Variations in ATP-Binding Cassette Transporter Regulation during the Progression of Human Nonalcoholic Fatty Liver Disease

Abstract

ABSTRACT:Transporters located on the sinusoidal and canalicular membranes of hepatocytes regulate the efflux of drugs and metabolites into blood and bile, respectively. Changes in the expression or function of these transporters during liver disease may lead to a greater risk of adverse drug reactions. Nonalcoholic fatty liver disease (NAFLD) is a progressive condition encompassing the relatively benign steatosis and the more severe, inflammatory state of nonalcoholic steatohepatitis (NASH). Here, we present an analysis of the effect of NAFLD progression on the major ATP-binding cassette (ABC) efflux transport proteins ABCC1-6, ABCB1, and ABCG2. Human liver samples diagnosed as normal, steatotic, NASH (fatty), and NASH (not fatty) were analyzed. Increasing trends in mRNA expression of ABCC1, ABCC4-5, ABCB1, and ABCG2 were found with NAFLD progression, whereas protein levels of all transporters exhibited increasing trends with disease progression. Immunohistochemical staining of ABCC3, ABCB1, and ABCG2 revealed no alterations in cellular localization during NAFLD progression. ABCC2 staining revealed an alternative mechanism of regulation in NASH in which the transporter appears to be internalized away from the canalicular membrane. This correlated with a preferential shift in the molecular mass of ABCC2 from 200 to 180 kDa in NASH, which has been shown to be associated with a loss of glycosylation and internalization of the protein. These data demonstrate increased expression of multiple efflux transporters as well as altered cellular localization of ABCC2 in NASH, which may have profound effects on the ability of patients with NASH to eliminate drugs in an appropriate manner.

Alcohol Cirrhosis Alters Nuclear Receptor and Drug Transporter Expression in Human Liver

“…The uptake transporter, SLCO1B1, however, remained unchanged with alcohol cirrhosis but went down with PBC (Zollner et al, 2003). Fatty and nonfatty NASH also enhanced the mRNA and protein expression of ABCC1, 4, and 5 in human livers (Hardwick et al, 2011). These comparisons of the present study with existing findings suggest that these alterations in transporter expression are likely a general response to cirrhosis of any cause.…”

Renal Xenobiotic Transporter Expression is Altered in Multiple Experimental Models of Nonalcoholic Steatohepatitis

“…Indeed, NASH causes extensive alterations in the regulation of hepatic xenobiotic transporters of both human and rodent models, leading to the functional disruption of acetaminophen, ezetimibe, methotrexate, and arsenic disposition (Lickteig et al, 2007;Hardwick et al, 2011Hardwick et al, , 2012Canet et al, 2012Canet et al, , 2014. A common observation in these studies is increased plasma retention coupled with decreased biliary elimination of xenobiotics, suggesting that patients with NASH may represent a unique population of individuals that are at higher risk of experiencing adverse drug reactions.…”

Altered UDP-Glucuronosyltransferase and Sulfotransferase Expression and Function during Progressive Stages of Human Nonalcoholic Fatty Liver Disease

“…Samples were categorized as NASH (not fatty) when fatty deposits within hepatocytes were reduced , 5% and accompanied by more marked inflammation and fibrotic branching. Representative histology images have been published previously (Fisher et al, 2009;Hardwick et al, 2010;Hardwick et al, 2011).…”