Expression of sterol 12α-hydroxylase alters bile acid pool composition in primary rat hepatocytes and in vivo

Pandak, William M.; Bohdan, Patricia; Franklund, C V; Mallonee, D H; Eggertsen, Gösta; Björkhem, Ingemar; Gil, Gregorio; Vlahčevič, Z. Reno; Hylemon, Phillip B.

doi:10.1053/gast.2001.24833

Cited by 59 publications

(47 citation statements)

References 31 publications

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“…8A), a finding that is consistent with the increased gallstone formation in PKC␤ Ϫ/Ϫ mice. Additionally, significantly reduced expression of the sterol 12␣-hydroxylase (CYP8b1) gene is expected to increase the bile hydrophobicity of PKC␤ Ϫ/Ϫ mice (40). The reduction in CYP7A1 expression was not accompanied by any alteration in expression of transcription factors (LXR␣, FXR, and SREBP-1c), which are known to regulate its expression (41)(42)(43).…”

Section: Pkc␤ ϫ/ϫ Mice Exhibit Lower Expression Of Hepatic Cholesteromentioning

confidence: 99%

Disruption of the Murine Protein Kinase Cβ Gene Promotes Gallstone Formation and Alters Biliary Lipid and Hepatic Cholesterol Metabolism

Huang¹,

Bansode

Rowland

et al. 2011

Journal of Biological Chemistry

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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 C␤ (PKC␤), a calcium-, diacylglycerol-, and phospholipid-dependent kinase, is critical for maintaining whole body triglyceride homeostasis. We now report that PKC␤ 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 PKC␤ ؊/؊ 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 PKC␤ ؊/؊ mice also displayed decreased expression of hepatic cholesterol-7␣-hydroxylase (CYP7A1) and sterol 12␣-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 PKC␤ ؊/؊ mice and was associated with dramatic increases in cholesterol saturation and hydrophobicity indices. Taken together, the findings reveal a hitherto unrecognized role of PKC␤ in fine tuning diet-induced cholesterol and bile acid homeostasis, thus identifying PKC␤ as a major physiological regulator of both triglyceride and cholesterol homeostasis.

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Section: Pkc␤ ϫ/ϫ Mice Exhibit Lower Expression Of Hepatic Cholesteromentioning

confidence: 99%

Disruption of the Murine Protein Kinase Cβ Gene Promotes Gallstone Formation and Alters Biliary Lipid and Hepatic Cholesterol Metabolism

Huang¹,

Bansode

Rowland

et al. 2011

Journal of Biological Chemistry

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“…Cells were routinely harvested after 72 h of culture as previously described (12). Unless specified, cells were maintained under conditions in which CYP7A1 activity is undetectable (i.e., cultured in the absence of thyroid hormone) (13).…”

Section: Isolation and Culture Of Primary Rat Hepatocytesmentioning

confidence: 99%

Effect of increasing the expression of cholesterol transporters (StAR, MLN64, and SCP-2) on bile acid synthesis

Ren

Hylemon

Marques

et al. 2004

Journal of Lipid Research

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There are two major pathways of bile acid synthesis: the "neutral" pathway, initiated by highly regulated microsomal cholesterol 7 ␣ -hydroxylase (CYP7A1), and an "alternative" pathway, initiated by mitochondrial sterol 27-hydroxylase (CYP27A1). In hepatocyte cultures, overexpression of CYP7A1 increases bile acid synthesis by Ͼ 8-fold. However, overexpression of CYP27A1 in hepatocytes only increases it by 1.5-fold, suggesting that additional rate-limiting steps must be involved in the regulation of this pathway. The effects of intracellular cholesterol transport proteins on bile acid synthesis have been investigated in the current study. Under culture conditions in which the neutral pathway was inactive, selective overexpression of the gene encoding steroidogenic acute regulatory protein (StAR), MLN64 (StAR homolog protein), and sterol carrier protein-2 (SCP-2) led to 5.7-, 1.2-, and 1.7-fold increases, respectively, in the rates of bile acid synthesis in primary rat hepatocytes. Surprisingly, co-overexpression of MLN64 with StAR, SCP-2, or CYP7A1 blunted the upregulated bile acid synthesis by 48, 47, and 45%, respectively.These results suggest that MLN64, in its full-length form, is not responsible for the transport of cholesterol to the mitochondria or the endoplasmic reticulum, where CYP27A1 or CYP7A1 is located, respectively. -Ren, S., P. Hylemon, D. Marques, E. Hall, K. Redford, G. Gil, and W. M. Pandak. Effect of increasing the expression of cholesterol transporters (StAR, MLN64, and SCP-2) on bile acid synthesis.

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“…In bile acid metabolism, SHP functions to repress activity of LRH-1 and HNF4 (2-6). These two factors drive expression of cholesterol 7a-hydroxylase (CYP7A1) and sterol 12 a-hydroxylase (CYP8B1), the two enzymes controlling the bile acid pool size and the hydrophobicity of the bile acid pool (7,8). In this manner, a classical negative feedback pathway is established in which bile acids regulate their own synthesis.…”

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confidence: 99%

Activation of farnesoid X receptor prevents atherosclerotic lesion formation in LDLR−/− and apoE−/− mice

Hartman¹,

Gardell²,

Petucci³

et al. 2009

Journal of Lipid Research

127

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The role of farnesoid X receptor (FXR) in the development of atherosclerosis has been unclear. Here, LDL receptor (LDLR 2/2 ) or apolipoprotein E (apoE 2/2 ) female or male mice were fed a Western diet and treated with a potent synthetic FXR agonist, WAY-362450. Activation of FXR blocked diet-induced hypertriglyceridemia and elevations of non-HDL cholesterol and produced a near complete inhibition of aortic lesion formation. WAY-362450 also induced small heterodimer partner (SHP) expression and repressed cholesterol 7a-hydroxylase (CYP7A1) and sterol 12 a-hydroxylase (CYP8B1) expression. To determine if SHP was essential for these protective activities, LDLR Farnesoid X receptor (FXR) is a nuclear hormone receptor critically involved in the regulation of bile acid homeostasis. It is now recognized that bile acids serve as the natural ligands for FXR (1). Once activated, FXR in turn induces the expression of another nuclear hormone receptor, small heterodimer partner (SHP). SHP does not contain a DNA binding domain, but functions as a transcriptional repressor by interacting with other transcription factors bound to DNA. In bile acid metabolism, SHP functions to repress activity of LRH-1 and HNF4 (2-6). These two factors drive expression of cholesterol 7a-hydroxylase (CYP7A1) and sterol 12 a-hydroxylase (CYP8B1), the two enzymes controlling the bile acid pool size and the hydrophobicity of the bile acid pool (7,8). In this manner, a classical negative feedback pathway is established in which bile acids regulate their own synthesis.In regard to lipid metabolism, the FXR activation by either bile acid ligands or potent synthetic ligands has been shown to consistently decrease plasma triglyceride (TG) levels. Multiple mechanisms are involved in this process, including control of lipoprotein lipase activity by FXR-induced stimulation of apoCII expression (9) and repression of apoCIII expression (10), as well as decreased production of VLDL due to diminished SREBP-1c activity and TG synthesis in the liver (11). In regard to cholesterol metabolism, a more complex picture has emerged. A major pathway for elimination of cholesterol from the body is conversion of cholesterol into bile acids. FXR repression of CYP7A1 expression might thus be predicted to increase dyslipidemia and atherosclerosis. Furthermore, FXR can repress apoAI expression and decrease HDL cholesterol levels (12), another potential detrimental effect. Conversely, bile acids are essential for cholesterol absorption (8), and inhibition of cholesterol absorption by ezetimibe strongly decreases plasma LDL cholesterol levels and atherosclerosis (13). Thus, activation of FXR could theoretically have either beneficial effects or negative effects on plasma cholesterol levels and atherosclerosis. Abbreviations: apoE, apolipoprotein E; BSEP, bile salt export protein; CYP7A1, cholesterol 7a-hydroxylase; CYP8B1, sterol 12 a-hydroxylase; FXR, farnesoid X receptor; IBABP, ileal bile acid binding protein; LDLR, low density lipoprotein receptor; LXR, liver X re...

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Expression of sterol 12α-hydroxylase alters bile acid pool composition in primary rat hepatocytes and in vivo

Cited by 59 publications

References 31 publications

Disruption of the Murine Protein Kinase Cβ Gene Promotes Gallstone Formation and Alters Biliary Lipid and Hepatic Cholesterol Metabolism

Disruption of the Murine Protein Kinase Cβ Gene Promotes Gallstone Formation and Alters Biliary Lipid and Hepatic Cholesterol Metabolism

Effect of increasing the expression of cholesterol transporters (StAR, MLN64, and SCP-2) on bile acid synthesis

Activation of farnesoid X receptor prevents atherosclerotic lesion formation in LDLR−/− and apoE−/− mice

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