| First Author | Huang W | Year | 2011 |
| Journal | J Biol Chem | Volume | 286 |
| Issue | 26 | Pages | 22795-805 |
| PubMed ID | 21550971 | Mgi Jnum | J:174802 |
| Mgi Id | MGI:5141187 | Doi | 10.1074/jbc.M111.250282 |
| Citation | Huang W, et al. (2011) Disruption of the murine protein kinase Cbeta gene promotes gallstone formation and alters biliary lipid and hepatic cholesterol metabolism. J Biol Chem 286(26):22795-805 |
| abstractText | The protein kinase C (PKC) family of Ca(2+) and/or lipid-activated serine-threonine protein kinases is implicated in the pathogenesis of obesity and insulin resistance. We recently reported that protein kinase Cbeta (PKCbeta), a calcium-, diacylglycerol-, and phospholipid-dependent kinase, is critical for maintaining whole body triglyceride homeostasis. We now report that PKCbeta deficiency has profound effects on murine hepatic cholesterol metabolism, including hypersensitivity to diet-induced gallstone formation. The incidence of gallstones increased from 9% in control mice to 95% in PKCbeta(-/-) mice. Gallstone formation in the mutant mice was accompanied by hyposecretion of bile acids with no alteration in fecal bile acid excretion, increased biliary cholesterol saturation and hydrophobicity indices, as well as hepatic p42/44(MAPK) activation, all of which enhance susceptibility to gallstone formation. Lithogenic diet-fed PKCbeta(-/-) mice also displayed decreased expression of hepatic cholesterol-7alpha-hydroxylase (CYP7A1) and sterol 12alpha-hydroxylase (CYP8b1). Finally, feeding a modified lithogenic diet supplemented with milk fat, instead of cocoa butter, both increased the severity of and shortened the interval for gallstone formation in PKCbeta(-/-) mice and was associated with dramatic increases in cholesterol saturation and hydrophobicity indices. Taken together, the findings reveal a hitherto unrecognized role of PKCbeta in fine tuning diet-induced cholesterol and bile acid homeostasis, thus identifying PKCbeta as a major physiological regulator of both triglyceride and cholesterol homeostasis. |
