The Farnesoid X-receptor Is an Essential Regulator of Cholesterol Homeostasis

Lambert, Gilles; Amar, Marcelo; Guo, Grace L.; Brewer, H. Bryan; Gonzalez, Frank J.; Sinal, Christopher J.

doi:10.1074/jbc.m209525200

Cited by 339 publications

(281 citation statements)

References 54 publications

(57 reference statements)

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“…When HDL-cholesterol was paired up with either VLDL-cholesterol, triacylglycerols or BMI in the bivariate analysis, the peak was located at 12q23.2, where the marker PAH closest to the peak has been shown to be a putative QTL with a LOD of 2.13 for HDLcholesterol levels in the Mexican American population in the San Antonio Family Heart Study [36]. In this region, the NR1H4 gene, also known as the FXR gene, is a key regulator of cholesterol homeostasis, as shown in Fxr −/− knockout mice [37].…”

Section: Discussionmentioning

confidence: 93%

Bivariate genome-wide scan for metabolic phenotypes in non-diabetic Chinese individuals from the Stanford, Asia and Pacific Program of Hypertension and Insulin Resistance Family Study

Chiu¹,

Chuang

Kao³

et al. 2007

Diabetologia

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Aims/hypothesis Hypertension, obesity, impaired glucose tolerance and dyslipidaemia are metabolic abnormalities that often cluster together more often than expected by chance alone. Since these metabolic variables are highly heritable and are at least partially genetically determined, the clustering of defects in these traits implies that pleiotropic effects, where a common set of genes influences more than one trait simultaneously, are likely.Methods We conducted bivariate linkage analyses for highly correlated traits, aiming to dissect the genetic architecture affecting these traits, in 411 Chinese families participating in the Stanford Asia-Pacific Program of Hypertension and Insulin Resistance Study. Results We confirmed the pleiotropic effects of the locus at 37 cM on chromosome 20 on the following pairs: (1) fasting insulin and insulin AUC (empirical p=0.0006); (2) fasting insulin and homeostasis model assessment of

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Section: Discussionmentioning

confidence: 93%

Bivariate genome-wide scan for metabolic phenotypes in non-diabetic Chinese individuals from the Stanford, Asia and Pacific Program of Hypertension and Insulin Resistance Family Study

Chiu¹,

Chuang

Kao³

et al. 2007

Diabetologia

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“…FXR is highly expressed in the enterohepatic system where it acts as a bile acid sensor that protects the body from elevated bile acid concentrations. The role of FXR in coordinating the expression of genes involved in bile acid homeostasis has been firmly established by the use of natural and synthetic FXR agonists and FXR knockout mice (19,23,24). The bile acidsensing function of FXR is largely achieved through the regulation of genes involved in bile acid transport and biosynthesis (25).…”

Section: Discussionmentioning

confidence: 99%

Farnesoid X Receptor Regulates Bile Acid-Amino Acid Conjugation

Pircher

Kitto

Petrowski

et al. 2003

Journal of Biological Chemistry

164

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“…However, the story is not as simple as it seems. FXR knockout mice, in fact, display increased intestinal absorption of cholesterol, suggesting a negative regulatory role for FXR on cholesterol absorption in the intestine [104]. Also, FXR might act as an enhancer of reverse cholesterol transport, the process of cholesterol delivery from peripheral tissues to the liver for biliary disposal [104].…”

Section: Farnesoid X Receptor (Fxr) Lipid Metabolism and Chronic Livmentioning

confidence: 99%

“…FXR knockout mice, in fact, display increased intestinal absorption of cholesterol, suggesting a negative regulatory role for FXR on cholesterol absorption in the intestine [104]. Also, FXR might act as an enhancer of reverse cholesterol transport, the process of cholesterol delivery from peripheral tissues to the liver for biliary disposal [104]. Overall, the role of FXR agonism-antagonism in cholesterol disposal and HDL cholesterol plasma levels is still controversial, and contradictory data in the literature provide the impetus to address this critical issue in the next future.…”

Section: Farnesoid X Receptor (Fxr) Lipid Metabolism and Chronic Livmentioning

confidence: 99%

From the metabolic syndrome to NAFLD or vice versa?

Vanni

Bugianesi

Kotronen

et al. 2010

Digestive and Liver Disease

419

333

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The metabolic syndrome encompasses metabolic and cardiovascular risk factors which predict diabetes and cardiovascular disease (CVD) better than any of its individual components. Nonalcoholic fatty liver disease (NAFLD) comprises a disease spectrum which includes variable degrees of simple steatosis (nonalcoholic fatty liver, NAFL), nonalcoholic steatohepatitis (NASH) and cirrhosis. NAFLD is the hepatic manifestation of the metabolic syndrome, with insulin resistance as the main pathogenetic mechanism. Recent data indicate that hyperinsulinemia is probably the consequence rather than cause of NAFLD and NAFLD can be considered an independent predictor of cardiovascular disease. Serum free fatty acids derived from lipolysis of visceral adipose tissue are the main source of hepatic triglycerides in NAFLD, although hepatic de novo lipogenesis and dietary fat supply contribute to the pathogenesis of NAFLD. Approximately 10-25% NAFLD patients develop NASH, the evolutive form of hepatic steatosis. Presumably in a genetically predisposed environment, this increased lipid overload overwhelms the oxidative capacity and reactive oxygen species are generated, leading to lipid peroxidation, cytokine induction, chemoattraction of inflammatory cells, hepatic stellate cell activation and finally fibrogenesis with extracellular matrix deposition. No currently available therapies for NAFLD and NASH exist. Recently nuclear receptors have emerged as key regulators of lipid and carbohydrate metabolism for which specific pharmacological ligands are available, making them attractive therapeutic targets for NAFLD and NASH.Abbreviations ALT, alanine aminotransferase; BMI, body mass index; CVD, cardiovascular disease; FFA, free fatty acids; HDL, high density lipoprotein; 1H-MRS, proton magnetic resonance spectroscopy; IDF, International Diabetes Federation; LDL, low density lipoprotein; NAFLD, nonalcoholic fatty liver disease; SNP, single nucleotide polymorphism; VLDL, very low density lipoprotein IntroductionThe metabolic syndrome is a cluster of metabolic and cardiovascular risk factors which predicts diabetes and cardiovascular disease (CVD) better than any of its individual components [1]. The latest definition of the metabolic syndrome by International Diabetes Federation (IDF) includes abdominal obesity defined by increased waist circumference (≥94 cm in men and ≥80 cm in women) and two or more of the following features: elevated blood pressure, fasting glucose or triglyceride concentrations, or low HDL cholesterol [1]. The term nonalcoholic fatty liver disease (NAFLD) comprises a disease spectrum which includes variable degrees of simple steatosis (nonalcoholic fatty liver, NAFL), nonalcoholic steatohepatitis (NASH) and cirrhosis [2] and [3]. NAFLD can be considered the hepatic manifestation of the metabolic syndrome. Simple steatosis is benign, whereas NASH is defined by the presence of hepatocyte injury, inflammation and/or fibrosis which can lead to cirrhosis, liver failure and hepatocellular carcinoma. In contrast to t...

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The Farnesoid X-receptor Is an Essential Regulator of Cholesterol Homeostasis

Cited by 339 publications

References 54 publications

Bivariate genome-wide scan for metabolic phenotypes in non-diabetic Chinese individuals from the Stanford, Asia and Pacific Program of Hypertension and Insulin Resistance Family Study

Bivariate genome-wide scan for metabolic phenotypes in non-diabetic Chinese individuals from the Stanford, Asia and Pacific Program of Hypertension and Insulin Resistance Family Study

Farnesoid X Receptor Regulates Bile Acid-Amino Acid Conjugation

From the metabolic syndrome to NAFLD or vice versa?

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