No abstract

Expression and functional changes in the organic anion transporting polypeptide (OATP)multidrug resistance associated protein (MRP) axis of transporters are well reported in nonalcoholic steatohepatitis (NASH) patients. These changes can impact plasma and tissue disposition of endo-and exogenous compounds. The transporter alterations are often assessed by administration of a xenobiotic, or by transporter proteomic analysis from liver biopsies. Using gene expression, proteomics and endogenous biomarkers, we show that the gene expression and activity of OATP and MRP transporters are associated with disease progression and recovery in humans and in preclinical animal models of NASH. Decreased OATP and increased MRP3/4 gene expression in two steatosis and NASH patient cohorts, as well as gene and protein expression in multiple NASH rodent models have been established. Coproporphyrin I and III (CP I and III) were established as substrates of MRP4. CP I plasma concentration increased significantly in four animal models of NASH, indicating the transporter changes. Upto a 60-fold increase in CP I plasma concentration was observed in the mouse bile duct ligated model compared to sham controls. In the choline deficient high This article has not been copyedited and formatted. The final version may differ from this version.