Fasting-induced upregulation of basolateral hepatic bile salt transporters in rats is mediated by the PGC–1alpha / HNF–4alpha pathway

Background & Aim: Fasting leads to extensive adaptive responses in the enterohepatic circulation of bile acids in rats including increased basolateral taurocholate-uptake in the presence of decreased intestinal absorption (Dumaswala AJP 1994). Since transport proteins may be involved in this regulatory process we studied expression and regulation of hepatic bile salt transporters. Methods: Rats (n=4) were fed with standard chow or starved for 48 hours. After RNA extraction, transporter expression of sodium dependent taurocholate cotransporting peptide (ntcp), organic anion transporting peptides (oatp) 1, 2 and 4, multidrug-resistance protein 2 (mrp2) and bile salt export pump (bsep) was assessed by Northern blotting. mRNA expression of PPARγ coactivator–1α (PGC–1α) and hepatocyte nuclear factor (HNF)–4α was quantified by RT-PCR. Results: mRNA of basolateral transporter was significantly upregulated in a coordinated fashion (Ntcp 155±10%, Oatp1 181±8%, Oatp2 316±18% and Oatp4 170±11% of fed controls, respectively, P<0.05). Canalicular transporters were differentially regulated (Bsep 165±24%, P<0.05; Mrp2 104±11%, P=n.s.). Changes in transporter expression appeared to be specific since Gapdh mRNA expression was unchanged. In response to fasting, expression of PGC–1α and HNF–4α was upregulated to 360±226% and 215±64%, respectively (P<0.05). Conclusions: Increased basolateral bile acid uptake during fasting is mediated by upregulated transporters of the SLC-family in the liver. This upregulation occurs as a result of PGC–1α-mediated activation of HNF–4α, which represents a common regulator of all basolateral transport systems. This pathway is not only involved in gluconeogenesis but obviously represents a common signalling cascade involved in a more global fasting response.