Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease, which can progress to nonalcoholic steatohepatitis (NASH). Previous investigations have demonstrated alterations in the expression and activity of hepatic drug transporters in NASH. Moreover, studies using rodent models of cholestasis suggest that compensatory changes in kidney transporter expression occur to facilitate renal excretion during states of hepatic stress; however, little information is currently known regarding extra-hepatic regulation of drug transporters in NASH. The purpose of the current study was to investigate the possibility of renal drug transporter regulation in NASH across multiple experimental rodent models. Both rat and mouse NASH models were utilized in this investigation and include: the MCD diet, atherogenic diet, fa/fa rat, ob/ob and db/db mice. Histologic and pathological evaluations confirmed that the MCD and atherogenic rats as well as the ob/ob and db/db mice all developed NASH. In contrast, the fa/fa rats did not develop NASH but did develop extensive renal injury in comparison to the other models. Renal mRNA and protein analyses of xenobiotic transporters suggest that compensatory changes occur in NASH to favor increased xenobiotic secretion. Specifically, both efflux and basolateral uptake transporters are induced, whereas the apical uptake transporter, Oatp1a1, is repressed. These results suggest that NASH may alter the expression and potentially function of renal drug transporters, thereby impacting drug elimination mechanisms in the kidney.
- efflux transporters (P-gp, BCRP, MRP, MATE, BSEP, etc)
- extrahepatic
- kidney/renal
- liver/hepatic
- pharmacokinetics
- Transporter-mediated drug/metabolite disposition
- Uptake transporters (OATP, OAT, OCT, PEPT, MCT, NTCP, ASBT, etc.)
- The American Society for Pharmacology and Experimental Therapeutics