Regulation of bile acid synthesis.
Humans; Animals; Gene Expression Regulation; Liver/metabolism; Cytochrome P-450 Enzyme System/metabolism; Bile Acids and Salts/*biosynthesis; Cholesterol/metabolism; Cholesterol 7-alpha-Hydroxylase/genetics/*metabolism; Cytochrome P450 Family 7; Cholestanetriol 26-Monooxygenase; Steroid 12-alpha-Hydroxylase/metabolism; Steroid Hydroxylases/metabolism
Bile acids are important physiological agents required for disposal of cholesterol and absorption of vitamins and fats. Bile acids are synthesized from cholesterol in the liver. Enterohepatic circulation of bile acids is very efficient and plays an important physiological role in lipid absorption and secretion, and regulation of bile acid biosynthesis and cholesterol homeostasis. Conversion of cholesterol to bile acids requires 15 different enzymatic steps. Four cytochrome P450 enzymes play important roles in bile acid biosynthesis. The classic bile acid biosynthesis pathway starts with modification of the sterol ring and followed by side chain cleavage reactions to synthesize cholic acid (CA) and chenodeoxycholic acid (CDCA), the primary bile acids in most species. The first and rate-limiting enzyme in this pathway is cholesterol 7alpha -hydroxylase, a microsomal cytochrome P450, CYP7A. Another microsomal cytochrome P450 sterol 12alpha-hydroxylase (CYP12) is required for the synthesis of cholic acid. Mitochondrial cytochrome P450 sterol 27-hydroxylase (CYP27) catalyzes sterol side chain oxidation to convert C27 sterol to C24 bile acids. An alternative bile acid biosynthesis pathway (acidic) has been known for sometime but only recently has attracted much attention. In this pathway, side chain oxidation precedes modification of the sterol ring. Mitochondrial sterol
Chiang J Y
Frontiers in bioscience : a journal and virtual library
1998
1998-02
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.2741/a273" target="_blank" rel="noreferrer noopener">10.2741/a273</a>
Glucose stimulates cholesterol 7alpha-hydroxylase gene transcription in human hepatocytes.
*Gene Expression Regulation; Acetylation; AMP-Activated Protein Kinases/metabolism; ATP Citrate (pro-S)-Lyase/genetics/metabolism; Bile Acids and Salts/metabolism; Cells; Cholesterol 7-alpha-Hydroxylase/genetics/*metabolism; Cultured; DNA-Binding Proteins/metabolism; Enzymologic; Epigenesis; Genes; Genetic; Glucose/*administration & dosage; Hep G2 Cells; Hepatocyte Nuclear Factor 4/metabolism; Hepatocytes/*enzymology/metabolism; Histones/metabolism; Humans; Hyperglycemia/enzymology/*metabolism; Messenger/metabolism; Methylation; Reporter; RNA; RNA Interference
Bile acids play important roles in the regulation of lipid, glucose, and energy homeostasis. Recent studies suggest that glucose regulates gene transcription in the liver. The aim of this study was to investigate the potential role of glucose in regulation of bile acid synthesis in human hepatocytes. High glucose stimulated bile acid synthesis and induced mRNA expression of cholesterol 7alpha-hydroxylase (CYP7A1), the key regulatory gene in bile acid synthesis. Activation of an AMP-activated protein kinase (AMPK) decreased CYP7A1 mRNA, hepatocyte nuclear factor 4alpha (HNF4alpha) protein, and binding to CYP7A1 chromatin. Glucose increased ATP levels to inhibit AMPK and induce HNF4alpha to stimulate CYP7A1 gene transcription. Furthermore, glucose increased histone acetylation and decreased H3K9 di- and tri-methylation in the CYP7A1 chromatin. Knockdown of ATP-citrate lyase, which converts citrate to acetyl-CoA, decreased histone acetylation and attenuated glucose induction of CYP7A1 mRNA expression. These results suggest that glucose signaling also induces CYP7A1 gene transcription by epigenetic regulation of the histone acetylation status. This study uncovers a novel link between hepatic glucose metabolism and bile acid synthesis. Glucose induction of bile acid synthesis may have an important implication in metabolic control of glucose, lipid, and energy homeostasis under normal and diabetic conditions.
Li Tiangang; Chanda Dipanjan; Zhang Yanqiao; Choi Hueng-Sik; Chiang John Y L
Journal of lipid research
2010
2010-04
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1194/jlr.M002782" target="_blank" rel="noreferrer noopener">10.1194/jlr.M002782</a>
Glucose and insulin induction of bile acid synthesis: mechanisms and implication in diabetes and obesity.
*Gene Expression Regulation; Animals; Bile Acids and Salts/*biosynthesis; Cholesterol 7-alpha-Hydroxylase/genetics/*metabolism; Cytoplasmic and Nuclear/genetics/metabolism; Diabetes Mellitus; Dietary Fats/administration & dosage/adverse effects; Enzymologic; Epigenesis; Experimental/genetics/*metabolism; Fasting/metabolism; Genetic/genetics; Glucose/*metabolism/pharmacology; Insulin/*metabolism; Mice; Obesity/etiology/genetics/*metabolism; Postprandial Period/genetics; Receptors; Sweetening Agents/pharmacology; Transgenic
Bile acids facilitate postprandial absorption of nutrients. Bile acids also activate the farnesoid X receptor (FXR) and the G protein-coupled receptor TGR5 and play a major role in regulating lipid, glucose, and energy metabolism. Transgenic expression of cholesterol 7alpha-hydroxylase (CYP7A1) prevented high fat diet-induced diabetes and obesity in mice. In this study, we investigated the nutrient effects on bile acid synthesis. Refeeding of a chow diet to fasted mice increased CYP7A1 expression, bile acid pool size, and serum bile acids in wild type and humanized CYP7A1-transgenic mice. Chromatin immunoprecipitation assays showed that glucose increased histone acetylation and decreased histone methylation on the CYP7A1 gene promoter. Refeeding also induced CYP7A1 in fxr-deficient mice, indicating that FXR signaling did not play a role in postprandial regulation of bile acid synthesis. In streptozocin-induced type I diabetic mice and genetically obese type II diabetic ob/ob mice, hyperglycemia increased histone acetylation status on the CYP7A1 gene promoter, leading to elevated basal Cyp7a1 expression and an enlarged bile acid pool with altered bile acid composition. However, refeeding did not further increase CYP7A1 expression in diabetic mice. In summary, this study demonstrates that glucose and insulin are major postprandial factors that induce CYP7A1 gene expression and bile acid synthesis. Glucose induces CYP7A1 gene expression mainly by epigenetic mechanisms. In diabetic mice, CYP7A1 chromatin is hyperacetylated, and fasting to refeeding response is impaired and may exacerbate metabolic disorders in diabetes.
Li Tiangang; Francl Jessica M; Boehme Shannon; Ochoa Adrian; Zhang Youcai; Klaassen Curtis D; Erickson Sandra K; Chiang John Y L
The Journal of biological chemistry
2012
2012-01
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1074/jbc.M111.305789" target="_blank" rel="noreferrer noopener">10.1074/jbc.M111.305789</a>
Regulation of cholesterol and bile acid homeostasis by the cholesterol 7alpha-hydroxylase/steroid response element-binding protein 2/microRNA-33a axis in mice.
Acetyl Coenzyme A/metabolism; Animal; Animals; Bile Acids and Salts/*metabolism; Cholesterol 7-alpha-Hydroxylase/genetics/*metabolism; Cholesterol/*metabolism; Homeostasis/*physiology; Knockout; Lipid Metabolism/physiology; Liver/metabolism; Male; Messenger/metabolism; Mice; MicroRNAs/*metabolism; Models; RNA; Signal Transduction/*physiology; Sterol Regulatory Element Binding Protein 2/*metabolism; Transgenic
UNLABELLED: Bile acid synthesis not only produces physiological detergents required for intestinal nutrient absorption, but also plays a critical role in regulating hepatic and whole-body metabolic homeostasis. We recently reported that overexpression of cholesterol 7alpha-hydroxylase (CYP7A1) in the liver resulted in improved metabolic homeostasis in Cyp7a1 transgenic (Cyp7a1-tg) mice. This study further investigated the molecular links between bile acid metabolism and lipid homeostasis. Microarray gene profiling revealed that CYP7A1 overexpression led to marked activation of the steroid response element-binding protein 2 (SREBP2)-regulated cholesterol metabolic network and absence of bile acid repression of lipogenic gene expression in livers of Cyp7a1-tg mice. Interestingly, Cyp7a1-tg mice showed significantly elevated hepatic cholesterol synthesis rates, but reduced hepatic fatty acid synthesis rates, which was accompanied by increased (14) C-glucose-derived acetyl-coenzyme A incorporation into sterols for fecal excretion. Induction of SREBP2 also coinduces intronic microRNA-33a (miR-33a) in the SREBP2 gene in Cyp7a1-tg mice. Overexpression of miR-33a in the liver resulted in decreased bile acid pool, increased hepatic cholesterol content, and lowered serum cholesterol in mice. CONCLUSION: This study suggests that a CYP7A1/SREBP2/miR-33a axis plays a critical role in regulation of hepatic cholesterol, bile acid, and fatty acid synthesis. Antagonism of miR-33a may be a potential strategy to increase bile acid synthesis to maintain lipid homeostasis and prevent nonalcoholic fatty liver disease, diabetes, and obesity.
Li Tiangang; Francl Jessica M; Boehme Shannon; Chiang John Y L
Hepatology (Baltimore, Md.)
2013
2013-09
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1002/hep.26427" target="_blank" rel="noreferrer noopener">10.1002/hep.26427</a>