PGC-1α Activates CYP7A1 and Bile Acid Biosynthesis

Shin, Dong Ju; Campos, José A.; Gil, Gregorio; Osborne, Timothy F.

doi:10.1074/jbc.m309736200

Cited by 96 publications

(86 citation statements)

References 21 publications

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“…In support of this connection, we found that CYP7A1 was induced by fasting and during streptozotocin induced diabetes (33), two stressful metabolic conditions where insulin signaling and glucose metabolism are compromised. More recently, other reports have also revealed an important role for bile acids in glucose metabolism (34,35).…”

supporting

confidence: 53%

“…Transient transfection was performed by the calcium phosphate coprecipitation method as described (33). Values represent the mean of duplicates Ϯ S.D.…”

Section: Methodsmentioning

confidence: 99%

“…For the induction of diabetes, 4-week-old 129SVE male mice (Taconic) were treated with streptozotocin by intraperitoneal injections (100 g/g of body weight) daily for 3 days to induce type I diabetes, as described previously (33). Mice were sacrificed, and livers were processed as described above.…”

Section: Methodsmentioning

confidence: 99%

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FGF15/FGFR4 Integrates Growth Factor Signaling with Hepatic Bile Acid Metabolism and Insulin Action

Shin

Osborne

2009

Journal of Biological Chemistry

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The current studies show FGF15 signaling decreases hepatic forkhead transcription factor 1 (FoxO1) activity through phosphatidylinositol (PI) 3-kinase-dependent phosphorylation. The bile acid receptor FXR (farnesoid X receptor) activates expression of fibroblast growth factor (FGF) 15 in the intestine, which acts through hepatic FGFR4 to suppress cholesterol-7␣ hydroxylase (CYP7A1) and limit bile acid production. Because FoxO1 activity and CYP7A1 gene expression are both increased by fasting, we hypothesized CYP7A1 might be a FoxO1 target gene. Consistent with recently reported results, we show CYP7A1 is a direct target of FoxO1. Additionally, we show that the PI 3-kinase pathway is key for both the induction of CYP7A1 by fasting and the suppression by FGF15. FGFR4 is the major hepatic FGF receptor isoform and is responsible for the hepatic effects of FGF15. We also show that expression of FGFR4 in liver was decreased by fasting, increased by insulin, and reduced by streptozotocin-induced diabetes, implicating FGFR4 as a primary target of insulin regulation. Because insulin and FGF both target the PI 3-kinase pathway, these observations suggest FoxO1 is a key node in the convergence of FGF and insulin signaling pathways and functions as a key integrator for the regulation of glucose and bile acid metabolism.Hepatic cholesterol is converted to bile acids, secreted into the gallbladder, and during a meal is released into the small intestine to enhance digestion and absorption of dietary lipids and fat-soluble vitamins. The majority of the bile acid pool (95%) is recycled back to the liver, whereas the remaining 5% is eliminated through fecal excretion (1, 2). This is an important route for the elimination of excess cholesterol and underscores the importance that bile acids play in regulating mammalian cholesterol metabolism. The initial and rate-controlling step in the classic pathway for cholesterol conversion into bile acids is catalyzed by cholesterol 7␣-hydroxylase (CYP7A1).2 CYP7A1 regulation is primarily transcriptional, and expression of its gene is dynamically regulated by hormones and metabolites (2-6). Importantly, bile acids themselves regulate CYP7A1 gene expression through a multicomponent negative feedback pathway. One of the molecular pathways for bile acid regulation is initiated by the activation of the farnesoid X receptor (FXR) responding directly to bile acid agonists (7). Ligand-activated FXR directly binds to a site in the promoter for the small heterodimer partner (SHP) gene and induces expression of SHP mRNA (8, 9). The translated SHP protein lacks the signature nuclear receptor zinc finger DNA binding domain but uses its conserved dimerization motif to form protein-protein contacts with DNA bound activators, usually other nuclear receptors, to inhibit or interfere with their activation potential (10, 11).The first identified target for SHP repression was the CYP7A1 promoter, and SHP was proposed to interfere with activation by the DNA-bound monomeric liver receptor homologue 1 (LRH-1) nucl...

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supporting

confidence: 53%

“…Transient transfection was performed by the calcium phosphate coprecipitation method as described (33). Values represent the mean of duplicates Ϯ S.D.…”

Section: Methodsmentioning

confidence: 99%

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FGF15/FGFR4 Integrates Growth Factor Signaling with Hepatic Bile Acid Metabolism and Insulin Action

Shin

Osborne

2009

Journal of Biological Chemistry

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“…Changes in the fatty acid and glycerolipid metabolism pathways may contribute to an improvement of lipid metabolism by repeated treatment with metformin, while some fatty acids might be important in modulating mRNA expression of genes such as G6pc [37]. Interestingly, changes of expression in the bile acid biosynthesis, but not the sterol biosynthesis pathway, were detected; indeed, coordinated transcriptional regulation between bile acids and gluconeogenesis [39,40], as well as suppression of gluconeogenenic genes by bile acid [31], have been reported recently. With regard to amino acid metabolism pathways, such as valine, leucine and isoleucine degradation, lysine degradation, arginine and proline metabolism and tryptophan metabolism, it has previously been reported that protein metabolism is abnormal in type 2 diabetes [41], although its relevance to the action of metformin remains to be elucidated.…”

Section: Discussionmentioning

confidence: 97%

Global gene expression analysis in liver of obese diabetic db/db mice treated with metformin

et al. 2006

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Aims/hypothesis: Metformin is widely used as a hypoglycaemic reagent for type 2 diabetes. While the reduction of hepatic gluconeogenesis is thought to be a key effect, the detailed molecular mechanism of action of metformin remains to be elucidated. To gain insight into this, we performed a global gene expression profiling study. Materials and methods: We performed DNA microarray analysis to study global gene expression in the livers of obese diabetic db/db mice 2 h after a single administration of metformin (400 mg/kg). Results: This analysis identified 14 genes that showed at least a 1.5-fold difference in expression following metformin treatment, including a reduction of glucose-6-phosphatase gene expression. The mRNA levels of glucose-6-phosphatase showed one of the best correlations with blood glucose levels among 12,000 genes. Enzymatic activity of glucose-6-phosphatase was also reduced in metformin-treated liver. Moreover, intensive analysis of the expression profile revealed that metformin effected significant alterations in gene expression across at least ten metabolic pathways, including those involved in glycolysis-gluconeogenesis, fatty acid metabolism and amino acid metabolism. Conclusions/interpretation: These results suggest that reduction of glucose-6-phosphatase activity, as well as suppression of mRNA expression levels of this gene, in liver is of prime importance for controlling blood glucose levels in vivo, at least at early time points after metformin treatment. Our results also suggest that metformin not only affects expression of specific genes, but also alters the expression level of multiple genes linked to the metabolic pathways involved in glucose and lipid metabolism in the liver.

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“…Moreover, cholesterol is synthesized and degraded in the liver accordingly to the needs by other tissues (12). Cyp7A1 is the key rate-limiting enzyme controlling cholesterol degradation through hepatic synthesis of bile acids (13,14). Efflux and influx through scavenge receptor B1 (SR-B1), low-density lipoprotein (LDL) receptor, and ABC transporters also plays an important role in regulating cholesterol levels (15)(16)(17).…”

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confidence: 99%

Fasting-dependent glucose and lipid metabolic response through hepatic sirtuin 1

Rodgers

Puigserver

2007

Proc. Natl. Acad. Sci. U.S.A.

491

448

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In the fasted state, induction of hepatic glucose output and fatty acid oxidation is essential to sustain energetic balance. Production and oxidation of glucose and fatty acids by the liver are controlled through a complex network of transcriptional regulators. Among them, the transcriptional coactivator PGC-1␣ plays an important role in hepatic and systemic glucose and lipid metabolism. We have previously demonstrated that sirtuin 1 (SIRT1) regulates genes involved in gluconeogenesis through interaction and deacetylation of PGC-1␣. Here, we show in vivo that hepatic SIRT1 is a factor in systemic and hepatic glucose, lipid, and cholesterol homeostasis. Knockdown of SIRT1 in liver caused mild hypoglycemia, increased systemic glucose and insulin sensitivity, and decreased glucose production. SIRT1 knockdown also decreased serum cholesterol and increased hepatic free fatty acid and cholesterol content. These metabolic phenotypes caused by SIRT1 knockdown tightly correlated with decreased expression of gluconeogenic, fatty acid oxidation and cholesterol degradation as well as efflux genes. Additionally, overexpression of SIRT1 reversed many of the changes caused by SIRT1 knockdown and depended on the presence of PGC-1␣. Interestingly, most of the effects of SIRT1 were only apparent in the fasted state. Our results indicate that hepatic SIRT1 is an important factor in the regulation of glucose and lipid metabolism in response to nutrient deprivation. As these pathways are dysregulated in metabolic diseases, SIRT1 may be a potential therapeutic target to control hyperglycemia and hypercholesterolemia.fasting response ͉ glucose metabolism ͉ lipid metabolism ͉ deacetylase ͉ transcriptional coactivator

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PGC-1α Activates CYP7A1 and Bile Acid Biosynthesis

Cited by 96 publications

References 21 publications

FGF15/FGFR4 Integrates Growth Factor Signaling with Hepatic Bile Acid Metabolism and Insulin Action

FGF15/FGFR4 Integrates Growth Factor Signaling with Hepatic Bile Acid Metabolism and Insulin Action

Global gene expression analysis in liver of obese diabetic db/db mice treated with metformin

Fasting-dependent glucose and lipid metabolic response through hepatic sirtuin 1

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