Nuclear-receptor-mediated regulation of drug- and bile-acid-transporter proteins in gut and liver

Abstract

Adverse drug events (ADEs) are a common cause of patient morbidity and mortality and are classically thought to result, in part, from variation in expression and activity of hepatic enzymes of drug metabolism. It is now known that alterations in the expression of genes that encode drug- and bile-acid-transporter proteins in both the gut and liver play a previously unrecognized role in determining patient drug response and eventual clinical outcome. Four nuclear receptor (NR) superfamily members, including pregnane X receptor (PXR, NR1I2), constitutive androstane receptor (NR1I3), farnesoid X receptor (NR1H4), and vitamin D receptor (NR1I1), play pivotal roles in drug- and bile-acid-activated programs of gene expression to coordinately regulate drug- and bile-acid transport activity in the intestine and liver. This review focuses on the NR-mediated gene activation of drug and bile-acid transporters in these tissues as well as the possible underlying molecular mechanisms.

Figure 1

NRs act as sensors in the regulation of enterohepatic drug transporters. Drugs and bile acids enter enterohepatic circulation by intestinal uptake transporters (e.g., ASBT). In many cases, these molecules are immediately transported back into the intestinal lumen by apical efflux transporters (e.g., MDR1, MRP2, and BCRP). Molecules that remain within the enterocyte can either serve as ligands to resident NRs, such as PXR, CAR, VDR, and FXR (bottom figure), or are effluxed into the portal circulation by sinusoidal efflux transporters (e.g., MRP3). After efflux to the portal vein, drugs and bile acids travel to the liver, where they are transported into hepatocytes by sinusoidal uptake transporters (e.g., OATPs and NTCP). Once inside hepatocytes, these molecules are either excreted into the bile canaliculus by canalicular efflux transporters (e.g., BSEP, MDR1, BCRP, and so forth) or serve as ligands to resident NRs, such as PXR, CAR, and FXR (top figure). Activation of these NRs in both the liver and intestine leads to their heterodimerization with RXRα. This NR/RXRα heterodimer, which is now bound to chromatin, initiates transcription of NR-specific target genes, including phase I and II drug-metabolizing enzymes as well as the drug transporters involved in uptake and efflux of NR-specific ligands (e.g., bile acids, drugs, and so forth). This drug-and bile-acid–induced regulation allows the enterohepatic system to maintain a homeostatic level of bile acids, drugs, and xenobiotics through feedback regulation that protects the body from potential toxic events.

Figure 2

Model for the FXR-mediated feed-forward and feedback regulation effects on gene expression. Feed-forward regulation by FXR in the liver and intestine is mediated by bile-acid activators of this NR superfamily member, primarily CA, and CDCA. Activated FXR, in turn, positively regulates the expression of FXR target genes that encode both drug- and bile-acid–transporter proteins OATP1B1, OATP1B3, OSTα/β, and BSEP. These transporter proteins function in the uptake and eventual elimination of drugs and bile acids from enterocytes and hepatocytes, hence the presence of excess bile acids in these tissues upregulates their own excretion and efflux. Feedback inhibition of primary bile-acid–uptake transporters ASBT and NTCP, in enterocytes and hepatocytes, respectively, is accomplished through a regulatory circuit that involves FXR-mediated induction of the expression and activity of SHP. The increased levels of the SHP nuclear receptor, which functions in a dominant-negative manner because of the lack of a functional DNA-binding domain, interacts with LRH-1 to repress the expression of genes encoding CYP7A1 and CYP8B1, enzymes centrally involved in the de novo production of additional bile acids from endogenous excess cholesterol. Increased SHP protein also represses the expression of its own gene through sequestration of LRH-1 from its own promoter. Thus, both synthesis of new bile acids from cholesterol, as well as uptake of old bile acids, is downregulated simultaneously to prevent the accumulation of excess bile acids in enterohepatic circulation.

Figure 3

Model for the gut-liver axis that involves the FGF15/19-signaling mechanism. Endocrine actions of FGF15. Expression of the gene encoding FGF15 is induced in the small intestine by bile acids acting on the FXR/RXRα heterodimer. Subsequently, FGF15 is secreted into the enterohepatic circulation to act in an endocrine manner by binding a receptor on hepatocytes called FGFR4. The activated FGFR4 receptor signals the liver to repress CYP7A1 expression and activity. The CYP7A1 enzyme is the rate-limiting step in the synthesis of bile acids from cholesterol. In this manner, FGF15 (FGF19 in humans) suppresses de novo synthesis of bile acids from cholesterol through a mechanism that requires SHP. The extent to which this mechanism functions to downregulate drug-and bile-acid–transporter proteins in hepatocytes is currently unknown, but is a likely fruitful area of future research.