Dietary fat/cholesterol-sensitive PKCβ-RB signaling: Potential role in NASH/HCC axis.
Huang W, Mehta D, Sif S, Kent LN, Jacob ST, Ghoshal K, Mehta KD
Oncotarget 8 73757-73765 09/26/2017
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, PKCβFull Text