Immunolocalization of farnesoid X receptor (FXR) in mouse tissues using tissue microarray

Higashiyama, Hiroyuki; Kinoshita, Mine; Asano, Shigetaka

doi:10.1016/j.acthis.2007.08.001

Cited by 62 publications

(33 citation statements)

References 17 publications

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“…These findings indicate a role for FXR in control of hepatic glucose metabolism, particularly during the fasting-feeding transition (12). Recent reports showed the presence of FXR in the absorptive epithelium of the small intestine (15). The results of the current study clearly show that Fxr Ϫ/Ϫ mice have delayed intestinal glucose absorption caused by an enhanced G6P turnover in the proximal enterocytes.…”

Section: Discussionsupporting

confidence: 68%

“…The presence of FXR in tissues that are normally not exposed to bile acids, e.g. adipose tissue, adrenal glands, and skin (15), suggests the existence of alternative endogenous FXR ligands.…”

Section: Discussionmentioning

confidence: 99%

“…The catalytic subunit of glucose-6-phosphatase (G6PC) dephosphorylates G6P and makes glucose available for transport across the basolateral membrane into the portal vein (13,14). Recent studies revealing the localization of the FXR protein in the absorptive epithelium of the small intestine (15) lead us to determine the physiological impact of intestinal FXR on glucose homeostasis and intestinal glucose absorption. For this, oral D-[U- 13 C]glucose tolerance tests (OGTT) were performed, and the absorption of glucose from the intestine was calculated in this non-steady-state situation.…”

mentioning

confidence: 99%

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An Increased Flux through the Glucose 6-Phosphate Pool in Enterocytes Delays Glucose Absorption in Fxr–/– Mice

Dijk¹,

Grefhorst

Oosterveer

et al. 2009

Journal of Biological Chemistry

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The farnesoid X receptor (FXR) is involved in regulation of bile acid and lipid metabolism. Recently, a role for FXR in control of glucose metabolism became evident. Because FXR is expressed along the length of the small intestine, we evaluated the potential role of FXR in glucose absorption and processing. During intravenous infusion of a trace amount of D-[6,6-2 H 2 ]glucose, a D-[U-13 C]glucose-enriched oral glucose bolus was given, and glucose kinetics were determined in wild-type and Fxr ؊/؊ mice. Compared with wild-type mice, Fxr ؊/؊ mice showed a delayed plasma appearance of orally administered glucose. Multicompartmental kinetic modeling revealed that this delay was caused by an increased flux through the glucose 6-phosphate pool in enterocytes. Thus, our results show involvement of FXR in intestinal glucose absorption, representing a novel physiological function for this nuclear receptor.The bile acid-activated farnesoid X receptor (FXR; NR1H4) 3 is a member of the nuclear receptor superfamily that is expressed in liver, adrenals, kidney, small intestine, and colon (1). Through FXR activation in the liver, bile acids induce transcription of the atypical nuclear receptor short heterodimer partner (NR0B2), which, in turn, represses transcription of the Cyp7a1 gene, encoding the rate-controlling enzyme in bile acid synthesis (2). FXR also suppresses transcription of the gene encoding the hepatobiliary bile acid uptake transporter NTCP (Na ϩ -taurocholate cotransporting polypeptide; Slc10a1) and induces transcription of genes encoding canalicular bile acid transporters such as the bile salt export pump (ABCB11) and multidrug resistance protein-2 (ABCC2) (see reviews in Refs. 1 and 3). In the intestine of mice, FXR stimulates transcription of the gene encoding the fibroblast growth factor 15 (4). Fibroblast growth factor 15 reduces hepatic bile acid synthesis by repressing Cyp7a1 transcription in the liver. Apart from its clearly established effects on bile acid synthesis and transport, FXR is involved in the control of lipid and lipoprotein homeostasis. Fxr Ϫ/Ϫ mice have elevated plasma triglyceride and cholesterol levels (5), and FXR activation decreases plasma triglyceride levels in mice (6). FXR negatively controls apoA-I (7) as well as apoCIII expression (6), which contributes to FXR-mediated control of plasma lipid levels.Recently, a link between FXR and glucose homeostasis has become evident. It was shown that glucose induces hepatic Fxr expression in rodent liver, probably via intermediates of the pentose-phosphate pathway (8). Recent publications indicate that FXR plays a role in the regulation of the transcription of various hepatic carbohydrate metabolism-related genes. Activated FXR represses the transcription of gluconeogenic genes, e.g. those encoding phosphenolpyruvate carboxykinase, fructose-1,6-biphosphatase-1, and glucose-6-phosphatase (G6PC) in vitro (9). In vivo experiments showed that Fxr Ϫ/Ϫ mice have a reduced peripheral insulin sensitivity (10, 11) and a reduced hepatic glucose produc...

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Section: Discussionsupporting

confidence: 68%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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An Increased Flux through the Glucose 6-Phosphate Pool in Enterocytes Delays Glucose Absorption in Fxr–/– Mice

Dijk¹,

Grefhorst

Oosterveer

et al. 2009

Journal of Biological Chemistry

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“…These reports highlight the importance of peripheral tissue FXR in the progress of dyslipidemia, and thus tissue-specific Fxr disruption might be more informative than whole-body knockouts in determining the role of agonism and antagonism of FXR in diet-induced metabolic diseases such as NAFLD. At the tissue level, FXR is predominantly expressed in the liver and intestine, but also in other tissues such as stomach, kidney, adrenal gland, tongue, and eye (54,55). A reporter mouse study further revealed constitutive FXR signaling in situ only in the terminal ileum of chow-fed mice in the absence of an exogenous FXR agonist (54), which likely reflects the presence of endogenous activators or inhibitors of FXR that may be influenced by microbiota metabolism of bile acids.…”

Section: Discussionmentioning

confidence: 99%

Intestinal farnesoid X receptor signaling promotes nonalcoholic fatty liver disease

Jiang¹,

Xie²,

Li³

et al. 2014

J. Clin. Invest.

558

513

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. measured for 8 days. The feces were collected every 2 days for 8 days. Ileal and fecal lipids were extracted as described in the Supplemental Methods. Triglycerides were measured with a triglyceride colorimetric assay kit (Bioassay Systems). Free fatty acids (FFAs) were measured using reagents from Wako.Statistics. Experimental values are presented as the mean ± SD. Statistical analyses were performed using the 2-tailed Student's t test and 1-way ANOVA with Tukey's confirmation. Weighted UniFrac analysis to assess changes in bacterial abundance was performed on the Galaxy web-based platform. Statistical models including PCA, PLS-DA, and OPLS-DA were established to represent the major latent variables in the data matrix. P values of less than 0.05 were considered significant. Study approval. All animal studies were performed in accordance with the Institute of Laboratory Animal Resources guidelines and approved by the IACUC of the NCI.

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“…71,119 Relatively high FXR expression levels have been detected in the adrenal cortex, as well as the renal tubules of the kidney. 120 Little is known about the function of FXR in these tissues. The organic solute transporters ␣ and ␤ (OST␣ and OST␤) are direct FXR target genes in both the adrenal gland and the kidney.…”

Section: Fxr Elsewherementioning

confidence: 99%

A Role of the Bile Salt Receptor FXR in Atherosclerosis

Hageman

Herrema

Groen

et al. 2010

ATVB

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Abstract-This study reviews current insights into the role of bile salts and bile salt receptors on the progression and regression of atherosclerosis. Bile salts have emerged as important modifiers of lipid and energy metabolism. At the molecular level, bile salts regulate lipid and energy homeostasis mainly via the bile salt receptors FXR and TGR5. Activation of FXR has been shown to improve plasma lipid profiles, whereas Fxr Ϫ/Ϫ mice have increased plasma triglyceride and very-low-density lipoprotein levels. Nevertheless, high-density lipoprotein cholesterol levels are increased in these mice, suggesting that FXR has both anti-and proatherosclerotic properties. Interestingly, there is increasing evidence for a role of FXR in "nonclassical" bile salt target tissues, eg, vasculature and macrophages. In these tissues, FXR has been shown to influence vascular tension and regulate the unloading of cholesterol from foam cells, respectively. Recent publications have provided insight into the antiinflammatory properties of FXR in atherosclerosis. Bile salt signaling via TGR5 might regulate energy homeostasis, which could serve as an attractive target to increase energy expenditure and weight loss. Interventions aiming to increase cholesterol turnover (eg, by bile salt sequestration) significantly improve plasma lipid profiles and diminish atherosclerosis in animal models. Bile salt metabolism and bile salt signaling pathways represent attractive therapeutic targets for the treatment of atherosclerosis.

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Immunolocalization of farnesoid X receptor (FXR) in mouse tissues using tissue microarray

Cited by 62 publications

References 17 publications

An Increased Flux through the Glucose 6-Phosphate Pool in Enterocytes Delays Glucose Absorption in Fxr–/– Mice

An Increased Flux through the Glucose 6-Phosphate Pool in Enterocytes Delays Glucose Absorption in Fxr–/– Mice

Intestinal farnesoid X receptor signaling promotes nonalcoholic fatty liver disease

A Role of the Bile Salt Receptor FXR in Atherosclerosis

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