Bile Acid Receptor Farnesoid X Receptor: A Novel Therapeutic Target for Metabolic Diseases
2
조회
0
다운로드
0
인용
0
참고문헌
키워드
초록
Bile acid has been well known to serve as a hormone in regulating transcriptional activity of Farnesoid X receptor (FXR), an endogenous bile acid nuclear receptor. Moreover, bile acid regulates diverse biological processes, including cholesterol/bile acid metabolism, glucose/lipid metabolism and energy expenditure. Alteration of bile acid metabolism has been revealed in type II diabetic (T2D) patients. FXR-mediated bile acid signaling has been reported to play key roles in improving metabolic parameters in vertical sleeve gastrectomy surgery, implying that FXR is an essential modulator in the metabolic homeostasis. Using a genetic mouse model, intestinal specific FXR-null mice have been reported to be resistant to diet-induced obesity and insulin resistance. Moreover, intestinal specific FXR agonism using gut-specific FXR synthetic agonist has been shown to enhance thermogenesis in brown adipose tissue and browning in white adipose tissue to increase energy expenditure, leading to reduced body weight gain and improved insulin resistance. Altogether, FXR is a potent therapeutic target for the treatment of metabolic diseases.
Abstract
Bile acid has been well known to serve as a hormone in regulating transcriptional activity of Farnesoid X receptor (FXR), an endogenous bile acid nuclear receptor. Moreover, bile acid regulates diverse biological processes, including cholesterol/bile acid metabolism, glucose/lipid metabolism and energy expenditure. Alteration of bile acid metabolism has been revealed in type II diabetic (T2D) patients. FXR-mediated bile acid signaling has been reported to play key roles in improving metabolic parameters in vertical sleeve gastrectomy surgery, implying that FXR is an essential modulator in the metabolic homeostasis. Using a genetic mouse model, intestinal specific FXR-null mice have been reported to be resistant to diet-induced obesity and insulin resistance. Moreover, intestinal specific FXR agonism using gut-specific FXR synthetic agonist has been shown to enhance thermogenesis in brown adipose tissue and browning in white adipose tissue to increase energy expenditure, leading to reduced body weight gain and improved insulin resistance. Altogether, FXR is a potent therapeutic target for the treatment of metabolic diseases.
참고문헌 (36)
- Russell DW, "The enzymes, regulation, and genetics of bile acid synthesis", Annu Rev Biochem, 72, pp.137~174 (2003)
- Tu H, "FXR, a bile acid receptor and biological sensor", Trends Cardiovasc Med, 10, pp.30~35 (2000)
- Makishima M, "Identification of a nuclear receptor for bile acids", Science, 284, pp.1362~1365 (1999)
- Forman BM, "Identification of a nuclear receptor that is activated by farnesol metabolites", Cell, 81, pp.687~693 (1995)
- Chiang JY, "Bile acid regulation of gene expression: roles of nuclear hormone receptors", Endocr Rev, 23, pp.443~463 (2002)
- Lee FY, "FXR, a multipurpose nuclear receptor", Trends Biochem Sci, 31, pp.572~580 (2006)
- Edwards PA, "BAREing it all: the adoption of LXR and FXR and their roles in lipid homeostasis", J Lipid Res, 43, pp.2~12 (2002)
- Liu J, "Potency of individual bile acids to regulate bile acid synthesis and transport genes in primary human hepatocyte cultures", Toxicol Sci, 141, pp.538~546 (2014)
- Modica S, "Deciphering the nuclear bile acid receptor FXR paradigm", Nucl Recept Signal, 8, pp.e005~ (2010)
- Fujita K, "Ursodeoxycholic acid suppresses lipogenesis in mouse liver: possible role of the decrease in beta-muricholic acid, a farnesoid X receptor antagonist", Lipids, 52, pp.335~344 (2017)
- Jones DE, "Obeticholic acid for the treatment of primary biliary cirrhosis", Expert Rev Gastroenterol Hepatol, 2, pp.1~9 (2016)
- Thomas H., "Therapy: obeticholic acid for PBC", Nat Rev Gastroenterol Hepatol, 13, pp.558~559 (2016)
- Li T, "Nuclear receptors in bile acid metabolism", Drug Metab Rev, 45, pp.145~155 (2013)
- Lee H, "FXR regulates organic solute transporters alpha and beta in the adrenal gland, kidney, and intestine", J Lipid Res, 47, pp.201~214 (2006)
- Li-Hawkins J, "Cholic acid mediates negative feedback regulation of bile acid synthesis in mice", J Clin Invest, 110, pp.1191~1200 (2002)
- Lu TT, "Molecular basis for feedback regulation of bile acid synthesis by nuclear receptors", Mol Cell, 6, pp.507~515 (2000)
- Wang L, "Redundant pathways for negative feedback regulation of bile acid production", Dev Cell, 2, pp.721~731 (2002)
- Kliewer SA, "Bile acids as hormones: the FXR-FGF15", 19 pathway, 2015, pp.33, 327~331
- Stroeve JH, "Intestinal FXR-mediated FGF15 production contributes to diurnal control of hepatic bile acid synthesis in mice", Lab Invest, 90, pp.1457~1467 (2010)
- Inagaki T, "Fibroblast growth factor 15functions as an enterohepatic signal to regulate bile acid homeostasis", Cell Metab, 2, pp.217~225 (2005)
- Song KH, "Bile acids activate fibroblast growth factor 19 signaling in human hepatocytes to inhibit cholesterol 7alpha-hydroxylase gene expression", Hepatology, 49, pp.297~305 (2009)
- Stayrook KR, "Regulation of carbohydrate metabolism by the farnesoid X receptor", Endocrinology, 146, pp.984~991 (2005)
- Ma K, "Farnesoid X receptor is essential for normal glucose homeostasis", J Clin Invest, 116, pp.1102~1109 (2006)
- Zhang Y, "Activation of the nuclear receptor FXR improves hyperglycemia and hyperlipidemia in diabetic mice", Proc Natl Acad Sci U S A, 103, pp.1006~1011 (2006)
- Zhang Y, "Identification of novel pathways that control farnesoid X receptor-mediated hypocholesterolemia", J Biol Chem, 285, pp.3035~3043 (2010)
- Sinal CJ, "Targeted disruption of the nuclear receptor FXR", BAR impairs bile acid and lipid homeostasis, 2000, pp.102, 731~744
- Inagaki T, "Regulation of antibacterial defense in the small intestine by the nuclear bile acid receptor", Proc Natl Acad Sci U S A, 103, pp.3920~3925 (2006)
- Zhou X, "PPARalpha-UGT axis activation represses intestinal FXR-FGF15 feedback signalling and exacerbates experimental colitis", Nat Commun, 5, pp.4573~ (2014)
- Modica S, "Nuclear bile acid receptor FXR protects against intestinal tumorigenesis", Cancer Res, 68, pp.9589~9594 (2008)
- Ryan KK, "FXR is a molecular target for the effects of vertical sleeve gastrectomy", Nature, 509, pp.183~188 (2014)
- Fang S, "Intestinal FXR agonism promotes adipose tissue browning and reduces obesity and insulin resistance", Nat Med, 21, pp.159~165 (2015)
- Li F, "Microbiome remodelling leads to inhibition of intestinal farnesoid X receptor signalling and decreased obesity", Nat Commun, 4, pp.2384~ (2013)
- Watanabe M, "Bile acids induce energy expenditure by promoting intracellular thyroid hormone activation", Nature, 439, pp.484~489 (2006)
- Gerhard GS, "A role for fibroblast growth factor 19 and bile acids in diabetes remission after Roux-en-Y gastric bypass", Diabetes Care, 36, pp.1859~1864 (2013)
- Kohli R, "Weight loss induced by Roux-en-Y gastric bypass but not laparoscopic adjustable gastric banding increases circulating bile acids", J Clin Endocrinol Metab, 98, pp.E708~E712 (2013)
- Liu Y, "Roux-en-Y gastric bypass-induced improvement of glucose tolerance and insulin resistance in type 2 diabetic rats are mediated by glucagon-like peptide-1", Obes Surg, 21, pp.1424~1431 (2011)