Dietary fat/cholesterol‐sensitive PKCbeta‐RB signaling: Potential role in diet‐induced NASH/HCC axis

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Hepatocellular carcinoma (HCC) is a frequent form of cancer with a poor prognosis. Recent studies suggest that abnormal lipid metabolism may play an essential role in nonalcoholic steatohepatitis (NASH) development and oncogenesis of HCC. Excess dietary cholesterol intake has been shown to cause development of experimental NASH in different animal models, especially in the setting of a concurrent high‐fat diet. Despite knowledge that Western‐style high‐fat and high‐cholesterol diet is a risk factor in the development of NASH and subsequent progression to HCC, diet‐induced signaling changes implicated in NASH/HCC axis are not well understood. Understanding molecular mechanisms altered by diet is crucial for developing preventive and therapeutic strategies. We previously assessed whether metabolic adaptation to high‐fat/cholesterol diet is associated with changes in hepatic PKCβ expression and also studied the consequence of PKCβ deficiency on diet‐induced hepatic cholesterol homeostasis. We reported that diets enriched with high‐fat and high‐cholesterol (with or without bile acid), shown to produce NASH and HCC, induce hepatic PKCβ expression, and a systemic loss of PKCβ promotes hepatic cholesterol accumulation in response to such diets. These results support the possibility that PKCβ is a physiological transducer of dietary fat/cholesterol and plays a critical role in hepatic adaptation to such diets. Here, we sought to determine how PKCβ and diet functionally interact during tumorigenesis. We examined effects of dietary fat/cholesterol on the PKCβ phosphorylation of retinoblastoma (RB) protein and family members, as well as compared PKCβ expression in human HCC versus normal tissue. We show that diet‐induced hepatic PKCβ expression is accompanied by increased phosphorylation of specific residues of RB protein in a time‐dependent manner. Intriguingly, PKCβ−/− livers exhibited reduced phospho‐RB and RB protein levels, which ultimately resulted in increased transcription of RB gene. It is also accompanied by reduced RBL‐1 with no significant effect on RBL‐2 protein level. To investigate the potential effect of PKCβ deficiency on DNA content of preneoplastic livers, flow cytometric analysis was conducted on hepatocytes obtained from high‐fat/cholesterol diet‐fed WT and PKCβ−/− mice. We also report reduced expression of PKCβ in HCC compared to an adjacent 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. Identification of PKCβ as a cellular relay in diet‐mediated change in RB functions can define the signaling events that could participate in diet‐induced oncogenesis.Support or Funding InformationThe Ohio State University College of Medicine Research Funds