Alpha-lipoic acid improves high-fat diet-induced hepatic steatosis by modulating the transcription factors SREBP-1, FoxO1 and Nrf2 via the SIRT1/LKB1/AMPK pathway

J Nutr Biochem. 2014 Nov;25(11):1207-1217. doi: 10.1016/j.jnutbio.2014.06.001. Epub 2014 Jul 15.

Abstract

Understanding the mechanism by which alpha-lipoic acid supplementation has a protective effect upon nonalcoholic fatty liver disease in vivo and in vitro may lead to targets for preventing hepatic steatosis. Male C57BL/6J mice were fed a normal diet, high-fat diet or high-fat diet supplemented with alpha-lipoic acid for 24 weeks. HepG2 cells were incubated with normal medium, palmitate or alpha-lipoic acid. The lipid-lowering effects were measured. The protein expression and distribution were analyzed by Western blot, immunoprecipitation and immunofluorescence, respectively. We found that alpha-lipoic acid enhanced sirtuin 1 deacetylase activity through liver kinase B1 and stimulated AMP-activated protein kinase. By activating the sirtuin 1/liver kinase B1/AMP-activated protein kinase pathway, the translocation of sterol regulatory element-binding protein-1 into the nucleus and forkhead box O1 into the cytoplasm was prevented. Alpha-lipoic acid increased adipose triacylglycerol lipase expression and decreased fatty acid synthase abundance. In in vivo and in vitro studies, alpha-lipoic acid also increased nuclear NF-E2-related factor 2 levels and downstream target amounts via the sirtuin 1 pathway. Alpha-lipoic acid eventually reduced intrahepatic and serum triglyceride content. The protective effects of alpha-lipoic acid on hepatic steatosis appear to be associated with the transcription factors sterol regulatory element-binding protein-1, forkhead box O1 and NF-E2-related factor 2.

Keywords: Alpha-lipoic acid; FoxO1; Nonalcoholic fatty liver disease; Nrf2; SIRT1; SREBP-1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenylate Kinase / metabolism*
  • Animals
  • Diet, High-Fat*
  • Fatty Liver / etiology*
  • Fatty Liver / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Protein-Serine-Threonine Kinases / metabolism*
  • Signal Transduction / drug effects
  • Sirtuin 1 / metabolism*
  • Thioctic Acid / pharmacology*
  • Transcription Factors / metabolism*

Substances

  • Transcription Factors
  • Thioctic Acid
  • Stk11 protein, mouse
  • Protein-Serine-Threonine Kinases
  • Adenylate Kinase
  • Sirt1 protein, mouse
  • Sirtuin 1