Hepatobiliary transporter expression in percutaneous liver biopsies of patients with cholestatic liver diseases

Abstract

Reduced hepatobiliary transporter expression could explain impaired hepatic uptake and excretion of bile salts and other biliary constituents resulting in cholestasis and jaundice. Because little is known about alterations of hepatobiliary transport systems in human cholestatic liver diseases, it was the aim of this study to investigate such potential changes. Hepatic mRNA levels in hepatobiliary transport systems for bile salts (NTCP, BSEP), organic anions (OATP2, MRP2, MRP3), organic cations (MDR1), phospholipids (MDR3), and aminophospholipids (FIC1) were determined in 37 human liver biopsies and control livers by competitive reverse-transcription polymerase chain reaction (RT-PCR). Transporter tissue distribution was investigated by immunofluorescence microscopy. In patients with inflammation-induced icteric cholestasis (mainly cholestatic alcoholic hepatitis), mRNA levels of NTCP, OATP2, and BSEP were reduced by 41% (P < .001), 49% (P < .005), and 34% (P < .05) compared with controls, respectively. In addition, NTCP and BSEP immunostaining was reduced. MRP2 mRNA levels remained unchanged, but canalicular immunolabeling for MRP2 was also decreased.

Expression of organic cation transporters OCT1 (SLC22A1) and OCT3 (SLC22A3) is affected by genetic factors and cholestasis in human liver

“…Whereas OCT1 and OCT3 expression has not yet been studied in cholestatic human liver, other hepatocellular uptake transporters such as Na ϩ /taurocholate cotransporter and organic anion transporter OATP1B1 are clearly down-regulated in patients with cholestatic liver disease. 46,47 Interestingly, obstructive and ethinylestradiol-induced cholestasis in rats significantly reduced hepatic Oct1 mRNA and protein levels, [48][49][50] which fits well with our data in humans. Further studies are warranted to elucidate, for instance, whether drug response to the OCT1 and OCT3 substrate metformin is altered in diabetic patients with cholestasis.…”

The apical conjugate efflux pump ABCC2 (MRP2)

“…Under these conditions, immunostaining of Abcc2 is no longer confined to the canalicular membrane, but appears "fuzzy," which is interpreted as an accumulation of transporter molecules within the hepatocyte. A comparable fuzzy immunostaining, indicative of endocytic retrieval of transporter molecules, has been described in human liver diseases, e.g., inflammation-induced icteric cholestasis [189], obstructive cholestasis [153,186], and advanced stages of primary biliary cirrhosis [88,101].…”

The emerging role of transport systems in liver function tests

“…For instance, progressive familial intrahepatic cholestasis leads to downregulation of NTCP, OATP1B1, OATP1B3, and MRP2, while MRP4 is upregulated (Keitel et al, 2005). Patients with inflammatory cholestasis, primary biliary cirrhosis or chronic hepatitis C show a reduction of protein expression for NTCP and OATP1B1 (Zollner et al, 2003;Zollner et al, 2001), while expression of MRP3, MRP2, MDR1, and MDR3 is upregulated and BSEP is not affected (Zollner et al, 2003). Hence, clearance prediction of liver function indicators is difficult in disease situations.…”