PKCδ Is Activated in a Dietary Model of Steatohepatitis and Regulates Endoplasmic Reticulum Stress and Cell Death

Hepatic steatosis can progress to the clinical condition of non-alcoholic steatohepatitis (NASH), which is a precursor of more serious liver diseases. The novel PKC isoforms delta and epsilon are activated by lipid metabolites and have been implicated in lipid-induced hepatic disease. Using a methionine-and choline- deficient (MCD) dietary model of NASH, we addressed the question of whether hepatic PKC delta and PKC epsilon are activated. With progression from steatosis to steatohepatitis, there was activation and increased PKC delta protein content coincident with hepatic endoplasmic reticulum (ER) stress parameters. To examine whether similar changes could be induced in vitro, McA-RH 7777 (McA) hepatoma cells were used. We observed that McA cells stored triglyceride and released alanine aminotransferase (ALT) when treated with MCD medium in the presence of fatty acids. Further, MCD medium with palmitic acid, but not oleic or linoleic acids, maximally activated PKC delta and stimulated ER stress. In PKC delta knockdown McA cells, MCD/fatty acid medium-induced ALT release and ER stress induction were completely blocked, but triglyceride storage was not. In addition, a reduction in the uptake of propidium iodide and the number of apoptotic nuclei and a significant increase in cell viability and DNA content were observed in PKC delta knockdown McA cells incubated in MCD medium with palmitic acid. Our studies show that PKC delta activation and protein levels are elevated in an animal model of steatohepatitis, which was recapitulated in a cell model, supporting the conclusion that PKC delta plays a role in ALT release, the ER stress signal, and cell death.