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Fagopyrum dibotrys extract alleviates hepatic steatosis and insulin resistance, and alters autophagy and gut microbiota diversity in mouse models of high-fat diet-induced non-alcoholic fatty liver disease.

ABSTRACT: Non-alcoholic fatty liver disease (NAFLD) is a major global health concern with increasing prevalence, with a lack of currently available effective treatment options; thus, the investigation of novel therapeutic approaches is necessary. The study aimed to investigate the outcomes and mechanisms of action of Fagopyrum dibotrys extract (FDE) in a high-fat diet (HFD)-induced mouse model of obesity. The findings showed that FDE supplementation attenuated glucose tolerance, insulin resistance (IR), hepatic steatosis, and abnormal lipid metabolism. In addition, FDE also promoted autophagic activity and inhibited the phosphorylation of transcription factor EB in HFD-fed mice. Furthermore, gut microbiota characterization via 16S rRNA sequencing revealed that the supplementation of FDE increased Bacteroidetes and Verrucomicrobia populations while decreased Firmicutes, thus modifying the gut microbiome. FDE also increased the relative abundance of Akkermansia. Our findings suggest that FDE may protect against HFD-induced NAFLD by activating autophagy and alleviating dysbiosis in the gut microbiome. FDE may be beneficial as a nutraceutical treatment for NAFLD.

SUBMITTER: Zhang D

PROVIDER: S-EPMC9704541 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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<i>Fagopyrum dibotrys</i> extract alleviates hepatic steatosis and insulin resistance, and alters autophagy and gut microbiota diversity in mouse models of high-fat diet-induced non-alcoholic fatty liver disease.

Zhang Dan D Xu Yongfang Y Chen Hang H Wang Da D Geng Zuotao Z Chen Yuanli Y Chen Yan Y Xiong Di D Yang Rongna R Liu Xiaoting X Zhang Yuke Y Xiang Ping P Ma Lanqing L Liu Jianjun J

Frontiers in nutrition 20221114

Non-alcoholic fatty liver disease (NAFLD) is a major global health concern with increasing prevalence, with a lack of currently available effective treatment options; thus, the investigation of novel therapeutic approaches is necessary. The study aimed to investigate the outcomes and mechanisms of action of <i>Fagopyrum dibotrys</i> extract (FDE) in a high-fat diet (HFD)-induced mouse model of obesity. The findings showed that FDE supplementation attenuated glucose tolerance, insulin resistance ...[more]

PMID: 36451739

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Project description:Liraglutide, a glucagon-like peptide-1 receptor agonist (GLP-1RA), has been demonstrated to alleviate non-alcoholic fatty liver disease (NAFLD). However, the underlying mechanism has not been fully elucidated. Increasing evidence suggests that autophagy is involved in the pathogenesis of hepatic steatosis. In this study, we examined whether liraglutide could alleviate hepatic steatosis through autophagy-dependent lipid degradation and investigated the underlying mechanisms. Herein, the effects of liraglutide on NAFLD were evaluated in a high-fat diet (HFD)-induced mouse model of NAFLD as well as in mouse primary and HepG2 hepatocytes exposed to palmitic acid (PA). The expression of the GLP-1 receptor (GLP-1R) was measured in vivo and in vitro. Oil red O staining was performed to detect lipid accumulation in hepatocytes. Electron microscopy was used to observe the morphology of autophagic vesicles and autolysosomes. Autophagic flux activity was measured by infecting HepG2 cells with mRFP-GFP-LC3 adenovirus. The roles of GLP-1R and transcription factor EB (TFEB) in autophagy-lysosomal activation were explored using small interfering RNA. Liraglutide treatment alleviated hepatic steatosis in vivo and in vitro. In models of hepatic steatosis, microtubule-associated protein 1B light chain-3-II (LC3-II) and SQSTM1/P62 levels were elevated in parallel to blockade of autophagic flux. Liraglutide treatment restored autophagic activity by improving lysosomal function. Furthermore, treatment with autophagy inhibitor chloroquine weakened liraglutide-induced autophagy activation and lipid degradation. TFEB has been identified as a key regulator of lysosome biogenesis and autophagy. The protein levels of nuclear TFEB and its downstream targets CTSB and LAMP1 were decreased in hepatocytes treated with PA, and these decreases were reversed by liraglutide treatment. Knockdown of TFEB expression compromised the effects of liraglutide on lysosome biogenesis and hepatic lipid accumulation. Mechanistically, GLP-1R expression was decreased in HFD mouse livers as well as PA-stimulated hepatocytes, and liraglutide treatment reversed the downregulation of GLP-1R expression in vivo and in vitro. Moreover, GLP-1R inhibition could mimic the effect of the TFEB downregulation-mediated decrease in lysosome biogenesis. Thus, our findings suggest that liraglutide attenuated hepatic steatosis via restoring autophagic flux, specifically the GLP-1R-TFEB-mediated autophagy-lysosomal pathway.

Project description:BackgroundBerberine effectively alleviates non-alcoholic fatty liver disease (NAFLD). Nevertheless, the mechanism is incompletely comprehended. It has been reported that SIRT1 mediates lipid metabolism in liver and berberine promotes the expression of SIRT1 in hepatocytes. We hypothesized that SIRT1 mediated the effect of berberine on NAFLD.MethodsThe effects of berberine on NAFLD were evaluated in C57BL/6J mice fed a high-fat diet (HFD) and in mouse primary hepatocytes and cell lines exposed to palmitate. The change of fatty acid oxidation (FAO) and the activity of CPT1A were observed in HepG2 cells. Quantitative real-time polymerase chain reaction and Western blot were employed to observe the expression of SIRT1 and lipid metabolism-related molecules. The interaction between SIRT1 and CPT1A was investigated by using co-immunoprecipitation assay in HEK293T cells.ResultsBerberine treatment attenuated hepatic steatosis, reduced triglyceride (190.1 ± 11.2 μmol/g liver vs 113.6 ± 7.6 μmol/g liver, P < 0.001) and cholesterol (11.3 ± 2.5 μmol/g liver vs 6.3 ± 0.4 μmol/g liver, P < 0.001) concentration in the liver, and improved lipid and glucose metabolism disorders compared with the HFD group. The expression of SIRT1 was reduced in the liver of NAFLD patients and mouse models. Berberine increased the expression of SIRT1 and promoted the protein level of CPT1A and its activity in HepG2 cells. SIRT1 overexpression mimicked the effect of berberine on reducing triglyceride levels in HepG2 cells, whereas SIRT1 knock-down attenuated the effect of berberine. Mechanistically, berberine increased the expression of SIRT1. SIRT1 deacetylated CPT1A at the Lys675 site, which suppressed its ubiquitin-dependent degradation, thereby promoting FAO and alleviating non-alcoholic liver steatosis.ConclusionsBerberine promoted SIRT1 deacetylation of CPT1A at the Lys675 site, which reduced the ubiquitin-dependent degradation of CPT1A and ameliorated non-alcoholic liver steatosis.

Dataset Information

Fagopyrum dibotrys extract alleviates hepatic steatosis and insulin resistance, and alters autophagy and gut microbiota diversity in mouse models of high-fat diet-induced non-alcoholic fatty liver disease.

Publications

<i>Fagopyrum dibotrys</i> extract alleviates hepatic steatosis and insulin resistance, and alters autophagy and gut microbiota diversity in mouse models of high-fat diet-induced non-alcoholic fatty liver disease.

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