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Increasing evidence has demonstrated the benefits of α-linolenic acid-rich flaxseed oil (ALA-FO) against lipid metabolism abnormality in both rodent models and humans. However, the metabolic response of FO to insulin resistance and type 2 diabetes is still inconsistent. This study aimed to explore the effect of FO on chronic high fat diet (HFD)-induced hepatic steatosis, insulin resistance, and inflammation, mainly focusing on hepatic n-3 fatty acid remodeling and endoplasmic reticulum (ER) unfolded protein response. The results showed that lard-based HFD feeding for 16 weeks (60% fat-derived calories) induced whole-body insulin resistance, lipid profile abnormality, and inflammation in mice, which was alleviated by FO in a dose-dependent manner. Moreover, FO effectively improved hepatic steatosis and insulin resistance in mice by modulating the specific location of ALA and its long-chain n-3 fatty acids across hepatic lipid fractions and enhancing insulin-stimulated phosphorylation of hepatic insulin receptor subtract-1 (IRS-1) tyrosine 632 and protein kinase B (AKT) ( p < 0.05). Importantly, the differential depositions of ALA and its long-chain n-3 fatty acids in plasma and ER membranes were observed, concomitant with the rescued ER unfolded protein response and Jun N-terminal kinase (JNK) signaling in mice liver.

Scope: Naturally occurring quercetin has been found to induce mitophagy and prevent nonalcoholic fatty liver disease (NAFLD). However, it still remains elusive whether frataxin upregulation by quercetin contributes to the beneficial effect through mitophagy or not., Methods and Results: Adult male C57BL/J mice were fed a high-fat diet (HFD, 60% of energy from fat) with quercetin (100 mg kg -1 body weight) or not for 10 weeks. Quercetin alleviated HFD-induced histopathological changes, disorders of lipid metabolism, and mitochondrial damage. Moreover, quercetin blocked mitophagy suppression by HFD based on the increased LC3II, PTEN-induced putative kinase 1 (PINK1) and Beclin1 expressions, as well as decreased p62 levels. Quercetin also improved the Parkin translocation to mitochondria confirmed by immunofluorescence. Specifically, frataxin was lowered in the liver of HFD-fed mice or HepG2 cell incubated with oleate/palmitate but restored by quercetin, and quercetin's regulation of frataxin may depend on p53. Furthermore, lentivirus-mediated stable knockdown of frataxin in HepG2 inhibited PINK1-Parkin-associated mitophagy and resulted in lipid accumulation. Frataxin was further decreased by free fatty acids in knockdown cells concomitantly with depressed PINK1-Parkin-associated mitophagy, which was partially normalized by quercetin., Conclusion: Quercetin alleviated hepatic steatosis by enhancing frataxin-mediated PINK1/Parkin-dependent mitophagy, highlighting a promising preventive strategy and mechanism for NAFLD by quercetin., (© 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Background: Whether cigarette smoking and moderate drinking are associated with non-alcoholic fatty liver disease (NAFLD)has not been fully described. This study investigated the separate and joint effects of smoking and moderate drinking on Chinese men with NAFLD. Methods: Across-sectional assay from DFTJ Cohort study was performed with a size of 9432 elderly Chinese men excluding excessive alcohol consumption (<210g/week). Fatty liver was diagnosed by standardized ultrasonographic inspection. The odds ratio (OR) of alcohol consumption and smoking for the prevalence of NAFLD were analyzed using multiple logistic regression with multiple adjustments. Results: The prevalence of NAFLD in current smokers (pack-year≥40) and drinkers (80~210g/week or drinking duration≥35years) was significantly higher than that in non-smokers and non-drinkers, respectively. The combination of current smoking (pack-year≥40) and drinking (80~210g/week) was associated with the highest risk of NAFLD (OR 1.85; 95% confidence interval [CI] 1.28–2.68;P<0.01). The similar combined effect was found in participants with pack-year≥40 and drinking duration≥35 years (OR 1.72; 95% CI 1.26–2.34;P<0.01). Moreover, an interaction was observed between current smoking and moderate drinking in NAFLD. Conclusions: In elderly Chinese men, cigarette smoking and moderate alcohol consumption exerts an evident joint effect and interaction on the prevalence of NAFLD, although both are significantly and independently associated with NAFLD prevalence. Such findings highlight particular significance of avoidance of cigarette and alcohol on NAFLD prevention. [ABSTRACT FROM AUTHOR]

Objectives: The aim of this study is to examine the bidirectional association between nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM). Methods: The data was derived from the Dongfeng-Tongji cohort study, which was established in 2008 and followed until October 2013. NAFLD was classified as none, mild, moderate/severe based on ultrasound examination. The analysis to examine the association between NAFLD and incident T2DM risk included 18,111 participants free of diabetes at baseline and the duration of follow-up was 4.60 ± 0.60 years. Cox proportional regression model was used to calculate the hazard ratio (HR) for the association. The analysis to investigate the association between T2DM and incident NAFLD risk included 12,435 participants free of NAFLD at baseline. Logistic regression model was used to calculate the odd ratio (OR) of NAFLD. Results: Compared with those without NAFLD, individuals with mild or moderate/severe NAFLD had a monotonic elevated risk of developing T2DM (HR: 1.88 [95% CI: 1.63–2.18] and 2.34 [1.85–2.96], respectively) after adjustment for potential confounders. In a parallel analysis, compared to participants with fasting plasma glucose < 6.1 mmol/L, the ORs of developing NAFLD in subjects with impaired fasting glucose and T2DM were 1.35 (95% CI: 1.16–1.57) and 1.40 (95% CI: 1.22–1.62), respectively. Conclusions: Our results provide compelling evidence that the NAFLD-T2DM association is bidirectional in Chinese population. [ABSTRACT FROM AUTHOR]

Background: We examined the association between metabolically healthy obese (MHO) and diabetes incidence in a middle-aged and elderly population and whether the association differed by the presence of nonalcoholic fatty liver disease (NAFLD).Methods: We examined 17 801 participants without diabetes at study entry (7980 males and 9821 females with a mean age of 63.2 years) derived from the Dongfeng-Tongji cohort study (median follow-up: 4.6 years). Participants were divided into six groups based on BMI (normal weight, overweight, or obese) and metabolic health (healthy/unhealthy) defined by the Adult Treatment Panel III criteria. The MHO was defined as BMI greater than 28.0 kg/m2 with 0 or 1 of four metabolic abnormalities (elevated blood pressure, triglyceridaemia, hyperglycaemia, low HDL cholesterol). The hazard ratio (HR) and 95% confidence interval (CI) for incident diabetes were derived from the Cox proportional hazard regression model.Results: During 79 843 person-years of follow-up, 1453 individuals developed diabetes. Compared with metabolically healthy normal weight (MH-NW) individuals, the multivariable-adjusted HRs (95% CI) were 1.74 (1.16-2.59) for MHO and 2.15 (1.65-2.81) for metabolically unhealthy obese subjects after adjusting for age, sex, smoking, alcohol drinking, physical activity, fruit and vegetable consumption, family history of diabetes, fasting glucose, waist circumference, and NAFLD. Among those without NAFLD, MHO individuals showed higher incidence of diabetes (multivariate-adjusted HR = 2.71, 95% CI: 1.47-5.00) than MH-NW individuals.Conclusions: The MHO phenotype was associated with increased incidence of diabetes in a middle-aged and elderly population, and the association did not differ by the presence or absence of NAFLD. [ABSTRACT FROM AUTHOR]

The consumption of a quercetin-rich diet has been well-established as a feasible method against non-alcoholic fatty liver disease (NAFLD); however, the molecular mechanisms underlying the progression of NAFLD and its intervention by quercetin remain largely obscure. Male Sprague-Dawley rats fed high-fat diet (HFD), and HepG2 cells stimulated with free fatty acid, were treated with quercetin and various pharmacological reagents to explore the effect of signaling pathways involved in endoplasmic reticulum stress on very low-density lipoprotein (VLDL) assembly and lipophagy. Quercetin intake decreased hepatic TG content by 39%, with a 1.5-fold increase in VLDL, and up-regulated spliced X-box binding protein 1 (XBP1s) expression compared with the HFD group. Thapsigargin or STF-083010 (an IRE1α endonuclease inhibitor) decreased VLDL content in a dose-dependent manner, partially counteracting the protective effects of quercetin, 4-PBA or APY-29 (an IRE1α endonuclease activator). Additionally, microsomal TG-transfer protein complex expression was increased with quercetin-treated and down-regulated by STF-083010. Moreover, quercetin increased co-localization of lysosomes with lipid droplets (LDs) accompanied by decreased p62 accumulation. STF-083010 partially abolished the effect of quercetin on LDs autophagy in an mTOR-independent manner. Collectively, these findings demonstrate that hepatic VLDL assembly and lipophagy are the main targets of quercetin against NAFLD via the IRE1a/XBP1s pathway. [ABSTRACT FROM AUTHOR]

Quercetin, a polyphenol widely present in the plant kingdom, has received great interest due to pleiotropic effects. As evidenced by animal and cellular studies, quercetin exerts hepatoprotection against non-alcoholic fatty liver disease (NAFLD), particularly in hepatic steatosis and hepatitis. Mechanically, various hypotheses of such protective effects have been actively proposed, including improving fatty acid metabolism, anti-inflammation, anti-oxidant, modulating gut microbiota and bile acid, etc. Here, the role of quercetin in NAFLD was summarized. With a particular focus on molecular mechanism, we comprehensively discussed the pathways of quercetin on NAFLD based on the analysis from Gene Expression Omnibus (GEO) database and experimental evidence. • Most studies show that quercetin and its derivatives exert hepatoprotection against NAFLD in vivo and in vitro. • Further clinical studies are needed to demonstrate the effect of quercetin on NAFLD. • Combined with GEO and experimental data, the mechanism of quercetin is summarized. • Quercetin mainly regulates oxidative stress, inflammation, gut microbiota, fatty acid and bile acids metabolism. • Although quercetin changes many pathways, the mechanism by which quercetin improves NAFLD requires further evidence. [ABSTRACT FROM AUTHOR]

Baicalein has been proved as a promising compound for non-alcoholic fatty liver disease (NAFLD); however, the molecular mechanisms underlying the progression of NAFLD and its intervention by baicalein remain largely obscure. Male C57BL/6J fed high-fat diet (HFD) and HepG2 cells stimulated with free fatty acid were treated with baicalein and various pharmacological reagents to explore the effect of signaling pathways involved in lysosomal acidification. Baicalein intake declined ALT and AST activities by 25.1% and 18.7%, respectively, compared with the HFD group. Moreover, baicalein markedly ameliorated the HFD-trigged lysosomal membrane permeabilization evidenced by declined cathepsin B release. Subsequent disorders, including cathepsin D maturation and mitochondrion membrane potential were also partially normalized by baicalein administration to HFD-fed mice. Meanwhile, an increase in V-ATPase V1 subunits expression in lysosomes, V-ATPase activity and the colocalization of cytosol V-ATPase V1 subunits and lysosomes was observed in baicalein-supplement mice. Bafilomycin A1 stimulation resulting in elevated lysosomal pH and triacylglycerol accumulation partially abolished the effect of baicalein. Furthermore, incubation with mTOR inhibitor rapamycin restored lysosomal pH and decreased cellular triacylglycerol content. Collectively, these findings demonstrate that hepatic lysosomal acidification is the main target of baicalein against NAFLD via maintaining lysosomal V-ATPase assembly through mTOR pathway. • Baicalein ameliorates LMP and MMP delivered by HFD. • Baicalein restores lysosomal acidification via promoting V-ATPase assembly. • The effect of baicalein on V-ATPase assembly is mediated by mTOR-dependent way. [ABSTRACT FROM AUTHOR]