Hepatic protein kinase Cbeta antagonizing p38MAPK to activate ERK1/2 to dysregulate biliary lipid composition upon lithogenic stress.

Lithogenic diet exposure disrupts biliary lipid homeostasis to promote precipitation of excess biliary cholesterol; however, the underlying pathogenic signaling mechanism remains unclear. Protein kinase Cbeta (PKCβ) is involved in regulating hepatic cholesterol and bile acid metabolism. In this study, we aimed to identify the initiating signaling and biological changes in the liver upon loss of hepatic PKCβ function under lithogenic stress. Transcriptome analysis of the liver revealed that hepatic deletion of PKCβ altered the expression of 183 liver genes, 118 of which were upregulated, and 65 were downregulated. We identified marked increases in the expression of genes involved in bile acid biosynthesis (Cyp7a1 and Cyp8b1) and a decrease in retinol metabolism (Cyp26b1) as the most relevant changes, with blunted expression of genes involved in bile acid and phosphatidylcholine transporters. Mechanistic studies revealed that the hepatic PKCβ deficiency was associated with reduced ERK1/2 phosphorylation in concert with increased p38^MAPK phosphorylation in the liver. Overexpression of PKCβ in the liver blocked p38^MAPK activation as well as resulted in increased ERK1/2 phosphorylation and was accompanied by suppression of both Cyp7a1 and Cyp8b1 expression, demonstrating that hepatic PKCβ functions as a positive regulator of ERK1/2 to suppress expression of both genes by antagonizing p38^MAPK. Furthermore, depletion of liver p38^MAPK in PKCβ^Hep-/- mice resulted in enhanced ERK1/2 phosphorylation and suppression of Cyp7a1 and Cyp8b1 expression. The findings yielded by this study support our understanding of the intricate interplay among PKCβ, p38^MAPK, and ERK1/2 signaling in vivo, and provide valuable insights into potential therapeutic targets for the development of novel strategies to combat cholelithiasis.