Lipid metabolism, oxidative stress and cell death are regulated by PKC delta in a dietary model of nonalcoholic steatohepatitis.

ABSTRACT: Steatosis, oxidative stress, and apoptosis underlie the development of nonalcoholic steatohepatitis (NASH). Protein kinase C delta (PKC?) has been implicated in fatty liver disease and is activated in the methionine and choline-deficient (MCD) diet model of NASH, yet its pathophysiological importance towards steatohepatitis progression is uncertain. We therefore addressed the role of PKC? in the development of steatosis, inflammation, oxidative stress, apoptosis, and fibrosis in an animal model of NASH. We fed PKC?(-/-) mice and wildtype littermates a control or MCD diet. PKC?(-/-) primary hepatocytes were used to evaluate the direct effects of fatty acids on hepatocyte lipid metabolism gene expression. A reduction in hepatic steatosis and triglyceride levels were observed between wildtype and PKC?(-/-) mice fed the MCD diet. The hepatic expression of key regulators of ?-oxidation and plasma triglyceride metabolism was significantly reduced in PKC?(-/-) mice and changes in serum triglyceride were blocked in PKC?(-/-) mice. MCD diet-induced hepatic oxidative stress and hepatocyte apoptosis were reduced in PKC?(-/-) mice. MCD diet-induced NADPH oxidase activity and p47(phox) membrane translocation were blunted and blocked, respectively, in PKC?(-/-) mice. Expression of pro-apoptotic genes and caspase 3 and 9 cleavage in the liver of MCD diet fed PKC?(-/-) mice were blunted and blocked, respectively. Surprisingly, no differences in MCD diet-induced fibrosis or pro-fibrotic gene expression were observed in 8 week MCD diet fed PKC?(-/-) mice. Our results suggest that PKC? plays a role in key pathological features of fatty liver disease but not ultimately in fibrosis in the MCD diet model of NASH.

SUBMITTER: Greene MW 

PROVIDER: S-EPMC3893275 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature