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Disruption of the Protein Kinase Cbeta Gene in Mice Impairs Biliary Lipid and Hepatic Cholesterol Metabolism

Quantitative trait mapping in mice identified a susceptibility locus for gallstones (Lith22) spanning the PKCbeta locus, encoding the lipid‐activated protein kinase Cbeta (PKCbeta). In the present study, we explored the in vivo role of PKCbeta in diet‐induced cholesterol homeostasis using PKCbeta‐deficient mice. Male C57BL/6J and C57BL/6J PKCbeta knockout mice were fed a standard chow or lithogenic diet. Hepatic biles were collected to determine biliary lipid secretion rates, bile flow, and bile salt pool size. Compared with chow‐fed WT mice, PKCbeta knockout mice had reduced bile salt pool size, decreased bile salt secretion, as well as increased cholesterol saturation and bile acid hydrophobicity indices. When fed a lithogenic diet for 8 weeks, PKCbeta knockout mice became hypercholesterolemic with an increased incidence of gallstone formation. Lithogenic diet‐fed PKCbeta knockout mice demonstrated increased biliary cholesterol secretion and hyposecretion of bile acids and is accompanied by increased cholesterol saturation and bile acid hydrophobicity indices. Among the possible mechanisms to account for this phenotype, expression of cholesterol 7alpha‐hydroxylase was significantly decreased in chow‐fed PKCbeta knockout mice, decreasing further in lithogenic diet‐fed mice. These results support a role of PKCbeta in hepatic cholesterol metabolism.