Farnesoid X receptor agonists suppress hepatic apolipoprotein CIII expression

Claudel, Thierry; Inoue, Yusuke; Barbier, Olivier; Durán-Sandoval, Daniel; Kosykh, V. P.; Fruchart, J. C.; Fruchart, Jean‐Charles; Gonzalez, Frank J.; Staels, Bart

doi:10.1016/s0016-5085(03)00896-5

Cited by 231 publications

(152 citation statements)

References 68 publications

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“…FXR is highly expressed in liver, kidney, intestine, colon, and adrenal glands. Similar to PPARs, FXR binds DNA as an obligate heterodimer with the retinoid X receptor (RXR) (10,11). The regulation of FXR in the kidney, however, has not been determined.…”

Section: Discussionmentioning

confidence: 99%

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Regulation of Renal Fatty Acid and Cholesterol Metabolism, Inflammation, and Fibrosis in Akita and OVE26 Mice With Type 1 Diabetes

et al. 2006

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In Akita and OVE26 mice, two genetic models of type 1 diabetes, diabetic nephropathy is characterized by mesangial expansion and loss of podocytes, resulting in glomerulosclerosis and proteinuria, and is associated with increased expression of profibrotic growth factors, proinflammatory cytokines, and increased oxidative stress. We have also found significant increases in renal triglyceride and cholesterol content. The increase in renal triglyceride content is associated with 1) increased expression of sterol regulatory element-binding protein (

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Section: Discussionmentioning

confidence: 99%

“…In addition, another nuclear receptor, the farnesoid X receptor (FXR), has also been shown to have an important role in the regulation of fatty acid metabolism in the liver by inhibiting SREBP-1 and ChREBP, while inducing peroxisome proliferator-activated receptor-␣ (PPAR-␣) (10,11). However, the regulation of FXR in the kidney has not been determined.…”

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Regulation of Renal Fatty Acid and Cholesterol Metabolism, Inflammation, and Fibrosis in Akita and OVE26 Mice With Type 1 Diabetes

et al. 2006

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“…High levels of plasma apoC-III in apoC-III transgenic mice cause hypertriglyceridemia [6], whereas the absence of apoC-III leads to the reduced plasma triglyceride levels, and resistance to diet-induced obesity [7,8]. It has been reported that apoC-III gene expression in the liver is regulated by various factors and drugs including insulin, bile acids, retinoids, statins and fibrates [9][10][11][12][13]. However, little is known about apoC-III expression in adipose tissue.…”

Section: Introductionmentioning

confidence: 99%

ApoC‐III gene expression is sharply increased during adipogenesis and is augmented by retinoid X receptor (RXR) agonists

et al. 2008

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a b s t r a c tApoC-III, a lipoprotein lipase inhibitor and a key regulator of the metabolism of triglyceride-rich lipoproteins, is mainly synthesized in liver and intestine, but little is known about its expression in adipocytes. We here show that apoC-III mRNA levels are dramatically induced during adipocyte differentiation. Among many transcriptional factors involved in adipocyte differentiation, RXRa, acting alone and not as a heterodimer partner of other nuclear receptors, solely regulates apoC-III gene expression. These results suggest that apoC-III may play a specific role in lipid storage and mobilization in adipocytes, non-lipoprotein-secreting cells, and indicate the functional role of RXRa during adipocyte differentiation.

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“…Importantly, through evaluation of FXR null mice, FXR has been shown to be involved in the regulation of lipid metabolism, as FXR-null mice display a proatherogenic lipid profile characterized by elevated cholesterol and triglyceride levels (16). Indeed, a number of genes regulating lipid metabolism, such as sterol response element binding protein, lipoprotein lipase, apolipoproteins E, AI, CII, and CIII, and scavenger receptor class B type I, are regulated by FXR (17)(18)(19)(20)(21). Furthermore, a growing body of evidence supports a role for FXR in carbohydrate metabolism (22)(23)(24)(25).…”

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Farnesoid X Receptor Agonist Reduces Serum Asymmetric Dimethylarginine Levels through Hepatic Dimethylarginine Dimethylaminohydrolase-1 Gene Regulation

Chouinard

Cox

et al. 2006

Journal of Biological Chemistry

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The farnesoid X receptor (FXR, NR1H4) is a bile acid-responsive nuclear receptor that plays critical roles in the transcriptional regulation genes involved in cholesterol, bile acid, triglyceride, and carbohydrate metabolism. By microarray analysis of hepatic genes from female Zucker diabetic fatty (ZDF) rats treated with the FXR agonist GW4064, we have identified dimethylarginine dimethylaminohydrolase-1 (DDAH1) as an FXR target gene. DDAH1 is a key catabolic enzyme of asymmetric dimethylarginine (ADMA), a major endogenous nitric-oxide synthase inhibitor. Sequence analysis of the DDAH1 gene reveals the presence of an FXR response element (FXRE) located 90 kb downstream of the transcription initiation site and within the first intron. Functional analysis of the putative FXRE demonstrated GW4064 dose-dependent transcriptional activation from the element, and we have demonstrated that the FXRE sequence binds the FXR-RXR heterodimer. In vivo administration of GW4064 to female ZDF rats promoted a dose-dependent and >6-fold increase in hepatic DDAH1 gene expression. The level of serum ADMA was reduced concomitantly. These findings provide a mechanism by which FXR may increase endothelium-derived nitric oxide levels through modulation of serum ADMA levels via direct regulation of hepatic DDAH1 gene expression. Thus, beneficial clinical outcomes of FXR agonist therapy may include prevention of atherosclerosis and improvement of the metabolic syndrome.The global epidemic of obesity has led to an increasing prevalence of metabolic syndrome, a wide spectrum of metabolic risk factors characterized by abdominal obesity, low levels of high density lipoprotein cholesterol, high triglycerides, hypertension, glucose intolerance, and a systemic proinflammatory state. These risk factors are closely associated with incidence of cardiovascular disease, a leading cause of mortality in industrialized nations (1, 2). In the last decade, several ligand-activated nuclear receptors, such as peroxisome proliferator-activated receptors, liver X receptors, and thyroid hormone receptors, have emerged as promising targets for pharmacological intervention in the treatment of metabolic syndrome (3).Nuclear receptors are transcription factors that serve as intracellular sensors for endocrine hormones and lipid metabolites, such as bile acids, fatty acids, oxysterols, and xenobiotics. To control a variety of physiological processes, receptors bind to specific cis-acting DNA elements and regulate the expression of target genes by cofactor recruitment upon activation by ligands (4). Based on their pharmacological and ligand-binding properties, the nuclear receptor superfamily can be divided into three groups (5). The first group consists of classical steroid hormone receptors that are activated by high affinity ligands. The second group comprises low affinity receptors for metabolic intermediates. The third group corresponds to orphan receptors that have no known ligands.The farnesoid X receptor (FXR, 2 NR1H4) belongs to the second group of the nuc...

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Farnesoid X receptor agonists suppress hepatic apolipoprotein CIII expression

Cited by 231 publications

References 68 publications

Regulation of Renal Fatty Acid and Cholesterol Metabolism, Inflammation, and Fibrosis in Akita and OVE26 Mice With Type 1 Diabetes

Regulation of Renal Fatty Acid and Cholesterol Metabolism, Inflammation, and Fibrosis in Akita and OVE26 Mice With Type 1 Diabetes

ApoC‐III gene expression is sharply increased during adipogenesis and is augmented by retinoid X receptor (RXR) agonists

Farnesoid X Receptor Agonist Reduces Serum Asymmetric Dimethylarginine Levels through Hepatic Dimethylarginine Dimethylaminohydrolase-1 Gene Regulation

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