NAFLD patients exhibit dysregulation of bile acid transport in association with apoptosis and liver fibrosis

Kocabayoglu, Peri; Bechmann, LP; Schmitt, Johannes; Kahraman, Alişan; Sowa, Jan; Wedemeyer, Inga; Treckmann, Juergen; Kılıçarslan, Alpaslan; Odenthal, M; Rust, Christian; Gerken, G; Geier, Andreas; Canbay, A

doi:10.1055/s-0030-1263847

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“…A moderate decrease in Ntcp and Bsep protein expression is in accordance with previous observations in fa/fa rats (Pizarro et al, 2004;Geier et al, 2005b). Dysregulation of NTCP is even more prominent in humans where higher mRNA expression levels have been linked to disease progression in human NAFLD (Kocabayoglu et al, 2009). Of note, Cheng and coworkers observed in ob/ob mice a decreased Ntcp (mRNA and protein) and Bsep (mRNA) expression and an even induced Mrp2 protein (mRNA unchanged compared with lean controls) (Cheng et al, 2008) which do not parallel other findings in humans (Martin et al, 2009), rats (Pizarro et al, 2004;Geier et al, 2005b) and mice with fatty livers.…”

Section: Discussionsupporting

confidence: 91%

“…This retention of bile acids is well in accordance to preliminary data from human patients with fatty liver disease which are also characterized by an increase in serum bile acid concentrations (Aranha et al, 2008;Kocabayoglu et al, 2009). Cholestasis in mice with fatty livers is accompanied by a downregulation of canalicular bile acid transporter Bsep and Mrp2 proteins as the rate-limiting step in bile acid secretion.…”

Section: Discussionsupporting

confidence: 88%

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Bile acid retention and activation of endogenous hepatic farnesoid-X-receptor in the pathogenesis of fatty liver disease in ob/ob-mice

Martin¹,

Schmitt²,

Minkenberg

et al. 2010

Biological Chemistry

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The nuclear bile acid receptor FXR (farnesoid-X-receptor) has recently been implicated in the pathophysiology of nonalcoholic fatty liver disease because selective FXR-agonists improve glucose and lipid metabolism in rodent models of obesity. However, the regulation of FXR and other relevant nuclear receptors as well as their lipogenic target genes in fatty liver is still not revealed in detail. Livers were harvested from 14-week-old male ob/ob mice and wild-type controls. Serum bile acids were quantified by radioimmunoassay. mRNA and protein expression of transporters and nuclear receptors was analyzed by reverse transcriptase-polymerase chain reaction and Western blotting, whereas DNA binding to the IR-1 element was examined by electrophoretic mobility shift assay. In this study we show: (i) bile acid retention in ob/ob mice, (ii) a resulting FXR upregulation and binding to the IR-1 element in ob/ob animals and (iii) concomitant activation of the fatty acid synthase as a potential lipogenic FXR target gene in vivo. The present study suggests a potential role of hepatic bile acid retention and FXR activation in the induction of lipogenic target genes. Differences between intestinal and hepatic FXR could explain apparent contradictory information regarding its effects on fatty liver disease.

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