Bile acid feeding increased proliferative activity and apical bile acid transporter expression in both small and large rat cholangiocytes

Abstract

Bile acids (BA) enter cholangiocytes by the Na(+)-dependent apical BA transporter (ABAT). By this mechanism, taurocholate (TC) and taurolithocholate (TLC) increase cholangiocyte proliferation. No in vivo studies exist regarding the anatomical sites involved in BA-regulation of cholangiocyte growth. Specific cholangiocyte subpopulations participate in BA-regulated proliferation. Proliferation was assessed in liver sections by determining the number of proliferating cellular nuclear antigen (PCNA)-positive cholangiocytes and cytokeratin-19 (CK-19)-positive ducts. We isolated small and large cholangiocytes from rats fed for 1 week TC, TLC, or BA control diet and determined PCNA and ABAT expression and BA transport activity. We evaluated if TC and TLC induction of ABAT expression was dependent on activation of PKC alpha. DNA replication was active only in large normal cholangiocytes. TC and TLC feeding increased proliferation of large cholangiocytes, induced the de novo activation of proliferation of small cholangiocytes, overexpression of ABAT and BA transport activity in large cholangiocytes, and de novo expression of ABAT and BA transport activity in small cholangiocytes. BA-stimulated ABAT expression was dependent on PKC activation in cholangiocytes. TC and TLC stimulate proliferation of small and large cholangiocytes associated with PKC-dependent up-regulation of ABAT.