Dietary fat/cholesterol-sensitive PKCβ-RB signaling: Potential role in NASH/HCC axis

Abstract

Hepatocellular carcinoma (HCC) is a frequent form of cancer with a poor prognosis, and environmental factors significantly contribute to the risk. Despite knowledge that a Western-style diet is a risk factor in the development of nonalcoholic steatohepatitis (NASH) and subsequent progression to HCC, diet-induced signaling changes are not well understood. Understanding molecular mechanisms altered by diet is crucial for developing preventive and therapeutic strategies. We have previously shown that diets enriched with high-fat and high-cholesterol, shown to produce NASH and HCC, induce hepatic protein kinase C beta (PKCβ) expression in mice, and a systemic loss of PKCβ promotes hepatic cholesterol accumulation in response to this diet. Here, we sought to determine how PKCβ and diet functionally interact during the pathogenesis of NASH and how it may promote hepatic carcinogenesis. We found that diet-induced hepatic PKCβ expression is accompanied by an increase in phosphorylation of Ser780 of retinoblastoma (RB) protein. Intriguingly, PKCβ^-/- livers exhibited reduced RB protein levels despite increased transcription of the RB gene. It is also accompanied by reduced RBL-1 with no significant effect on RBL-2 protein levels. We also found reduced expression of the PKCβ in HCC compared to non-tumorous liver in human patients. These results raise an interesting possibility that diet-induced PKCβ activation represents an important mediator in the functional wiring of cholesterol metabolism and tumorigenesis through modulating stability of cell cycle-associated proteins. The potential role of PKCβ in the suppression of tumorigenesis is discussed.