Molecular mechanisms of lipotoxicity in nonalcoholic fatty liver disease

Research output: Contribution to journalReview article

364 Scopus citations

Abstract

Nonalcoholic fatty liver disease (NAFLD) is characterized by insulin resistance, which results in elevated serum concentration of free fatty acids (FFAs). Circulating FFAs provide the substrate for triacylglycerol formation in the liver, and may also be directly cytotoxic. Hepatocyte apoptosis is a key histologic feature of NAFLD, and correlates with progressive inflammation and fibrosis. The molecular pathways leading to hepatocyte apoptosis are not fully defined; however, recent studies suggest that FFA-induced apoptosis contributes to the pathogenesis of nonalcoholic steatohepatitis. FFAs directly engage the core apoptotic machinery by activating the proapoptotic protein Bax, in a c-jun N-terminal kinase-dependent manner. FFAs also activate the lysosomal pathway of cell death and regulate death receptor gene expression. The role of ER stress and oxidative stress in the pathogenesis of nonalcoholic steatohepatitis has also been described. Understanding the molecular mediators of liver injury should promote development of mechanism-based therapeutic interventions.

Original languageEnglish (US)
Pages (from-to)360-369
Number of pages10
JournalSeminars in liver disease
Volume28
Issue number4
DOIs
StatePublished - Nov 2008

Keywords

  • Bim
  • C-jun N-terminal kinase
  • Hepatocyte injury
  • Oleic acid
  • Palmitic acid

ASJC Scopus subject areas

  • Hepatology

Fingerprint Dive into the research topics of 'Molecular mechanisms of lipotoxicity in nonalcoholic fatty liver disease'. Together they form a unique fingerprint.

  • Cite this