The study aimed to explore the relationships of skeletal muscle mass with disease severity in metabolic-associated fatty liver disease (MAFLD) patients with different methods. Consecutive subjects undergoing bioelectrical impedance analysis were included. The steatosis grade and liver fibrosis were evaluated by MRI-derived proton density fat fraction and two-dimensional shear wave elastography. The appendicular skeletal muscle mass (ASM) was adjusted by height2 (ASM/H2), weight (ASM/W) and BMI (ASM/BMI). Overall, 2223 subjects (50·5 %, MAFLD; 46·9 %, male) were included, with the mean age 37·4 ± 10·6 years. In multivariate logistic regression analysis, the subjects with the lowest quartile (Q1) of ASM/W or ASM/BMI had higher risk ratios for MAFLD (OR (95 % CI) in male: 2·57 (1·35, 4·89), 2·11(1·22, 3·64); in female: 4·85 (2·33, 10·01), 4·81 (2·52, 9·16), all P < 0·05, all for Q1 v. Q4). The MAFLD patients with lower quartiles of ASM/W had the higher risk OR for insulin resistance (IR), both in male and female (2·14 (1·16, 3·97), 4·26 (1·29, 14·02) for Q4 v. Q1, both P < 0·05). While the significant OR were not observed when ASM/H2 and ASM/BMI were used. There were significant dose-dependent associations between decreased ASM/W as well as ASM/BMI and moderate–severe steatosis (2·85(1·54, 5·29), 1·90(1·09, 3·31), both P < 0·05) in male MAFLD patients. In conclusion, ASM/W is superior to ASM/H2 and ASM/BMI in predicting the degree of MAFLD. A lower ASM/W is associated with IR and moderate–severe steatosis in non-elderly male MAFLD.

Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome. Recent evidence has suggested the protective effects of honey consumption against the metabolic syndrome, but the association between honey intake and NAFLD is still unclear. We investigated how the consumption frequency of honey was associated with NAFLD in the general population. This was a cross-sectional study of 21 979 adults aged 20–90 years. NAFLD was diagnosed based on the ultrasound-diagnosed fatty liver without significant alcohol intake and other liver diseases. Diet information, including consumption frequency of honey, was assessed by a validated 100-item FFQ. OR with 95 % CI were calculated by the binary logistic regression model, adjusting for confounding factors identified by the directed acyclic graph. Overall, 6513 adults (29·6 %) had NAFLD. Compared with participants consuming ≤1 time/week of honey, the multivariable OR of NAFLD were 0·86 (95 % CI 0·77, 0·97) for 2–6 times/week and 1·10 (95 % CI 0·95, 1·27) for ≥1 times/d (Pfor trend = 0·90). The results were generally similar in subgroups of BMI at a cut-point of 24·0 kg/m2 (Pfor interaction = 0·10). In this large-scale study, consuming honey 2–6 times/week was inversely associated with NAFLD, whereas consuming honey ≥1 times/d had no association with NAFLD. These results need replication in other large-scale prospective studies.

Non-pharmacological early weaning (NPEW) induces liver damage in male progeny at adulthood; however, pharmacological early weaning (PEW) does not cause this dysfunction. To elucidate this difference in liver dysfunction between these two models and determine the phenotype of female offspring, de novo lipogenesis, β-oxidation, very low-density lipoprotein (VLDL) export, and gluconeogenesis in both sexes were investigated in the adult Wistar rats that were weaned after a normal period of lactation (control group) or early weaned either by restriction of access to the dams’ teats (NPEW group) or by reduction of dams’ milk production with bromocriptine (PEW group). The offspring received standard diet from weaning to euthanasia (PN180). NPEW males had higher plasma triglycerides and TyG index, liver triglycerides, and cholesterol by de novo lipogenesis, which leads to intracellular lipids accumulation. As expected, hepatic morphology was preserved in PEW males, but they showed increased liver triglycerides. The only molecular difference between PEW and NPEW males was in acetyl-CoA carboxylase-1 (ACC-1) and stearoyl-CoA desaturase-1 (SCD-1), which were lower in PEW animals. Both early weaning (EW) females had no changes in liver cholesterol and triglyceride contents, and the hepatic cytoarchitecture was preserved. The expression of microsomal triglyceride transfer protein was increased in both the female EW groups, which could constitute a protective factor. The changes in hepatic lipid metabolism in EW offspring were less marked in females. EW impacted in the hepatic cytoarchitecture only in NPEW males, which showed higher ACC-1 and SCD-1 when compared to the PEW group. As these enzymes are lipogenic, it could explain a worsened liver function in NPEW males.

Mono-2-ethylhexyl phthalate (MEHP) is the primary metabolite of the ubiquitous plasticizer and toxicant, di-2-ethylhexyl phthalate. MEHP exposure has been linked to abnormal development, increased oxidative stress, and metabolic syndrome in vertebrates. Nuclear factor, Erythroid 2 Like 2 (Nrf2), is a transcription factor that regulates gene expression in response to oxidative stress. We investigated the role of Nrf2a in larval steatosis following embryonic exposure to MEHP. Wild-type and nrf2a mutant (m) zebrafish embryos were exposed to 0 or 200 μg/l MEHP from 6 to either 96 (histology) or 120 hours post fertilization (hpf). At 120 hpf, exposures were ceased and fish were maintained in clean conditions until 15 days post fertilization (dpf). At 15 dpf, fish lengths and lipid content were examined, and the expression of genes involved in the antioxidant response and lipid processing was quantified. At 96 hpf, a subset of animals treated with MEHP had vacuolization in the liver. At 15 dpf, deficient Nrf2a signaling attenuated fish length by 7.7%. MEHP exposure increased hepatic steatosis and increased expression of peroxisome proliferator-activated receptor alpha target fabp1a1. Cumulatively, these data indicate that developmental exposure alone to MEHP may increase risk for hepatic steatosis and that Nrf2a does not play a major role in this phenotype.

Animal studies have suggested that mushroom intake can alleviate non-alcoholic fatty liver disease (NAFLD) due to its anti-inflammatory and antioxidant properties. However, the association between mushroom intake and NAFLD is unknown in humans. We aimed to investigate the association of mushroom intake with NAFLD among Chinese adults. This is a cross-sectional study of 24 236 adults (mean (standard deviation) age: 40·7 (sd 11·9) years; 11 394 men (47·0 %)). Mushroom intake was assessed via a validated FFQ. Newly diagnosed NAFLD was identified based on the results of annual health examinations, including ultrasound findings and a self-reported history of the disease. Multiple logistic models were used to examine the association between mushroom intake and NAFLD. The prevalence of newly diagnosed NAFLD was 19·0 %. Compared with those consuming mushrooms less frequently (≤1 time/week), the fully adjusted OR of newly diagnosed NAFLD were 0·95 (95 % CI 0·86, 1·05) for those consuming 2–3 times/week and 0·76 (95 % CI 0·63, 0·92) for those consuming ≥4 times/week (Pfor trend = 0·01). The inverse association was consistent in subgroups defined by age, sex and BMI. In conclusion, higher mushroom intake was significantly associated with lower prevalence of NAFLD among Chinese adults. Future research is required to understand the causal association between mushroom intake and NAFLD.

Non-alcoholic fatty liver disease (NAFLD) is considered to be the hepatic component of the metabolic syndrome and its prevalence is rapidly increasing due to its strong association with insulin resistance and obesity. At present, given that NAFLD is highly prevalent and therapies are limited, much attention is focused on identifying effective dietary strategies for the prevention and treatment of the disease. Polyphenols are a group of plant bioactive compounds whose regular consumption have been associated with a reduction in the risk of a number of metabolic disorders associated with NAFLD. Here we review the emerging and relatively consistent evidence from cell culture and rodent studies showing that select polyphenols positively modulate a variety of contributors to the NAFLD phenotype, through diverse and complementary mechanisms of action. In particular, the reduction of de novo lipogenesis (via sterol regulatory element-binding protein 1c) and increased fatty acid β-oxidation, presumably involving AMP-activated protein kinase activation, will be discussed. The indirect antioxidant and anti-inflammatory properties of polyphenols which have been reported to contribute to the amelioration of NAFLD will also be addressed. In addition to a direct study of the liver, rodent studies have provided insight into the impact of polyphenols on adipose tissue function and whole body insulin sensitivity, which are likely to in part modulate their impact on NAFLD development. Finally an overview of the limited data from clinical trials will be given along with a discussion of the dose extrapolation from animal studies to human subjects.

Herein we hypothesise the positive effects of kojibiose (KJ), a prebiotic disaccharide, selected for reducing hepatic expression of inflammatory markers in vivo that could modulate the severity of saturated arachidic acid (ARa)-induced liver dysfunction in hyperglycaemic rats. Animals were fed daily (20 d) with ARa (0·3 mg) together or not with KJ (22 mg approximately 0·5 %, w/w diet). Glucose, total TAG and cholesterol contents and the phospholipid profile were determined in serum samples. Liver sections were collected for the expression (mRNA) of enzymes and innate biomarkers, and intrahepatic macrophage and T-cell populations were analysed by flow cytometry. ARa administration increased the proportion of liver to body weight that was associated with an increased (by 11 %) intrahepatic macrophage population. These effects were ameliorated when feeding with KJ, which also normalised the plasmatic levels of TAG and N-acyl-phosphatidylethenolamine in response to tissue damage. These results indicate that daily supplementation of KJ significantly improves the severity of ARa-induced hepatic alterations.

The incidence of metabolic syndrome components including obesity, lipid deregulation, insulin resistance (IR) and non-alcoholic fatty liver disease is increasing rapidly in wealthy societies. The present study was designed to determine the effect of different nutritional lipid patterns (quantity and quality) on lipid utilisation and oxidative stress in the liver and muscle of rats in an integrated fashion. A total of forty-eight Wistar male rats were fed for 12 weeks with a mixed, lard or fish-oil diet, containing either 50 or 300 g lipid/kg. Rats developed liver steatosis associated with moderate liver injury when fed the 30 % lipid diets, in spite of the absence of overt obesity or IR, except when fed the lard 30 % lipid diet. The intake of the 30 % lipid diets decreased hepatic lipogenesis and mitochondriogenesis and increased lipid peroxidation and protein oxidation. Surprisingly, muscle lipid content was not modified whatever the administered diet. The intake of the 30 % lipid diets increased the muscle protein expression of fatty acid (FA) translocase/cluster of differentiation 36 (FAT/CD36), PPARγ co-activator 1α (PGC-1α) and muscle carnitine palmitoyltransferase 1 (m-CPT1), reflecting increased FA transport in the muscle associated with increased oxidative metabolism. The lard 30 % lipid diet led to IR without modifying the muscle lipid content. The fish-oil 30 % lipid diet failed to prevent the development of hepatic steatosis and made the tissues more prone to oxidation. Overall, the present study suggests that the FA composition of muscle is more important than lipid accumulation itself in the modulation of insulin sensitivity, and indicates that precaution should be taken when advising an unphysiologically high (pharmacological) supplementation with long-chain n-3 PUFA.

Ascorbic acid uptake is a key step in determining the overall bioactivity of this vitamin. Expression of Na-dependent vitamin C transporters (SVCT; SLC23A1 and SLC23A2) during long-term oxidative stress occurring in several chronic liver diseases may determine the antioxidant defence in this organ. In patients with hepatocellular cholestasis, primary biliary cirrhosis, haemochromatosis and non-alcoholic steatohepatitis, using real-time RT-PCR, an enhanced hepatic expression of both SLC23A1 and SLC23A2, but not other organic anions transporters, such as OATP1A2, OATP1B1 and OATP1B3, was found. To further investigate these findings, we used secondary biliary cirrhosis induced in rats by long-term biliary obstruction as a model of chronic liver disease accompanied by oxidative stress because of bile acid accumulation. In control rat liver, expression of Slc23a1 was low at birth, increased progressively up to adulthood and decreased in senescence, whereas expression of Slc23a2 did not change significantly after birth. In 8-week-old rats, immunohistochemistry and confocal microscopy studies revealed the expression in hepatocytes and bile duct cells of mainly Slc23a1, whereas both Slc23a1 and Slc23a2 were expressed in endothelial, stellate and Kupffer cells. In adult rats, when obstructive cholestasis was maintained for 8 weeks, a significant up-regulation of Slc23a2 accompanied by a down-regulation of Slc23a1 was found. In sum, there is a selective cell-type distribution of SVCT in the liver tissue, which, in addition to differential control in the expression of both isoforms, may play a role in the ability of different liver cell types to take up vitamin C under physiological and pathological conditions.

Non-alcoholic fatty liver disease (NAFLD) is one of the most common manifestations of chronic liver disease worldwide. The aim of the present study was to assess the effect of resveratrol on liver fat accumulation, as well as on the activity of those enzymes involved in lipogenesis and fatty acid oxidation in fa/fa Zucker rats. A total of thirty rats were assigned to three experimental groups and orally treated with resveratrol for 6 weeks, or without resveratrol (C: control group; RSV15 group: 15 mg/kg body weight per d; RSV45 group: 45 mg/kg body weight per d). Liver histological analysis was performed by microscopy. Levels of hepatic carnitine palmitoyltransferase-Ia (CPT-Ia), acyl-coenzyme A oxidase (ACO), fatty acid synthase, glucose-6-phosphate dehydrogenase and malic enzyme were assessed by spectrophotometry, and acetyl-CoA carboxylase was assessed by radiometry. Commercial kits were used to determine serum TAG, NEFA, total HDL and non-HDL-cholesterol, glycerol, ketonic bodies, glucose, insulin, adiponectin, aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase (ALP), hepatic TAG, thiobarbituric acid reactive substrates, GSH (GSSG) and superoxide dismutase. Resveratrol reduced liver weight and TAG content. It did not modify the activity of lipogenic enzymes but it did increase CPT-Ia and ACO activities. NEFA and ALP were reduced in both resveratrol-treated groups. AST/GOT was reduced only by the lowest dose. ALT/GPT, TAG and adiponectin remained unchanged. Resveratrol reduced liver oxidative stress. This study demonstrates that resveratrol can protect the liver from NAFLD by reducing fatty acid availability. Moreover, resveratrol also protects liver from oxidative stress.

We have identified the effects of oligonol, a low-molecular polyphenol derived from lychee fruit, on oxidative stress and lipid metabolism in a type 2 diabetic model. Oligonol was orally administered at 10 or 20 mg per kg body weight per d for 8 weeks to db/db mice, and its effects were compared with those of the vehicle in db/db and m/m mice. Serum and hepatic biochemical factors, and protein and mRNA expression related to lipid metabolism were measured. In the oligonol-administered group, there were significant reductions of reactive oxygen species (ROS), lipid peroxidation, and the TAG and total cholesterol concentrations in both the serum and liver. Additionally, oligonol attenuated oxidative stress through the inhibition of advanced glycation endproduct formation and its receptor expression. Furthermore, augmented expressions of NF-κBp65 and inducible NO synthase were down-regulated to the levels of m/m mice in the group treated with oligonol at 20 mg/kg. Regarding lipid metabolism, lower hepatic lipid resulted from the down-regulation of sterol regulatory element-binding protein-1 and its target gene of lipogenic enzymes in the liver of db/db mice. The present results suggest that oligonol has protective effects against ROS-related inflammation and excess lipid deposition in the type 2 diabetic liver.

Non-alcoholic steatohepatitis (NASH) is becoming a prevalent disease in developing countries with no effective therapy. Isoflavones such as genistein have been shown to prevent NASH in a rat model, but the effects of neonatal exposure to genistein on lipid metabolism have been rarely studied. In the present study, three doses of genistein (30, 300 or 1200 μg/rat per d) were injected (subcutaneously) into neonatal male Sprague–Dawley rats at postnatal days 1–5. After weaning, these rats were allowed free access to a high-fat diet for 6 weeks. The results demonstrate that NASH was induced by high fat feeding in the control rats, whereas genistein-treated rats displayed smaller body weight, and lower hepatic inflammation and steatosis. The mid dose of genistein was most effective. Neonatal exposure to genistein also resulted in a lower incidence of apoptotic cells in the liver. Additionally, neonatal genistein-treated rats showed lower hepatic expression of fatty acid synthase and sterol regulatory element-binding protein-1, but higher expression of PPARα, indicative of lower rates of lipid synthesis and higher rates of β-oxidation. These results indicate that neonatal treatment with genistein has a prolonged effect on hepatic lipid metabolism that is maintained post-weaning, offering a potential approach for the prevention of hepatic steatosis and NASH.

Non-alcoholic steatohepatitis (NASH) may be associated with a number of clinical conditions, but it occurs most commonly in patients with insulin resistance. There is as yet no established disease-modifying treatment, and a safe and broadly available agent that targets hepatic steatosis, insulin resistance, inflammation and fibrosis is necessary. The polyphenolic compound curcumin exhibits antioxidant and anti-inflammatory properties, inhibits NF-κB and activates PPAR-γ. In rodents, curcumin prevents dietary-induced hepatic steatosis, hepatic stellate cell activation and production of fibrotic proteins, and ameliorates steatohepatitis induced by the intake of alcohol or a methionine–choline-deficient diet. Indirect evidence suggests that curcumin may improve insulin sensitivity in diabetes and inflammatory states. The present paper reviews the numerous cellular and animal studies indicating that curcumin attenuates many of the pathophysiological processes involved in the development and progression of NASH. It is suggested that basic and clinical studies on curcumin in the development and progression of NASH are indicated.

Casein-based diets containing a low (LDI) or high (HDI) dose of soya protein concentrate enriched with isoflavones were fed to obese Zucker rats for 6 weeks. HDI feeding, but not LDI feeding, reduced the fatty liver and decreased the plasma levels of alanine transaminase and aspartate transaminase. This was accompanied by increased activities of mitochondrial and peroxisomal β-oxidation, acetyl-CoA carboxylase, fatty acid synthase and glycerol-3-phosphate acyltransferase in liver and increased triacylglycerol level in plasma. The decreased fatty liver and the increased plasma triacylglycerol level appeared not to be caused by an increased secretion of VLDL, as HDI decreased the hepatic mRNA levels of apo B and arylacetamide deacetylase. However, the gene expression of VLDL receptor was markedly decreased in liver, but unchanged in epididymal white adipose tissue and skeletal muscle of rats fed HDI, indicating that the liver may be the key organ for the reduced clearance of triacylglycerol-rich lipoproteins from plasma after HDI feeding. The n−3/n−6, 20:4n-/8:2n−6 and (20:5n−3+22:6n−3)/18:3n−3 ratios were increased in liver triacylglycerol by HDI. The phospholipids in liver of rats fed HDI contained a low level of 20:4n−6 and a high level of 20:5n−3, favouring the production of anti-inflammatory eicosanoids. When obese Zucker rats were fed soya protein, this also resulted in reduced fatty liver, possibly through reduced clearance of VLDL by the liver. We conclude that the isoflavone-enriched soya concentrate as well as soya protein may be promising dietary supplements for treatment of non-alcoholic fatty liver.

Inulin and oligofructose, besides their effect on the gastro-intestinal tract, are also able to exert ‘systemic’ effect, namely by modifying the hepatic metabolism of lipids in several animal models. Feeding male Wistar rats on a carbohydrate-rich diet containing 10 % inulin or oligofructose significantly lowers serum triacylglycerol (TAG) and phospholipid concentrations. A lower hepatic lipogenesis, through a coordinate reduction of the activity and mRNA of lipogenic enzymes is a key event in the reduction of very low-density lipoprotein-TAG secretion by oligofructose. Oligofructose is also able to counteract triglyceride metabolism disorder occurring through dietary manipulation in animals, and sometimes independently on lipogenesis modulation: oligofructose reduces post-prandial triglyceridemia by 50 % and avoids the increase in serum free cholesterol level occurring in rats fed a Western-type high fat diet. Oligofructose protects rats against liver TAG accumulation (steatosis) induced by fructose, or occurring in obese Zucker fa/fa rats. The protective effect of dietary inulin and oligofructose on steatosis in animals, would be interesting, if confirmed in humans, since steatosis is one of the most frequent liver disorders, occurring together with the plurimetabolic syndrome, in overweight people. The panel of putative mediators of the systemic effects of inulin and oligofructose consists in either modifications in glucose/insulin homeostasis, the end-products of their colonic fermentation (i.e. propionate) reaching the liver by the portal vein, incretins and/or the availability of other nutrients. The identification of the key mediators of the systemic effects of inulin and oligofructose is the key to identify target function(s) (or dysfunction(s)), and finally individuals who would take an advantage of increasing their dietary intake.