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

Jan 27, 2017Molecular metabolism

Celastrol may reduce liver damage from a high-fat diet by activating a key metabolic regulator

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Abstract

Celastrol treatment in high-fat diet mice resulted in significant reductions in body weight and liver lipid droplet formation.

Celastrol administration decreased subcutaneous and visceral fat content, along with lowering hepatic intracellular triglyceride levels.
The treatment improved glucose tolerance and insulin sensitivity in high-fat diet mice.
Celastrol reduced the expression of a key fat synthesis regulator, Srebp-1c, and enhanced the activation of AMPKα, a protein involved in energy balance.
The compound also improved anti-inflammatory and antioxidant responses by inhibiting NFκB activity and increasing the expression of protective genes in the liver.
In liver-specific deficient mice, Celastrol's protective effects against high-fat diet damage were diminished, indicating that Sirt1 plays a crucial role in its mechanism.

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OBJECTIVE: Celastrol 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.

METHODS: Functional studies were performed using wild-type C57BL/6J (WT) mice and liver specific-deficient (LKO) mice. The molecular mechanism was explored in primary mouse liver and primary hepatocytes. Sirt1

RESULTS: When 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,and. Moreover, Celastrol induced hepatic Sirt1 expression in WT mice,and. 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. in vivo in vitro in vivo in vitro

CONCLUSIONS: Celastrol 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.

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

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