Abstract

Unsafe use of alcohol results in approximately 2.5 million deaths worldwide, with cirrhosis contributing to 16.6% of reported deaths. Serum insulin levels are often elevated in alcoholism, which may result in diabetes; which is why alcoholic liver disease and diabetes often are co-present. Because there is a sizable population that presents with these diseases alone or in combination, the purpose of this study was to determine whether transporter expression in human liver is affected with alcoholic cirrhosis, diabetes, and alcohol cirrhosis co-existing with diabetes. Transporters aid in hepatobiliary excretion of many drugs and toxic chemicals, and can be determinants of drug-induced liver injury. Drug transporter and transcription factor relative mRNA and protein expression in normal, diabetic, cirrhotic and cirrhosis with diabetes human livers were quantified. Cirrhosis significantly increased ABCC4, 5, ABCG2 and SLCO2B1 mRNA expression, and decreased SLCO1B3 mRNA expression in liver. ABCC1, 3-5, ABCG2 protein expression was also upregulated by alcohol cirrhosis. ABCC3-5, and ABCG2 protein expression was also upregulated in diabetic-cirrhosis. Cirrhosis increased NRF2 mRNA expression, whereas it decreased PXR and FXR mRNA expression in comparison to normal livers. Hierarchical cluster analysis indicated that expressions of ABCC2, 3 and 6; SLCO1B1 and 1B3; and ABCC4 and 5 were more closely related in the livers from this cohort. Overall, alcohol cirrhosis altered transporter expression in human liver.