title: Disruption of the murine protein kinase Cbeta gene promotes gallstone formation and alters biliary lipid and hepatic cholesterol metabolism.
abstract: 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 Cβ (PKCβ), a calcium-, diacylglycerol-, and phospholipid-dependent kinase, is critical for maintaining whole body triglyceride homeostasis. We now report that PKCβ 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 PKCβ(-/-) 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 PKCβ(-/-) mice also displayed decreased expression of hepatic cholesterol-7α-hydroxylase (CYP7A1) and sterol 12α-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 PKCβ(-/-) mice and was associated with dramatic increases in cholesterol saturation and hydrophobicity indices. Taken together, the findings reveal a hitherto unrecognized role of PKCβ in fine tuning diet-induced cholesterol and bile acid homeostasis, thus identifying PKCβ as a major physiological regulator of both triglyceride and cholesterol homeostasis.
authors.affiliation: Department of Molecular and Cellular Biochemistry, The Dorothy M. Davis Heart and Lung Research Institute, Ohio State University College of Medicine, Columbus, Ohio 43210, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Huang
authors.forename: Rishipal R
authors.initials: RR
authors.lastname: Bansode
authors.forename: Yan
authors.initials: Y
authors.lastname: Xie
authors.forename: Leslie
authors.initials: L
authors.lastname: Rowland
authors.forename: Madhu
authors.initials: M
authors.lastname: Mehta
authors.forename: Nicholas O
authors.initials: NO
authors.lastname: Davidson
authors.forename: Kamal D
authors.initials: KD
authors.lastname: Mehta
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000235:genetics / Q000378:metabolism*; D002784:Cholesterol / Q000235:genetics / Q000378:metabolism*; D002790:Cholesterol 7-alpha-Hydroxylase / Q000235:genetics / Q000378:metabolism; D004789:Enzyme Activation / Q000235:genetics; D042882:Gallstones / Q000201:enzymology* / Q000235:genetics; D008099:Liver / Q000201:enzymology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*
chemical_list: D001647:Bile Acids and Salts; D002784:Cholesterol; D002790:Cholesterol 7-alpha-Hydroxylase; C502772:Cyp7a1 protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D019950:Mitogen-Activated Protein Kinase 1