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Bile acid sequestrants for lipid and glucose control.

Staels B, Handelsman Y, Fonseca V - Curr. Diab. Rep. (2010)

Bottom Line: Recently, bile acids emerged as signaling molecules that, as ligands for the bile acid receptors farnesoid X receptor (FXR) and TGR5, activate and integrate multiple complex signaling pathways involved in lipid and glucose metabolism.Bile acid sequestrants are pharmacologic molecules that bind to bile acids in the intestine resulting in the interruption of bile acid homeostasis and, consequently, reduction in low-density lipoprotein cholesterol levels in hypercholesterolemia.This article examines the mechanisms by which bile acid-mediated activation of FXR and TGR5 signaling pathways regulate lipid and glucose metabolism and the potential implications for bile acid sequestrant-mediated regulation of lipid and glucose levels in T2DM.

View Article: PubMed Central - PubMed

Affiliation: Institut Pasteur de Lille, 1 rue Calmette BP245, 59019, Lille cedex, France. Bart.Staels@pasteur-lille.fr

ABSTRACT
Bile acids are generated in the liver and are traditionally recognized for their regulatory role in multiple metabolic processes including bile acid homeostasis, nutrient absorption, and cholesterol homeostasis. Recently, bile acids emerged as signaling molecules that, as ligands for the bile acid receptors farnesoid X receptor (FXR) and TGR5, activate and integrate multiple complex signaling pathways involved in lipid and glucose metabolism. Bile acid sequestrants are pharmacologic molecules that bind to bile acids in the intestine resulting in the interruption of bile acid homeostasis and, consequently, reduction in low-density lipoprotein cholesterol levels in hypercholesterolemia. Bile acid sequestrants also reduce glucose levels and improve glycemic control in persons with type 2 diabetes mellitus (T2DM). This article examines the mechanisms by which bile acid-mediated activation of FXR and TGR5 signaling pathways regulate lipid and glucose metabolism and the potential implications for bile acid sequestrant-mediated regulation of lipid and glucose levels in T2DM.

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FXR- and TGR5-mediated regulation of bile acid synthesis and lipid and glucose metabolism in the liver and intestine. Bile acid synthesis and lipid and glucose metabolism are regulated in the liver and intestine via pathways involving the bile acid receptors FXR and TGR5. In the liver, bile acids activate FXR resulting in upregulation of SHP, an inhibitor of bile acid synthesis, gluconeogenesis, and fatty acid synthesis. In the intestine, bile acid activation of FXR upregulates FGF-15/19 and ultimately inhibits bile acid synthesis. CYP7A1—cytochrome P450 enzyme cholesterol 7 α-hydroxylase; FGF-15/19—fibroblast growth factor 15/19; FGFR4—fibroblast growth factor receptor 4; FXR—farnesoid X receptor; GLP-1—glucagon-like peptide-1; GR—glucocorticoid receptor; HNF-4—hepatocyte nuclear factor-4; JNK—c-jun N-terminal kinase; LRH-1—liver receptor homologue-1; PEPCK—phosphoenolpyruvate carboxykinase; SHP—small heterodimer partner; SREBP-1c—sterol regulatory element-binding protein-1c; TGs—triglycerides; VLDL—very low density lipoprotein. (Adapted from Staels [49] and Thomas et al. [50].)
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Fig1: FXR- and TGR5-mediated regulation of bile acid synthesis and lipid and glucose metabolism in the liver and intestine. Bile acid synthesis and lipid and glucose metabolism are regulated in the liver and intestine via pathways involving the bile acid receptors FXR and TGR5. In the liver, bile acids activate FXR resulting in upregulation of SHP, an inhibitor of bile acid synthesis, gluconeogenesis, and fatty acid synthesis. In the intestine, bile acid activation of FXR upregulates FGF-15/19 and ultimately inhibits bile acid synthesis. CYP7A1—cytochrome P450 enzyme cholesterol 7 α-hydroxylase; FGF-15/19—fibroblast growth factor 15/19; FGFR4—fibroblast growth factor receptor 4; FXR—farnesoid X receptor; GLP-1—glucagon-like peptide-1; GR—glucocorticoid receptor; HNF-4—hepatocyte nuclear factor-4; JNK—c-jun N-terminal kinase; LRH-1—liver receptor homologue-1; PEPCK—phosphoenolpyruvate carboxykinase; SHP—small heterodimer partner; SREBP-1c—sterol regulatory element-binding protein-1c; TGs—triglycerides; VLDL—very low density lipoprotein. (Adapted from Staels [49] and Thomas et al. [50].)

Mentions: FXR is a member of the nuclear receptor superfamily of ligand-activated transcription factors. FXR is expressed at high levels in the liver and intestine and is most potently activated by the primary bile acid chenodeoxycholic acid [15]. In the liver, as the bile acid pool increases in size, bile acid activation of FXR upregulates expression of the gene encoding the inhibitory nuclear receptor small heterodimer partner (SHP) [15]. SHP represses activation of several transcription factors including liver X receptor, liver receptor homologue-1 (LRH-1), and hepatocyte nuclear factor-4α (HNF-4α), subsequently suppressing, in humans, the LRH-1–mediated activation of CYP7A1, thereby inhibiting the first step in cholesterol catabolism (Fig. 1). Bile acid–mediated repression of HNF-4α also inhibits transcription of CYP7A1 [16].Fig. 1


Bile acid sequestrants for lipid and glucose control.

Staels B, Handelsman Y, Fonseca V - Curr. Diab. Rep. (2010)

FXR- and TGR5-mediated regulation of bile acid synthesis and lipid and glucose metabolism in the liver and intestine. Bile acid synthesis and lipid and glucose metabolism are regulated in the liver and intestine via pathways involving the bile acid receptors FXR and TGR5. In the liver, bile acids activate FXR resulting in upregulation of SHP, an inhibitor of bile acid synthesis, gluconeogenesis, and fatty acid synthesis. In the intestine, bile acid activation of FXR upregulates FGF-15/19 and ultimately inhibits bile acid synthesis. CYP7A1—cytochrome P450 enzyme cholesterol 7 α-hydroxylase; FGF-15/19—fibroblast growth factor 15/19; FGFR4—fibroblast growth factor receptor 4; FXR—farnesoid X receptor; GLP-1—glucagon-like peptide-1; GR—glucocorticoid receptor; HNF-4—hepatocyte nuclear factor-4; JNK—c-jun N-terminal kinase; LRH-1—liver receptor homologue-1; PEPCK—phosphoenolpyruvate carboxykinase; SHP—small heterodimer partner; SREBP-1c—sterol regulatory element-binding protein-1c; TGs—triglycerides; VLDL—very low density lipoprotein. (Adapted from Staels [49] and Thomas et al. [50].)
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2821506&req=5

Fig1: FXR- and TGR5-mediated regulation of bile acid synthesis and lipid and glucose metabolism in the liver and intestine. Bile acid synthesis and lipid and glucose metabolism are regulated in the liver and intestine via pathways involving the bile acid receptors FXR and TGR5. In the liver, bile acids activate FXR resulting in upregulation of SHP, an inhibitor of bile acid synthesis, gluconeogenesis, and fatty acid synthesis. In the intestine, bile acid activation of FXR upregulates FGF-15/19 and ultimately inhibits bile acid synthesis. CYP7A1—cytochrome P450 enzyme cholesterol 7 α-hydroxylase; FGF-15/19—fibroblast growth factor 15/19; FGFR4—fibroblast growth factor receptor 4; FXR—farnesoid X receptor; GLP-1—glucagon-like peptide-1; GR—glucocorticoid receptor; HNF-4—hepatocyte nuclear factor-4; JNK—c-jun N-terminal kinase; LRH-1—liver receptor homologue-1; PEPCK—phosphoenolpyruvate carboxykinase; SHP—small heterodimer partner; SREBP-1c—sterol regulatory element-binding protein-1c; TGs—triglycerides; VLDL—very low density lipoprotein. (Adapted from Staels [49] and Thomas et al. [50].)
Mentions: FXR is a member of the nuclear receptor superfamily of ligand-activated transcription factors. FXR is expressed at high levels in the liver and intestine and is most potently activated by the primary bile acid chenodeoxycholic acid [15]. In the liver, as the bile acid pool increases in size, bile acid activation of FXR upregulates expression of the gene encoding the inhibitory nuclear receptor small heterodimer partner (SHP) [15]. SHP represses activation of several transcription factors including liver X receptor, liver receptor homologue-1 (LRH-1), and hepatocyte nuclear factor-4α (HNF-4α), subsequently suppressing, in humans, the LRH-1–mediated activation of CYP7A1, thereby inhibiting the first step in cholesterol catabolism (Fig. 1). Bile acid–mediated repression of HNF-4α also inhibits transcription of CYP7A1 [16].Fig. 1

Bottom Line: Recently, bile acids emerged as signaling molecules that, as ligands for the bile acid receptors farnesoid X receptor (FXR) and TGR5, activate and integrate multiple complex signaling pathways involved in lipid and glucose metabolism.Bile acid sequestrants are pharmacologic molecules that bind to bile acids in the intestine resulting in the interruption of bile acid homeostasis and, consequently, reduction in low-density lipoprotein cholesterol levels in hypercholesterolemia.This article examines the mechanisms by which bile acid-mediated activation of FXR and TGR5 signaling pathways regulate lipid and glucose metabolism and the potential implications for bile acid sequestrant-mediated regulation of lipid and glucose levels in T2DM.

View Article: PubMed Central - PubMed

Affiliation: Institut Pasteur de Lille, 1 rue Calmette BP245, 59019, Lille cedex, France. Bart.Staels@pasteur-lille.fr

ABSTRACT
Bile acids are generated in the liver and are traditionally recognized for their regulatory role in multiple metabolic processes including bile acid homeostasis, nutrient absorption, and cholesterol homeostasis. Recently, bile acids emerged as signaling molecules that, as ligands for the bile acid receptors farnesoid X receptor (FXR) and TGR5, activate and integrate multiple complex signaling pathways involved in lipid and glucose metabolism. Bile acid sequestrants are pharmacologic molecules that bind to bile acids in the intestine resulting in the interruption of bile acid homeostasis and, consequently, reduction in low-density lipoprotein cholesterol levels in hypercholesterolemia. Bile acid sequestrants also reduce glucose levels and improve glycemic control in persons with type 2 diabetes mellitus (T2DM). This article examines the mechanisms by which bile acid-mediated activation of FXR and TGR5 signaling pathways regulate lipid and glucose metabolism and the potential implications for bile acid sequestrant-mediated regulation of lipid and glucose levels in T2DM.

Show MeSH
Related in: MedlinePlus