Bile acid-activated nuclear receptor FXR suppresses apolipoprotein A-I transcription via a negative FXR response element

Claudel, Thierry; Sturm, Ekkehard; Duez, Hélène; Pineda-Torra, Inés; Sirvent, Audrey; Kosykh, V. P.; Fruchart, Jean‐Charles; Dallongeville, Jean; Hum, Dean W.; Kuipers, Folkert; Staels, Bart

doi:10.1172/jci0214505

Cited by 281 publications

(180 citation statements)

References 64 publications

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“…Yet, despite a considerable rescue of TICE activity in these mice there was very little effect on plasma cholesterol. It is therefore most conceivable that reduction of plasma cholesterol upon PX treatment in mice that do express hepatic FXR is due to suppressed transcription of apolipoprotein A-I 36 and enhanced expression of scavenger receptor class B-I (SCARB1/SR-BI) upon FXR activation, as reported previously by others. 37 In keeping with this hypothesis, we found upregulation of hepatic SR-BI mRNA as well as protein (data not shown).…”

Section: Discussionsupporting

confidence: 54%

Intestinal Farnesoid X Receptor Controls Transintestinal Cholesterol Excretion in Mice

et al. 2017

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Section: Discussionsupporting

confidence: 54%

Intestinal Farnesoid X Receptor Controls Transintestinal Cholesterol Excretion in Mice

et al. 2017

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“…It has been found that dietary cholic acid decreases plasma HDL via downregulation of APO-AI levels [34][35][36] and greatly enhances intestinal cholesterol absorption, mainly by increasing intraluminal micellar cholesterol solubilization. 37 Our current results show that under the high cholesterol plus cholic acid feeding conditions, biliary cholesterol secretion is significantly increased in wildtype and Apob 48/48 mice, which is consistent with previous studies.…”

Section: Discussionmentioning

confidence: 99%

Reduced Susceptibility to Cholesterol Gallstone Formation in Mice That Do Not Produce Apolipoprotein B48 in the Intestine *

Wang

2005

Hepatology

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It has been found that polymorphisms in the apolipoprotein (APO)-B gene are associated with cholesterol gallstones in humans. We hypothesized that APO-B plays a major regulatory role in the response of biliary cholesterol secretion to high dietary cholesterol and contributes to cholesterol gallstone formation. In the present study, we investigated whether lack of expression of intestinal Apob48 or Apob100 reduces susceptibility to cholesterol gallstones by decreasing intestinal absorption and biliary secretion of cholesterol in male mice homozygous for an "APO-B48 only" allele (Apob 48/48 ), an "APO-B100 only" allele (Apob 100/100 ), or a wild-type APO-B allele (Apob ؉/؉ ) before and during an 8-week lithogenic diet. We found that cholesterol absorption was significantly decreased as a result of the APO-B48 deficiency in Apob 100/100 mice compared with wild-type and Apob 48/48 mice, regardless of whether chow or the lithogenic diet was administered. Consequently, hepatic cholesterol synthesis was significantly increased in Apob 100/ 100 mice compared with wild-type and Apob 48/48 mice. On chow, the APO-B100 deficiency in S tudies in humans and inbred mice have demonstrated that a complex genetic basis determines the individual and strain predisposition to develop cholesterol gallstones in response to environmental factors. 1 The primary pathophysiological defect involved in cholesterol gallstone formation is increased biliary secretion of cholesterol from the liver, which produces bile supersaturated with cholesterol. 2 Subsequently, biliary cholesterol precipitates as "anhydrous" and monohydrate crystals, which grow and agglomerate toward the formation of macroscopic stones in the gallbladder. Biliary cholesterol is mostly derived from circulating lipoproteins, which originate from the hepatic uptake of plasma high-density lipoprotein (HDL) and chylomicron remnants. [3][4][5][6][7][8] Thus, the potential interrelationship between lipoprotein metabolism-related genes and cholesterol gallstones requires further investigation. In particular, it has been found that polymorphisms in the apolipoprotein (APO)-B gene are associated with cholesterol gallstones in humans. 9-12 Therefore, we hypothesized that APO-B plays a major regulatory role in the response of biliary cholesterol secretion to high dietary cholesterol and contributes to the formation of cholesterol gallstones. APO-B has two different isoforms, APO-B48 and APO-B100, and plays a particularly critical role in the Abbreviations: APO, apolipoprotein; HDL, VLDL, LDL, mRNA, messenger RNA.

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“…Ligand-activated FXR binds to response elements of target genes either as a classical FXRRXRa (retinoid X receptor alpha) heterodimer or as a monomer (2)(3)(4). FXR plays an important role in regulating the metabolisms of bile acid, cholesterol, triglyceride, and glucose (5).…”

Section: Introductionmentioning

confidence: 99%

Downregulation of Human Farnesoid X Receptor by miR-421 Promotes Proliferation and Migration of Hepatocellular Carcinoma Cells

Zhang

Gong

Dai

et al. 2012

Molecular Cancer Research

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The farnesoid X receptor (FXR) is a member of the nuclear receptor superfamily that is highly expressed in liver, kidney, adrenal gland, and intestine. It plays an important role in regulating the progression of several cancers including hepatocellular carcinoma (HCC). So it is necessary to study the regulation of FXR. In this study, we found that the expression of miR-421 was inversely correlated with FXR protein level in HCC cell lines. Treatment with miR-421 mimic repressed FXR translation. The reporter assay revealed that miR-421 targeted 3 0 untranslated region of human FXR mRNA. Furthermore, downregulation of FXR by miR-421 promoted the proliferation, migration, and invasion of HCC cells. These results suggest that miR-421 may serve as a novel molecular target for manipulating FXR expression in hepatocyte and for the treatment of HCC. Mol Cancer Res; 10(4); 516-22. Ó2012 AACR. IntroductionThe farnesoid X receptor (FXR) is a ligand-activated transcription factor and a member of the nuclear receptor superfamily that is mainly expressed in liver, intestine, kidney, and adrenal gland (1). Ligand-activated FXR binds to response elements of target genes either as a classical FXRRXRa (retinoid X receptor alpha) heterodimer or as a monomer (2-4). FXR plays an important role in regulating the metabolisms of bile acid, cholesterol, triglyceride, and glucose (5). Recent studies show that FXR is also involved in the regulation of liver regeneration and protection against the liver carcinogenesis (6). Therefore, FXR has received increasing attention as a therapeutic target for the treatments of certain metabolic diseases and liver carcinoma.As a multiple functional transcriptional factor, FXR regulates so many target genes, but its own regulation is not well known. It has been reported that several transcriptional coregulators, including PGC-1a, Brg-1, p300, CARM1, PRMT1, and ASCOM, can potentially modulate FXR expression (7). Moreover, glucose and insulin (8) as well as the cytokines tumor necrosis factor-a and interleukin-1 (9) have also been identified to regulate FXR level. Recently, posttranslational modifications, such as phosphorylation,

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Bile acid-activated nuclear receptor FXR suppresses apolipoprotein A-I transcription via a negative FXR response element

Cited by 281 publications

References 64 publications

Intestinal Farnesoid X Receptor Controls Transintestinal Cholesterol Excretion in Mice

Intestinal Farnesoid X Receptor Controls Transintestinal Cholesterol Excretion in Mice

Reduced Susceptibility to Cholesterol Gallstone Formation in Mice That Do Not Produce Apolipoprotein B48 in the Intestine *

Downregulation of Human Farnesoid X Receptor by miR-421 Promotes Proliferation and Migration of Hepatocellular Carcinoma Cells

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