dysfunction and genetic risk factors in the pathogenesis of nonalcoholic fatty liver disease. J Hepatol 2022;76:526–535.

59. Schwarz JM, Neese RA, Turner S, Dare D, Hellerstein MK. Shortterm alterations in carbohydrate energy intake in humans. Striking effects on hepatic glucose production, de novo lipogenesis, lipolysis, and whole-body fuel selection. J Clin Invest 1995;96:2735–2743.

60. Hudgins LC, Hellerstein MK, Seidman CE, Neese RA, Tremaroli JD, Hirsch J. Relationship between carbohydrate-induced hypertriglyceridemia and fatty acid synthesis in lean and obese subjects. J Lipid Res 2000;41:595–604.

61. Wilke MS, French MA, Goh YK, Ryan EA, Jones PJ, Clandinin MT. Synthesis of specific fatty acids contributes to VLDLtriacylglycerol composition in humans with and without type 2 diabetes. Diabetologia 2009;52:1628–1637.

62. Lambert JE, Ramos-Roman MA, Browning JD, Parks EJ. Increased de novo lipogenesis is a distinct characteristic of individuals with nonalcoholic fatty liver disease. Gastroenterology 2014;146:726–735.

63. Cohen CC, Li KW, Alazraki AL, Beysen C, Carrier CA, Cleeton RL, et al. Dietary sugar restriction reduces hepatic de novo lipogenesis in adolescent boys with fatty liver disease. J Clin Invest 2021;131e150996.

64. Ebbeling CB, Bielak L, Lakin PR, Klein GL, Wong JMW, Luoto PK, et al. Energy requirement is higher during weight-loss maintenance in adults consuming a low- compared with highcarbohydrate diet. J Nutr 2020;150:2009–2015.

65. Rosenbaum M, Leibel RL. Adaptive thermogenesis in humans. Int J Obes (Lond) 2010;34 Suppl 1:S47–S55.

66. Hall KD, Guo J. Obesity energetics: body weight regulation and the effects of diet composition. Gastroenterology 2017;152:1718–1727.e3.

67. Zelber-Sagi S, Salomone F, Mlynarsky L. The Mediterranean dietary pattern as the diet of choice for non-alcoholic fatty liver disease: evidence and plausible mechanisms. Liver Int 2017;37:936–949.

68. Trichopoulou A, Martínez-González MA, Tong TY, Forouhi NG, Khandelwal S, Prabhakaran D, et al. Definitions and potential health benefits of the Mediterranean diet: views from experts around the world. BMC Med 2014;12:112.

69. Kastorini CM, Milionis HJ, Esposito K, Giugliano D, Goudevenos JA, Panagiotakos DB. The effect of Mediterranean diet on metabolic syndrome and its components: a meta-analysis of 50 studies and 534,906 individuals. J Am Coll Cardiol 2011;57:1299–1313.

70. Estruch R, Ros E, Salas-Salvadó J, Covas MI, Corella D, Arós F, et al. Primary prevention of cardiovascular disease with a Mediterranean diet. N Engl J Med 2013;368:1279–1290.

71. Ma J, Hennein R, Liu C, Long MT, Hoffmann U, Jacques PF, et al. Improved diet quality associates with reduction in liver fat, particularly in individuals with high genetic risk scores for nonalcoholic fatty liver disease. Gastroenterology 2018;155:107–117.

72. Kontogianni MD, Tileli N, Margariti A, Georgoulis M, Deutsch M, Tiniakos D, et al. Adherence to the Mediterranean diet is associated with the severity of non-alcoholic fatty liver disease. Clin Nutr 2014;33:678–683.

73. Baratta F, Pastori D, Polimeni L, Bucci T, Ceci F, Calabrese C, et al. Adherence to Mediterranean diet and non-alcoholic fatty liver disease: effect on insulin resistance. Am J Gastroenterol 2017;112:1832–1839.

74. Khalatbari-Soltani S, Imamura F, Brage S, De Lucia Rolfe E, Griffin SJ, Wareham NJ, et al. The association between adherence to the Mediterranean diet and hepatic steatosis: crosssectional analysis of two independent studies, the UK Fenland Study and the Swiss CoLaus Study. BMC Med 2019;17:19.

75. Trovato FM, Catalano D, Martines GF, Pace P, Trovato GM. Mediterranean diet and non-alcoholic fatty liver disease: the need of extended and comprehensive interventions. Clin Nutr 2015;34:86–88.

76. Ryan MC, Itsiopoulos C, Thodis T, Ward G, Trost N, Hofferberth S, et al. The Mediterranean diet improves hepatic steatosis and insulin sensitivity in individuals with non-alcoholic fatty liver disease. J Hepatol 2013;59:138–143.

77. Misciagna G, del Pilar Díaz M, Caramia DV, Bonfiglio C, Franco I, Noviello MR, et al. Effect of a low glycemic index Mediterranean diet on non-alcoholic fatty liver disease. A randomized controlled clinici trial. J Nutr Health Aging 2017;21:404–412.

78. Katsagoni CN, Papatheodoridis GV, Ioannidou P, Deutsch M, Alexopoulou A, Papadopoulos N, et al. Improvements in clinical characteristics of patients with non-alcoholic fatty liver disease, after an intervention based on the Mediterranean lifestyle: a randomised controlled clinical trial. Br J Nutr 2018;120:164–175.

79. Azzu V, Vacca M, Virtue S, Allison M, Vidal-Puig A. Adipose tissue-liver cross talk in the control of whole-body metabolism: implications in nonalcoholic fatty liver disease. Gastroenterology 2020;158:1899–1912.

80. Gepner Y, Shelef I, Schwarzfuchs D, Zelicha H, Tene L, Yaskolka Meir A, et al. Effect of distinct lifestyle interventions on mobilization of fat storage pools: CENTRAL magnetic resonance imaging randomized controlled trial. Circulation 2018;137:1143–1157.

81. Gepner Y, Shelef I, Komy O, Cohen N, Schwarzfuchs D, Bril N, et al. The beneficial effects of Mediterranean diet over lowfat diet may be mediated by decreasing hepatic fat content. J Hepatol 2019;71:379–388.

82. Davis C, Bryan J, Hodgson J, Murphy K. Definition of the Mediterranean diet; a literature review. Nutrients 2015;7:9139–9153.

83. Bondonno NP, Dalgaard F, Kyrø C, Murray K, Bondonno CP, Lewis JR, et al. Flavonoid intake is associated with lower mortality in the Danish Diet Cancer and Health Cohort. Nat Commun 2019;10:3651.

84. Kim Y, Je Y. Flavonoid intake and mortality from cardiovascular disease and all causes: a meta-analysis of prospective cohort studies. Clin Nutr ESPEN 2017;20:68–77.

85. Salomone F, Godos J, Zelber-Sagi S. Natural antioxidants for non-alcoholic fatty liver disease: molecular targets and clinical perspectives. Liver Int 2016;36:5–20.

86. Zhao LG, Zhang QL, Zheng JL, Li HL, Zhang W, Tang WG, et al. Dietary, circulating beta-carotene and risk of all-cause mortality: a meta-analysis from prospective studies. Sci Rep 2016;6:26983.

87. Murillo AG, DiMarco DM, Fernandez ML. The potential of nonprovitamin A carotenoids for the prevention and treatment of non-alcoholic fatty liver disease. Biology (Basel) 2016;5:42.

88. Bjermo H, Iggman D, Kullberg J, Dahlman I, Johansson L, Persson L, et al. Effects of n-6 PUFAs compared with SFAs on liver fat, lipoproteins, and inflammation in abdominal obesity: a randomized controlled trial. Am J Clin Nutr 2012;95:1003–1012.

89. Rosqvist F, Iggman D, Kullberg J, Cedernaes J, Johansson HE, Larsson A, et al. Overfeeding polyunsaturated and saturated fat causes distinct effects on liver and visceral fat accumulation in humans. Diabetes 2014;63:2356–2368.

90. Luukkonen PK, Sädevirta S, Zhou Y, Kayser B, Ali A, Ahonen L, et al. Saturated fat is more metabolically harmful for the human liver than unsaturated fat or simple sugars. Diabetes Care 2018;41:1732–1739.

91. Rosqvist F, Kullberg J, Ståhlman M, Cedernaes J, Heurling K, Johansson HE, et al. Overeating saturated fat promotes fatty liver and ceramides compared with polyunsaturated fat: a randomized trial. J Clin Endocrinol Metab 2019;104:6207–6219.

92. Bozzetto L, Prinster A, Annuzzi G, Costagliola L, Mangione A, Vitelli A, et al. Liver fat is reduced by an isoenergetic MUFA diet in a controlled randomized study in type 2 diabetic patients. Diabetes Care 2012;35:1429–1435.

93. Errazuriz I, Dube S, Slama M, Visentin R, Nayar S, O’Connor H, et al. Randomized controlled trial of a MUFA or fiber-rich diet on hepatic fat in prediabetes. J Clin Endocrinol Metab 2017;102:1765–1774.

94. Delgado-Lista J, Alcala-Diaz JF, Torres-Peña JD, QuintanaNavarro GM, Fuentes F, Garcia-Rios A, et al. Long-term secondary prevention of cardiovascular disease with a Mediterranean diet and a low-fat diet (CORDIOPREV): a randomised controlled trial. Lancet 2022;399:1876–1885.

95. He K, Li Y, Guo X, Zhong L, Tang S. Food groups and the likelihood of non-alcoholic fatty liver disease: a systematic review and meta-analysis. Br J Nutr 2020;124:1–13.

96. Semmler G, Bachmayer S, Wernly S, Wernly B, Niederseer D, Huber-Schönauer U, et al. Nut consumption and the prevalence and severity of non-alcoholic fatty liver disease. PLoS One 2020;15e0244514.

97. Sindhunata DP, Meijnikman AS, Gerdes VEA, Nieuwdorp M. Dietary fructose as a metabolic risk factor. Am J Physiol Cell Physiol 2022;323:C847–C856.

98. Tappy L, Lê KA. Metabolic effects of fructose and the worldwide increase in obesity. Physiol Rev 2010;90:23–46.

99. Softic S, Stanhope KL, Boucher J, Divanovic S, Lanaspa MA, Johnson RJ, et al. Fructose and hepatic insulin resistance. Crit Rev Clin Lab Sci 2020;57:308–322.

100. Abdelmalek MF, Lazo M, Horska A, Bonekamp S, Lipkin EW, Balasubramanyam A, et al. Higher dietary fructose is associated with impaired hepatic adenosine triphosphate homeostasis in obese individuals with type 2 diabetes. Hepatology 2012;56:952–960.

101. Pinnick KE, Hodson L. Challenging metabolic tissues with fructose: tissue-specific and sex-specific responses. J Physiol 2019;597:3527–3537.

102. Choo VL, Viguiliouk E, Blanco Mejia S, Cozma AI, Khan TA, Ha V, et al. Food sources of fructose-containing sugars and glycaemic control: systematic review and meta-analysis of controlled intervention studies. BMJ 2018;363:k4644. Erratum in: BMJ 2019;367:l5524.

103. Semnani-Azad Z, Khan TA, Blanco Mejia S, de Souza RJ, Leiter LA, Kendall CWC, et al. Association of major food sources of fructose-containing sugars with incident metabolic syndrome: a systematic review and meta-analysis. JAMA Netw Open 2020;3e209993.

104. Lee D, Chiavaroli L, Ayoub-Charette S, Khan TA, Zurbau A, AuYeung F, et al. Important food sources of fructose-containing sugars and non-alcoholic fatty liver disease: a systematic review and meta-analysis of controlled trials. Nutrients 2022;14:2846.

105. Smajis S, Gajdošk M, Pfleger L, Traussnigg S, Kienbacher C, Halilbasic E, et al. Metabolic effects of a prolonged, very-high-dose dietary fructose challenge in healthy subjects. Am J Clin Nutr 2020;111:369–377. Erratum in: Am J Clin Nutr 2020;111:490.

106. Schmidt KA, Jones RB, Rios C, Corona Y, Berger PK, Plows JF, et al. Clinical intervention to reduce dietary sugar does not affect liver fat in Latino youth, regardless of PNPLA3 genotype: a randomized controlled trial. J Nutr 2022;152:1655–1665.

107. Ma J, Fox CS, Jacques PF, Speliotes EK, Hoffmann U, Smith CE, et al. Sugar-sweetened beverage, diet soda, and fatty liver disease in the Framingham Heart Study cohorts. J Hepatol 2015;63:462–469.

108. Chen H, Wang J, Li Z, Lam CWK, Xiao Y, Wu Q, et al. Consumption of sugar-sweetened beverages has a dose-dependent effect on the risk of non-alcoholic fatty liver disease: an updated systematic review and dose-response meta-analysis. Int J Environ Res Public Health 2019;16:2192.

109. Asgari-Taee F, Zerafati-Shoae N, Dehghani M, Sadeghi M, Baradaran HR, Jazayeri S. Association of sugar sweetened beverages consumption with non-alcoholic fatty liver disease: a systematic review and meta-analysis. Eur J Nutr 2019;58:1759–1769.

110. Abid A, Taha O, Nseir W, Farah R, Grosovski M, Assy N. Soft drink consumption is associated with fatty liver disease independent of metabolic syndrome. J Hepatol 2009;51:918–924.

111. Mosca A, Nobili V, De Vito R, Crudele A, Scorletti E, Villani A, et al. Serum uric acid concentrations and fructose consumption are independently associated with NASH in children and adolescents. J Hepatol 2017;66:1031–1036.

112. Abdelmalek MF, Suzuki A, Guy C, Unalp-Arida A, Colvin R, Johnson RJ, et al. Increased fructose consumption is associated with fibrosis severity in patients with nonalcoholic fatty liver disease. Hepatology 2010;51:1961–1971.

113. Geidl-Flueck B, Hochuli M, Németh Á, Eberl A, Derron N, Köfeler HC, et al. Fructose- and sucrose- but not glucosesweetened beverages promote hepatic de novo lipogenesis: a randomized controlled trial. J Hepatol 2021;75:46–54.

114. Schwimmer JB, Ugalde-Nicalo P, Welsh JA, Angeles JE, Cordero M, Harlow KE, et al. Effect of a low free sugar diet vs usual diet on nonalcoholic fatty liver disease in adolescent boys: a randomized clinical trial. JAMA 2019;321:256–265. Erratum in: JAMA 2019;322:469.

115. Simons N, Veeraiah P, Simons PIHG, Schaper NC, Kooi ME, Schrauwen-Hinderling VB, et al. Effects of fructose restriction on liver steatosis (FRUITLESS); a double-blind randomized controlled trial. Am J Clin Nutr 2021;113:391–400.

116. Khodami B, Hatami B, Yari Z, Alavian SM, Sadeghi A, Varkaneh HK, et al. Effects of a low free sugar diet on the management of nonalcoholic fatty liver disease: a randomized clinical trial. Eur J Clin Nutr 2022;76:987–994.

117. DiStefano JK. Fructose-mediated effects on gene expression and epigenetic mechanisms associated with NAFLD pathogenesis. Cell Mol Life Sci 2020;77:2079–2090.

118. Zhao S, Jang C, Liu J, Uehara K, Gilbert M, Izzo L, et al. Dietary fructose feeds hepatic lipogenesis via microbiota-derived acetate. Nature 2020;579:586–591.

119. Taylor SR, Ramsamooj S, Liang RJ, Katti A, Pozovskiy R, Vasan N, et al. Dietary fructose improves intestinal cell survival and nutrient absorption. Nature 2021;597:263–267.

120. Zelber-Sagi S, Nitzan-Kaluski D, Goldsmith R, Webb M, Blendis L, Halpern Z, et al. Long term nutritional intake and the risk for non-alcoholic fatty liver disease (NAFLD): a population based study. J Hepatol 2007;47:711–717.

121. Alferink LJ, Kiefte-de Jong JC, Erler NS, Veldt BJ, Schoufour JD, de Knegt RJ, et al. Association of dietary macronutrient composition and non-alcoholic fatty liver disease in an ageing population: the Rotterdam Study. Gut 2019;68:1088–1098.

122. Hashemian M, Merat S, Poustchi H, Jafari E, Radmard AR, Kamangar F, et al. Red meat consumption and risk of nonalcoholic fatty liver disease in a population with low meat consumption: the Golestan Cohort Study. Am J Gastroenterol 2021;116:1667–1675.

123. Ivancovsky-Wajcman D, Fliss-Isakov N, Grinshpan LS, Salomone F, Lazarus JV, Webb M, et al. High meat consumption is prospectively associated with the risk of non-alcoholic fatty liver disease and presumed significant fibrosis. Nutrients 2022;14:3533.

124. Hashemian M, Poustchi H, Merat S, Abnet C, Malekzadeh R, Etemadi A. Red meat consumption and risk of nonalcoholic fatty liver disease in a population with low red meat consumption. Curr Dev Nutr 2020;4(Suppl 2):1413.

125. Zelber-Sagi S, Ivancovsky-Wajcman D, Fliss Isakov N, Webb M, Orenstein D, Shibolet O, et al. High red and processed meat consumption is associated with non-alcoholic fatty liver disease and insulin resistance. J Hepatol 2018;68:1239–1246.

126. Noureddin M, Zelber-Sagi S, Wilkens LR, Porcel J, Boushey CJ, Le Marchand L, et al. Diet associations with nonalcoholic fatty liver disease in an ethnically diverse population: the multiethnic cohort. Hepatology 2020;71:1940–1952.

127. Rietman A, Sluik D, Feskens EJM, Kok FJ, Mensink M. Associations between dietary factors and markers of NAFLD in a general Dutch adult population. Eur J Clin Nutr 2018;72:117–123.

128. Kim MN, Lo CH, Corey KE, Luo X, Long L, Zhang X, et al. Red meat consumption, obesity, and the risk of nonalcoholic fatty liver disease among women: evidence from mediation analysis. Clin Nutr 2022;41:356–364.

129. Alferink LJM, Kiefte-de Jong JC, Erler NS, de Knegt RJ, Hoorn EJ, Ikram MA, et al. Diet-dependent acid load-the missing link between an animal protein-rich diet and nonalcoholic fatty liver disease? J Clin Endocrinol Metab 2019;104:6325–6337.

130. Ströhle A, Hahn A, Sebastian A. Estimation of the diet-dependent net acid load in 229 worldwide historically studied hunter-gatherer societies. Am J Clin Nutr 2010;91:406–412.

131. Remer T. Influence of diet on acid-base balance. Semin Dial 2000;13:221–226.

132. Vessby B, Uusitupa M, Hermansen K, Riccardi G, Rivellese AA, Tapsell LC, et al. Substituting dietary saturated for monounsaturated fat impairs insulin sensitivity in healthy men and women: the KANWU Study. Diabetologia 2001;44:312–319.

133. Roumans KHM, Lindeboom L, Veeraiah P, Remie CME, Phielix E, Havekes B, et al. Hepatic saturated fatty acid fraction is associated with de novo lipogenesis and hepatic insulin resistance. Nat Commun 2020;11:1891.

134. Fang X, An P, Wang H, Wang X, Shen X, Li X, et al. Dietary intake of heme iron and risk of cardiovascular disease: a doseresponse meta-analysis of prospective cohort studies. Nutr Metab Cardiovasc Dis 2015;25:24–35.

135. Yang W, Li B, Dong X, Zhang XQ, Zeng Y, Zhou JL, et al. Is heme iron intake associated with risk of coronary heart disease? A meta-analysis of prospective studies. Eur J Nutr 2014;53:395–400.

136. Etemadi A, Sinha R, Ward MH, Graubard BI, Inoue-Choi M, Dawsey SM, et al. Mortality from different causes associated with meat, heme iron, nitrates, and nitrites in the NIH-AARP Diet and Health Study: population based cohort study. BMJ 2017;357:j1957.

137. Koeth RA, Wang Z, Levison BS, Buffa JA, Org E, Sheehy BT, et al. Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis. Nat Med 2013;19:576–585.

138. Foerster J, Maskarinec G, Reichardt N, Tett A, Narbad A, Blaut M, et al. The influence of whole grain products and red meat on intestinal microbiota composition in normal weight adults: a randomized crossover intervention trial. PLoS One 2014;9e109606.

139. Zheng W, Lee SA. Well-done meat intake, heterocyclic amine exposure, and cancer risk. Nutr Cancer 2009;61:437–446.

140. Carvalho AM, Miranda AM, Santos FA, Loureiro AP, Fisberg RM, Marchioni DM. High intake of heterocyclic amines from meat is associated with oxidative stress. Br J Nutr 2015;113:1301–1307.

141. Xie Z, Sun Y, Ye Y, Hu D, Zhang H, He Z, et al. Randomized controlled trial for time-restricted eating in healthy volunteers without obesity. Nat Commun 2022;13:1003.

142. Duregon E, Pomatto-Watson LCDD, Bernier M, Price NL, de Cabo R. Intermittent fasting: from calories to time restriction. Geroscience 2021;43:1083–1092.

143. de Cabo R, Mattson MP. Effects of intermittent fasting on health, aging, and disease. N Engl J Med 2019;381:2541–2551. Erratum in: N Engl J Med 2020;382:298. Erratum in: N Engl J Med 2020;382:978.

144. Saran AR, Dave S, Zarrinpar A. Circadian rhythms in the pathogenesis and treatment of fatty liver disease. Gastroenterology 2020;158:1948–1966.e1.

145. Queiroz JDN, Macedo RCO, Tinsley GM, Reischak-Oliveira A. Time-restricted eating and circadian rhythms: the biological clock is ticking. Crit Rev Food Sci Nutr 2021;61:2863–2875.

146. Stekovic S, Hofer SJ, Tripolt N, Aon MA, Royer P, Pein L, et al. Alternate day fasting improves physiological and molecular markers of aging in healthy, non-obese humans. Cell Metab 2019;30:462–476.e6. Erratum in: Cell Metab 2020;31:878-881.

147. Patikorn C, Roubal K, Veettil SK, Chandran V, Pham T, Lee YY, et al. Intermittent fasting and obesity-related health outcomes: an umbrella review of meta-analyses of randomized clinical trials. JAMA Netw Open 2021;4e2139558.

148. Cai H, Qin YL, Shi ZY, Chen JH, Zeng MJ, Zhou W, et al. Effects of alternate-day fasting on body weight and dyslipidaemia in patients with non-alcoholic fatty liver disease: a randomised controlled trial. BMC Gastroenterol 2019;19:219.

149. Kord Varkaneh H, Salehi Sahlabadi A, Găman MA, Rajabnia M, Sedanur Macit-Çelebi M, Santos HO, et al. Effects of the 5:2 intermittent fasting diet on non-alcoholic fatty liver disease: a randomized controlled trial. Front Nutr 2022;9:948655.

150. Xiao Y, Liu Y, Zhao L, Zhou Y. Effect of 5:2 fasting diet on liver fat content in patients with type 2 diabetic with nonalcoholic fatty liver disease. Metab Syndr Relat Disord 2022;20:459–465.

151. Aliasghari F, Izadi A, Gargari BP, Ebrahimi S. The effects of Ramadan fasting on body composition, blood pressure, glucose metabolism, and markers of inflammation in NAFLD patients: an observational trial. J Am Coll Nutr 2017;36:640–645.

152. Mari A, Khoury T, Baker M, Said Ahmad H, Abu Baker F, Mahamid M. The impact of Ramadan fasting on fatty liver disease severity: a retrospective case control study from Israel. Isr Med Assoc J 2021;23:94–98.

153. Madkour MI, Malhab LJB, Abdel-Rahman WM, Abdelrahim DN, Saber-Ayad M, Faris ME. Ramadan diurnal intermittent fasting is associated with attenuated FTO gene expression in subjects with overweight and obesity: a prospective cohort study. Front Nutr 2022;8:741811.

154. Peng S, Zhu Y, Xu F, Ren X, Li X, Lai M. FTO gene polymorphisms and obesity risk: a meta-analysis. BMC Med 2011;9:71.

155. Livingstone KM, Celis-Morales C, Lara J, Ashor AW, Lovegrove JA, Martinez JA, et al. Associations between FTO genotype and total energy and macronutrient intake in adults: a systematic review and meta-analysis. Obes Rev 2015;16:666–678.

156. Alhamdan BA, Garcia-Alvarez A, Alzahrnai AH, Karanxha J, Stretchberry DR, Contrera KJ, et al. Alternate-day versus daily energy restriction diets: which is more effective for weight loss? A systematic review and meta-analysis. Obes Sci Pract 2016;2:293–302.

157. Trepanowski JF, Kroeger CM, Barnosky A, Klempel MC, Bhutani S, Hoddy KK, et al. Effect of alternate-day fasting on weight loss, weight maintenance, and cardioprotection among metabolically healthy obese adults: a randomized clinical trial. JAMA Intern Med 2017;177:930–938.

158. Gu L, Fu R, Hong J, Ni H, Yu K, Lou H. Effects of intermittent fasting in human compared to a non-intervention diet and caloric restriction: a meta-analysis of randomized controlled trials. Front Nutr 2022;9:871682.

159. Lowe DA, Wu N, Rohdin-Bibby L, Moore AH, Kelly N, Liu YE, et al. Effects of time-restricted eating on weight loss and other metabolic parameters in women and men with overweight and obesity: the TREAT randomized clinical trial. JAMA Intern Med 2020;180:1491–1499. Erratum in: JAMA Intern Med 2020;180:1555. Erratum in: JAMA Intern Med 2021;181:883.

160. Carter S, Clifton PM, Keogh JB. Effect of intermittent compared with continuous energy restricted diet on glycemic control in patients with type 2 diabetes: a randomized noninferiority trial. JAMA Netw Open 2018;1e180756.

161. Corley BT, Carroll RW, Hall RM, Weatherall M, Parry-Strong A, Krebs JD. Intermittent fasting in Type 2 diabetes mellitus and the risk of hypoglycaemia: a randomized controlled trial. Diabet Med 2018;35:588–594.

162. Tinsley GM, Paoli A. Time-restricted eating and age-related muscle loss. Aging (Albany NY) 2019;11:8741–8742.

163. Laurens C, Grundler F, Damiot A, Chery I, Le Maho AL, Zahariev A, et al. Is muscle and protein loss relevant in long-term fasting in healthy men? A prospective trial on physiological adaptations. J Cachexia Sarcopenia Muscle 2021;12:1690–1703.

164. Williamson E, Moore DR. A muscle-centric perspective on intermittent fasting: a suboptimal dietary strategy for supporting muscle protein remodeling and muscle mass? Front Nutr 2021;8:640621.

165. Mooli RGR, Ramakrishnan SK. Emerging role of hepatic ketogenesis in fatty liver disease. Front Physiol 2022;13:946474.

166. Puchalska P, Crawford PA. Multi-dimensional roles of ketone bodies in fuel metabolism, signaling, and therapeutics. Cell Metab 2017;25:262–284.

167. Diraison F, Moulin P, Beylot M. Contribution of hepatic de novo lipogenesis and reesterification of plasma non esterified fatty acids to plasma triglyceride synthesis during non-alcoholic fatty liver disease. Diabetes Metab 2003;29:478–485.

168. Fletcher JA, Deja S, Satapati S, Fu X, Burgess SC, Browning JD. Impaired ketogenesis and increased acetyl-CoA oxidation promote hyperglycemia in human fatty liver. JCI Insight 2019;5e127737.

169. Miller VJ, Villamena FA, Volek JS. Nutritional ketosis and mitohormesis: potential implications for mitochondrial function and human health. J Nutr Metab 2018;2018:5157645.

170. Newman JC, Verdin E. β-Hydroxybutyrate: a signaling metabolite. Annu Rev Nutr 2017;37:51–76.

171. d’Avignon DA, Puchalska P, Ercal B, Chang Y, Martin SE, Graham MJ, et al. Hepatic ketogenic insufficiency reprograms hepatic glycogen metabolism and the lipidome. JCI Insight 2018;3e99762.

172. Liu X, Zhang Y, Ma C, Lin J, Du J. Alternate-day fasting alleviates high fat diet induced non-alcoholic fatty liver disease through controlling PPARα/Fgf21 signaling. Mol Biol Rep 2022;49:3113–3122. Erratum in: Mol Biol Rep 2022;49:8195-8196.

173. Grabacka M, Pierzchalska M, Dean M, Reiss K. Regulation of ketone body metabolism and the role of PPARα. Int J Mol Sci 2016;17:2093.

174. Kim HY. Recent advances in nonalcoholic fatty liver disease metabolomics. Clin Mol Hepatol 2021;27:553–559.

175. National Institutes of Health. 2020-2030 Strategic plan for NIH nutrition research - a report of the NIH Nutrition Research Task Force Bethesda (MD): National Institutes of Health; 2020.

176. Sookoian S, Pirola CJ. Precision medicine in nonalcoholic fatty liver disease: new therapeutic insights from genetics and systems biology. Clin Mol Hepatol 2020;26:461–475.

177. Zeevi D, Korem T, Zmora N, Israeli D, Rothschild D, Weinberger A, et al. Personalized nutrition by prediction of glycemic responses. Cell 2015;163:1079–1094.

178. Korem T, Zeevi D, Zmora N, Weissbrod O, Bar N, Lotan-Pompan M, et al. Bread affects clinical parameters and induces gut microbiome-associated personal glycemic responses. Cell Metab 2017;25:1243–1253.e5.

179. Berry SE, Valdes AM, Drew DA, Asnicar F, Mazidi M, Wolf J, et al. Human postprandial responses to food and potential for precision nutrition. Nat Med 2020;26:964–973. Erratum in: Nat Med 2020;26:1802.

180. Du F, Huang R, Lin D, Wang Y, Yang X, Huang X, et al. Resveratrol improves liver steatosis and insulin resistance in non-alcoholic fatty liver disease in association with the gut microbiota. Front Microbiol 2021;12:611323.

181. Meroni M, Longo M, Rustichelli A, Dongiovanni P. Nutrition and genetics in NAFLD: the perfect binomium. Int J Mol Sci 2020;21:2986.

182. Davis JN, Lê KA, Walker RW, Vikman S, Spruijt-Metz D, Weigensberg MJ, et al. Increased hepatic fat in overweight Hispanic youth influenced by interaction between genetic variation in PNPLA3 and high dietary carbohydrate and sugar consumption. Am J Clin Nutr 2010;92:1522–1527.

183. Sevastianova K, Kotronen A, Gastaldelli A, Perttilä J, Hakkarainen A, Lundbom J, et al. Genetic variation in PNPLA3 (adiponutrin) confers sensitivity to weight loss-induced decrease in liver fat in humans. Am J Clin Nutr 2011;94:104–111.

184. Shen J, Wong GL, Chan HL, Chan RS, Chan HY, Chu WC, et al. PNPLA3 gene polymorphism and response to lifestyle modification in patients with nonalcoholic fatty liver disease. J Gastroenterol Hepatol 2015;30:139–146.

185. Van Name MA, Savoye M, Chick JM, Galuppo BT, Feldstein AE, Pierpont B, et al. A low ω-6 to ω-3 PUFA ratio (n-6:n-3 PUFA) diet to treat fatty liver disease in obese youth. J Nutr 2020;150:2314–2321.

186. Santoro N, Savoye M, Kim G, Marotto K, Shaw MM, Pierpont B, et al. Hepatic fat accumulation is modulated by the interaction between the rs738409 variant in the PNPLA3 gene and the dietary omega6/omega3 PUFA intake. PLoS One 2012;7e37827.

187. Vilar-Gomez E, Pirola CJ, Sookoian S, Wilson LA, Belt P, Liang T, et al. Impact of the association between PNPLA3 genetic variation and dietary intake on the risk of significant fibrosis in patients with NAFLD. Am J Gastroenterol 2021;116:994–1006.

188. Rankinen T, Bouchard C. Genetics of food intake and eating behavior phenotypes in humans. Annu Rev Nutr 2006;26:413–434.

189. Søberg S, Sandholt CH, Jespersen NZ, Toft U, Madsen AL, von Holstein-Rathlou S, et al. FGF21 is a sugar-induced hormone associated with sweet intake and preference in humans. Cell Metab 2017;25:1045–1053.e6.

190. Chu AY, Workalemahu T, Paynter NP, Rose LM, Giulianini F, Tanaka T, et al. Novel locus including FGF21 is associated with dietary macronutrient intake. Hum Mol Genet 2013;22:1895–1902.

191. Tanaka T, Ngwa JS, van Rooij FJ, Zillikens MC, Wojczynski MK, Frazier-Wood AC, et al. Genome-wide meta-analysis of observational studies shows common genetic variants associated with macronutrient intake. Am J Clin Nutr 2013;97:1395–1402.

192. Qi Q, Kilpeläinen TO, Downer MK, Tanaka T, Smith CE, Sluijs I, et al. FTO genetic variants, dietary intake and body mass index: insights from 177,330 individuals. Hum Mol Genet 2014;23:6961–6972.

193. Livingstone KM, Celis-Morales C, Papandonatos GD, Erar B, Florez JC, Jablonski KA, et al. FTO genotype and weight loss: systematic review and meta-analysis of 9563 individual participant data from eight randomised controlled trials. BMJ 2016;354:i4707. Erratum in: BMJ 2017;356:j263.

194. Xiang L, Wu H, Pan A, Patel B, Xiang G, Qi L, et al. FTO genotype and weight loss in diet and lifestyle interventions: a systematic review and meta-analysis. Am J Clin Nutr 2016;103:1162–1170.

Article information Continued

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.