Crosstalk Between Nuclear Receptor and Cytokine-activated Pathways in the Regulation of Ntcp Gene Expression

摘要

Over the past few years it has become increasingly recognized that nuclear receptor-regulated pathways play important roles in a wide variety of key hepatic functions including: intermediary metabolism, cholesterol metabolism, bile acid (BA) and organic anion transport and the adaptive response to cholestasis1. These Jigand-activated transcriptional regulators are composed of several key domains, which mediate their abilities to respond to their environment and alter target gene expression. In brief, the main domains are transcriptional activation, DNA binding, ligand binding, heterodimerization, and co-regulator recruitment2'3. Recent identification of the ligands that regulate nuclear receptor activity includes many substances that are natively present in hepatocytes, or those that the hepatocyte are exposed to. These include cholesterol derivatives, BA, fatty acids, and prostaglandins, as well as a variety of drugs, toxins, and xenobiotics. Thus, nuclear receptors are poised to participate in the hepatic response to metabolic and environmental needs and challenges, and therefore are of substantial importance for the maintenance of hepatic function, and adaptation in disease. Recent studies have shown that nuclear receptors are involved in the hepatic adaptation to cholestasis, whereby they coordinate the response to elevated intra-cellular BA concentrations by directing compensatory means of reducing BA concentration.