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Neohesperidin enhances PGC-1?-mediated mitochondrial biogenesis and alleviates hepatic steatosis in high fat diet fed mice.

ABSTRACT: BACKGROUNDS:Mitochondria plays a critical role in the development and pathogenesis of nonalcoholic fatty liver disease (NAFLD). Neohesperidin (NHP) could lower blood glucose and prevent obesity in mice. However, the direct effect of NHP on hepatic steatosis has not been reported. METHODS:Mice were fed with either a chow diet or HFD with or without oral gavage of NHP for 12 weeks. A variety of biochemical and histological indicators were examined. In vitro cell culture model was utilized to demonstrate underlying molecular mechanism of the effect induced by NHP treatment. RESULTS:NHP increases mitochondrial biogenesis, improves hepatic steatosis and systematic insulin resistance in high fat diet (HFD) fed mice. NHP elevates hepatic mitochondrial biogenesis and fatty acid oxidation by increasing PGC-1? expression. Mechanistically, the activation of AMP-activated protein kinase (AMPK) is involved in NHP induced PGC-1? expression. CONCLUSIONS:PGC-1?-mediated mitochondrial biogenesis plays a vital role in the mitigation of hepatic steatosis treated by NHP. Our result suggests that NHP is a good candidate to be dietary supplement for the auxiliary treatment of NAFLD.

SUBMITTER: Wang SW

PROVIDER: S-EPMC7406515 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Neohesperidin enhances PGC-1α-mediated mitochondrial biogenesis and alleviates hepatic steatosis in high fat diet fed mice.

Wang Si-Wei SW Sheng Hao H Bai Yong-Feng YF Weng Yuan-Yuan YY Fan Xue-Yu XY Lou Li-Jun LJ Zhang Feng F

Nutrition & diabetes 20200805 1

<h4>Backgrounds</h4>Mitochondria plays a critical role in the development and pathogenesis of nonalcoholic fatty liver disease (NAFLD). Neohesperidin (NHP) could lower blood glucose and prevent obesity in mice. However, the direct effect of NHP on hepatic steatosis has not been reported.<h4>Methods</h4>Mice were fed with either a chow diet or HFD with or without oral gavage of NHP for 12 weeks. A variety of biochemical and histological indicators were examined. In vitro cell culture model was ut ...[more]

PMID: 32759940

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Project description:Objective: Recent studies demonstrate circulating serum spexin levels are reduced in obesity or type 2 diabetes mellitus (T2DM) patients and may play a role in glucose metabolism. The mechanism underlying is not known. In this study, we explore whether spexin has a role in insulin resistance and hepatic glucose metabolism. Methods: The correlation between serum spexin levels and the homeostasis model assessment of insulin resistance (HOMA-IR) was studied in newly diagnosed T2DM patients. After intraperitoneal injection of exogenous spexin for 8 weeks, the effect of spexin on exogenous glucose infusion rates (GIR), and hepatic glucose production (HGP) were assessed by extended hyperinsulinemic-euglycemic clamp in high-fat-diet (HFD)-induced rats. Glucose concentration with CRISPR/Cas9-mediated disruption of spexin expression in HepG2 cells culture was observed. Expression of transcription factors (Forkhead box O1, FoxO1 and peroxisome proliferator-activated receptor gamma coactivator 1-alpha, PGC-1α) and key enzymes (G-6-Pase and PEPCK) of gluconeogenesis pathway were observed in vitro and in vivo. Results: The serum spexin level was significantly low in newly diagnosed T2DM patients as compared with healthy patients and significantly negatively correlated with the HOMA-IR values. Exogenous spexin treatment resulted in weight loss and decrease of HOMA-IR value in high-fat-diet (HFD)-induced rats. The exogenous glucose infusion rates (GIR) were higher in the HFD + spexin group than that in the HFD group (358 ± 32 vs. 285 ± 24 μmol/kg/min, P < 0.05). Steady-state hepatic glucose production (HGP) was also suppressed by ~50% in the HFD + spexin group as compared with that in the HFD group. Furthermore, spexin inhibited gluconeogenesis in dose-dependent and time-dependent manner in the insulin-resistant cell model. CRISPR/Cas9-mediated knockdown of spexin in HepG2 cells activated gluconeogenesis. Moreover, spexin was shown regulating gluconeogenesis by inhibiting FoxO1/PGC-1α pathway, and key gluconeogenic enzymes, (PEPCK and G-6-Pase) in both HFD-induced rats and insulin-resistant cells. Conclusions: Spexin plays an important role in insulin resistance in HFD-induced rats and insulin-resistant cells. Regulation of the effects of spexin on insulin resistance may hold therapeutic value for metabolic diseases.

Project description:BackgroundNonalcoholic fatty liver disease (NAFLD) is considered the hepatic component of metabolic syndrome and has attracted widespread attention due to its increased prevalence. Daily dietary management is an effective strategy for the prevention of NAFLD. Quinoa, a nutritious pseudocereal, is abundant in antioxidative bioactive phytochemicals. In the present study, the effects of different amounts of quinoa on the progression of NAFLD and the related molecular mechanism were investigated.MethodsMale SD rats were simultaneously administered a high fat diet (HF) and different amounts of quinoa (equivalent to 100 g/day and 300 g/day of human intake, respectively). After 12 weeks of the intervention, hepatic TG (triglyceride) and TC (total cholesterol) as well as serum antioxidative parameters were determined, and hematoxylin-eosin staining (H&E) staining was used to evaluate hepatic steatosis. Differential metabolites in serum and hepatic tissue were identified using UPLC-QTOF-MSE. The mRNA expression profile was investigated using RNA-Seq and further verified using real-time polymerase chain reaction (RT-PCR).ResultsLow amounts of quinoa (equivalent to 100 g/d of human intake) effectively controlled the weight of rats fed a high-fat diet. In addition, quinoa effectively inhibited the increase in hepatic TG and TC levels, mitigated pathological injury, promoted the increase in SOD and GSH-Px activities, and decreased MDA levels. Nontarget metabolic profile analysis showed that quinoa regulated lipid metabolites in the circulation system and liver such as LysoPC and PC. RNA-Seq and RT-PCR verification revealed that a high amount of quinoa more effectively upregulated genes related to lipid metabolism [Apoa (apolipoprotein)5, Apoa4, Apoc2] and downregulated genes related to the immune response [lrf (interferon regulatory factor)5, Tlr6 (Toll-like receptor), Tlr10, Tlr11, Tlr12].ConclusionQuinoa effectively prevented NAFLD by controlling body weight, mitigating oxidative stress, and regulating the lipid metabolic profile and the expression of genes related to lipid metabolism and the immune response.

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Neohesperidin enhances PGC-1?-mediated mitochondrial biogenesis and alleviates hepatic steatosis in high fat diet fed mice.

Publications

Neohesperidin enhances PGC-1α-mediated mitochondrial biogenesis and alleviates hepatic steatosis in high fat diet fed mice.

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