Celastrol ameliorates liver metabolic damage caused by a high-fat diet through Sirt1

Abstract

ObjectiveCelastrol was recently identified as a potential novel treatment for obesity. However, the effect of Celastrol on nonalcoholic fatty liver disease (NAFLD) remains elusive. The aim of this study is to evaluate the role of Celastrol in NAFLD.MethodsFunctional studies were performed using wild-type C57BL/6J (WT) mice and liver specific Sirt1-deficient (LKO) mice. The molecular mechanism was explored in primary mouse liver and primary hepatocytes.ResultsWhen WT mice receiving a high-fat diet (HFD) were treated with Celastrol, reductions in body weight, subcutaneous and visceral fat content, and liver lipid droplet formation were observed, along with reduced hepatic intracellular triglyceride and serum triglyceride, free fatty acid, and ALT concentrations. Furthermore, Celastrol decreased hepatic sterol regulatory element binding protein 1c (Srebp-1c) expression, enhanced the phosphorylation of hepatic AMP-activated protein kinase α (AMPKα), and increased the expression of hepatic serine–threonine liver kinase B1 (LKB1). Additionally, Celastrol treatment improved glucose tolerance and insulin sensitivity in WT mice fed the HFD. Celastrol administration also improved the anti-inflammatory and anti-oxidative status by inhibiting nuclear factor kappa B (NFκB) activity and the mRNA levels of proinflammatory cytokines and increasing mitochondrial DNA copy number and anti-oxidative stress genes expression in WT mice liver, in vivo and in vitro. Moreover, Celastrol induced hepatic Sirt1 expression in WT mice, in vivo and in vitro. These Celastrol-mediated protective effects in WT mice fed a HFD were abolished in LKO mice fed a HFD. It was more interesting that Celastrol aggravated HFD-induced liver damage in LKO mice fed a HFD by inhibiting the phosphorylation of AMPKα and boosting the translocation of NFκB into the nucleus, thereby resulting in the increase of Srebp-1c expression and the mRNA levels of liver proinflammatory cytokines.ConclusionsCelastrol ameliorates NAFLD by decreasing lipid synthesis and improving the anti-oxidative and anti-inflammatory status. And Sirt1 has an important role in Celastrol-ameliorating liver metabolic damage caused by HFD.

WITHDRAWN: Ginkgolide B reduces hepatic lipid accumulation and ameliorates nonalcoholic fatty liver disease in high-fat diet–induced obese mice

“…Increased fat decomposition to reduce lipid accumulation in fatty liver cells is an important strategy [29]. If the models used here also show accelerated lipid decomposition in liver cells, the result could validate the current implications that ginkgolide B effectively decreases lipid accumulation in fatty liver.…”

“…For example, 6-gingerol is linked to reduced body weight and inhibition of lipid accumulation of hepatocytes in obese mice [28]. Celastrol has been associated with increased Sirt-1 expression, suggesting improved liver lipid metabolism, and with reduced liver damage in HFDinduced obese mice [29]. Curcumin and astaxanthin can inhibit liver inflammation and fibrosis and decrease lipid and adipose tissue accumulation [30,31].…”

A Novel Role of SIRT1/ FGF-21 in Taurine Protection Against Cafeteria Diet-Induced Steatohepatitis in Rats

“…SIRT1 and its activators play a key role in lipid and glucose homeostasis and insulin sensitivity via regulating mitochondrial biogenesis and β-oxidation, and improving anti-inflammatory activities. Previous studies indicated that the activation of SIRT1 in the liver protects against high-fat diet (HFD)-induced metabolic damage [15, 16], and that the regulation of hepatic lipid metabolism is postulated by SIRT1 deacetylation of sterol regulatory element-binding protein (SREBP)-1c, thus decreasing its expression [17, 18]. Despite the high prevalence of NAFLD, an approved standardized treatment is still lacking, contributing to a serious challenge to health care systems.…”

Effects of bound phenolic from defatted Moringa oleifera seed flour on diet-induced hypercholesterolemic mice

“…The results reveal that there was a significant ( p < .05) increase in body weight and liver weight in HFCD fed group, whereas treated groups and control group were comparable. Increase in relative liver weight in mice fed with HFCD without treatment due to the fatty liver caused by the increase in fat mass (Zhang et al, ). The treated group (HFCD + BP and HFCD + CA) showed reduction in relative liver weight when compared with HFCD fed group, suggesting improvement in liver cells.…”