Bile acids enhance the activity of the insulin receptor and glycogen synthase in primary rodent hepatocytes

Han, Song Iy; Studer, Elaine; Gupta, Seema; Fang, Yan; Qiao, Li; Li, Weiqun; Grant, Steven; Hylemon, Philip B.; Dent, Paul

doi:10.1002/hep.20043

Cited by 60 publications

(49 citation statements)

References 47 publications

(53 reference statements)

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“…expression of many target genes relevant for lipid and glucose metabolism at the transcription level (29)(30)(31). Increasing evidence suggests that FXR may play an important role in liver detoxification, regeneration, and carcinogenesis (6,32,33).…”

Section: Discussionmentioning

confidence: 99%

Farnesoid X receptor (FXR) gene deficiency impairs urine concentration in mice

Zhang

Huang

Гао

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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The farnesoid X receptor (FXR) is a ligand-activated transcription factor belonging to the nuclear receptor superfamily. FXR is mainly expressed in liver and small intestine, where it plays an important role in bile acid, lipid, and glucose metabolism. The kidney also has a high FXR expression level, with its physiological function unknown. Here we demonstrate that FXR is ubiquitously distributed in renal tubules. FXR agonist treatment significantly lowered urine volume and increased urine osmolality, whereas FXR knockout mice exhibited an impaired urine concentrating ability, which led to a polyuria phenotype. We further found that treatment of C57BL/6 mice with chenodeoxycholic acid, an FXR endogenous ligand, significantly up-regulated renal aquaporin 2 (AQP2) expression, whereas FXR gene deficiency markedly reduced AQP2 expression levels in the kidney. In vitro studies showed that the AQP2 gene promoter contained a putative FXR response element site, which can be bound and activated by FXR, resulting in a significant increase of AQP2 transcription in cultured primary inner medullary collecting duct cells. In conclusion, the present study demonstrates that FXR plays a critical role in the regulation of urine volume, and its activation increases urinary concentrating capacity mainly via up-regulating its target gene AQP2 expression in the collecting ducts.water homeostasis | bile acid receptor T he farnesoid X receptor (FXR) is a member of the nuclear receptor superfamily, with the typical functional domains including the DNA binding domain and the ligand binding domain. Upon binding to its ligands, FXR forms a heterodimer with another nuclear receptor, retinoid X receptor, whereupon the receptor dimer binds to the FXR response element (FXRE) located in the promoter regions of FXR target genes, thereby regulating the transcription of these genes (1-3). The single FXR gene gives rise to two isoforms, designated as FXRα and FXRβ, as a result of alternative use of the promoters (4). In addition, each FXR isoform has two variants (FXRα1/FXRβ1 and FXRα2/ β2), depending on the presence or absence of an insert of four amino acids (MYTG) immediately adjacent to the DNA binding domain in the hinge domain (5). Because FXRβ constitutes a pseudogene in humans and primates, all recent studies focus on FXRα (6).FXR is highly expressed in the liver and intestine, where it functions as an intracellular sensor of bile acids and is required for the negative feedback regulation of bile acid biosynthesis and its enterohepatic cycle (7,8). Most recently FXR has been found to be involved in the regulation of adrenal and vascular function, as well as hepatic glucose and lipid metabolism, which suggests an important role for FXR in many tissues beyond the hepatointestinal system (9-12). Among most tissues tested, the kidney exhibits the highest expression levels (13). However, the role of FXR in the kidney remains largely unknown. It has been previously reported that FXR may negatively regulate sterol regulatory element-binding protei...

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Section: Discussionmentioning

confidence: 99%

Farnesoid X receptor (FXR) gene deficiency impairs urine concentration in mice

Zhang

Huang

Гао

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…Since bile acids have no known transmembrane receptors, transactivation of receptor tyrosine kinases by DCA may be responsible for reduced tyrosine phosphorylation and catalytic activity of FAK. In this regard, DCA has been implicated in ligandindependent activation of EGFR and insulin receptor but not IGF-1R in primary rat hepatocytes (26). Furthermore, bile acid transporters have not been identified in the colon, and labeled bile acids are not taken up by colon cancer cells in vitro (53).…”

Section: Discussionmentioning

confidence: 99%

Deoxycholic acid differentially regulates focal adhesion kinase phosphorylation: role of tyrosine phosphatase ShP2

Khare¹,

Holgren²,

Samarel³

2006

American Journal of Physiology-Gastrointestinal and Liver Physi

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Khare S, Holgren C, Samarel AM. Deoxycholic acid differentially regulates focal adhesion kinase phosphorylation: role of tyrosine phosphatase ShP2. Am J Physiol Gastrointest Liver Physiol 291: G1100 -G1112, 2006. First published August 17, 2006 doi:10.1152/ajpgi.00008.2006.-Environmental factors, including dietary fats, are implicated in colonic carcinogenesis. Dietary fats modulate secondary bile acids including deoxycholic acid (DCA) concentrations in the colon, which are thought to contribute to the nutritional-related component of colon cancer risk. Here we demonstrate, for the first time, that DCA differentially regulated the sitespecific phosphorylation of focal adhesion kinase (FAK). DCA decreased adhesion of HCA-7 cells to the substratum and induced dephosphorylation of FAK at tyrosine-576/577 (Tyr-576/577) and Tyr-925. Tyrosine phosphorylation of FAK at Tyr-397 remained unaffected by DCA stimulation. Interestingly, we found that c-Src was constitutively associated with FAK and DCA actually activated Src, despite no change in FAK-397 and an inhibition of FAK-576 phosphorylation. DCA concomitantly and significantly increased association of tyrosine phosphatase ShP2 with FAK. Incubation of immunoprecipitated FAK, in vitro, with glutathione-S-transferaseShP2 fusion protein resulted in tyrosine dephosphorylation of FAK in a concentration-dependent manner. Antisense oligodeoxynucleotides directed against ShP2 decreased ShP2 protein levels and attenuated DCA-induced FAK dephosphorylation. Inhibition of FAK by adenoviral-mediated overexpression of FAK-related nonkinase and gene silencing of Shp2 both abolished DCA's effect on cell adhesion, thus providing a possible mechanism for inside-out signaling by DCA in colon cancer cells. Our results suggest that DCA differentially regulates focal adhesion complexes and that tyrosine phosphatase ShP2 has a role in DCA signaling.

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“…In this case, the bile acid containing fl uorophores attached to the side chain. Fluorophores have a signifi cant impact, since the bound bile acids, aff ect on the transport of hepatocytes and enterocytes [4]. Pass through the cell membrane and aff ect on the biotransformation of hepatocytes during transport [5].…”

Section: Introductionmentioning

confidence: 99%

“…Mutation certain DR1 sequences drastically reduces the basal activity of CYP7A1 promoter and his answers to the inhibition of bile acid. Insulin regulates transcription factors Fox O1 is associated with insulin sequence in response to the CYP7A1 promoter in rats and contributions CYP7A1 transcription in rats [4,22].…”

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confidence: 99%