Severe diabetes and leptin resistance cause differential hepatic and renal transporter expression in mice

Abstract

BackgroundType-2 Diabetes is a major health concern in the United States and other Westernized countries, with prevalence increasing yearly. There is a need to better model and predict adverse drug reactions, drug-induced liver injury, and drug efficacy in this population. Because transporters significantly contribute to drug clearance and disposition, it is highly significant to determine whether a severe diabetes phenotype alters drug transporter expression, and whether diabetic mouse models have altered disposition of acetaminophen (APAP) metabolites.ResultsTransporter mRNA and protein expression were quantified in livers and kidneys of adult C57BKS and db/db mice, which have a severe diabetes phenotype due to a lack of a functional leptin receptor. The urinary excretion of acetaminophen-glucuronide, a substrate for multidrug resistance-associated proteins transporters was also determined. The mRNA expression of major uptake transporters, such as organic anion transporting polypeptide Slco1a1 in liver and kidney, 1a4 in liver, and Slc22a7 in kidney was decreased in db/db mice. In contrast, Abcc3 and 4 mRNA and protein expression was more than 2 fold higher in db/db male mouse livers as compared to C57BKS controls. Urine levels of APAP-glucuronide, -sulfate, and N-acetyl cysteine metabolites were higher in db/db mice.ConclusionA severe diabetes phenotype/presentation significantly altered drug transporter expression in liver and kidney, which corresponded with urinary APAP metabolite levels.

Effect of Caloric Restriction and AMPK Activation on Hepatic Nuclear Receptor, Biotransformation Enzyme, and Transporter Expression in Lean and Obese Mice

“…ezetimibe, acetaminophen), as well as, altered endogenous metabolite levels, such as cholesterol and bilirubin (6,7). Acetaminophen-glucuronide concentration in plasma and urine was higher in children with NAFLD (6), similar to what has been reported in db/db mice that exhibit hepatic steatosis (8). This likely occurs because Phase-I, -II biotransformation enzyme, and drug transporter expression is altered compared to non-steatotic livers (9,10).…”

Diabetes Induces Aberrant DNA Methylation in the Proximal Tubules of the Kidney

“…This potentially leads to sodium wasting, but the contribution of Cyp4a10 in the PT to BP still needs to be determined. Transports wide variety of anionic, cationic, zwitterionic, and neutral chemicals 24 Genes with differentially methylated CpG sites in the PTs between the control and diabetic mice. The percentage DNA methylation in the PT in db/db mice was subtracted from that in db/m mice.…”

“…PT cells obtained from the diabetic and control mice showed a rather similar DNA methylation patterns, but the methylation pattern significantly differed among the eight genes with potentially functional roles (Table 1, Supplemental Figure 3). [16][17][18][19][20][21][22][23][24] Quantitative RT-PCR analysis demonstrated that the mRNA expressions of these genes in the PT cells were significantly different between the diabetic and control mice ( Table 1, Supplemental Figure 3). An inverse correlation between expression and methylation was seen at these loci except for Met.…”

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

“…Western blots were used to quantify the relative expression of transport proteins in human liver tissues, as described in our previous publication (More and Slitt, 2011;More et al, 2012). Briefly, the membrane/ nuclear extracts were separated on polyacrylamide gel (10% resolving, 4% stacking), transblotted on polyvinylidene fluoride membrane, and blocked with 2% nonfat dry milk in phosphate-buffered saline with Tween 20.…”

“…Hepatic steatosis resulting from obesity or diabetes resulted in significant alterations in transporter expression in hepatocytes, as demonstrated in mouse models (Cheng et al, 2008;More and Slitt, 2011;More et al, 2012). Compared with steatosis, cirrhosis is a significant hepatic stress with replacement of normal functional tissue by scar tissue, which is unable to maintain the functions of the liver.…”