microRNA-206 modulates the hepatic expression of the organic anion-transporting polypeptide 1B1.

BACKGROUND & AIMS: The organic anion-transporting polypeptide 1B1 (OATP1B1) is an anion exchanger expressed at the hepatocyte sinusoidal membrane, which mediates the uptake of several endogenous metabolites and drugs. OATP1B1 expression level and activity are major sources of inter-patient variability of pharmacokinetics and pharmacodynamics of several drugs. Besides the genotype, factors that contribute to the inter-individual variability in OATP1B1 expression level are practically unknown. The aim of this work was to uncover novel epigenetic mechanisms of OATP1B1 regulation. METHODS: A functional screening strategy to assess the effect of microRNAs on the uptake of estrone-3-sulphate, an OATP1B1 substrate, into human hepatocellular carcinoma (Huh-7) cells was used. microRNA-206 (miR-206) expression in human liver tissues was measured by real-time RT-PCR. OATP1B1 expression in Huh-7 and in human liver tissues was assessed by real-time RT-PCR, Western blotting and immunostaining. The mRNA-miRNA interaction was assessed by reporter assay. RESULTS: miR-206 mimic repressed mRNA and protein expression of OATP1B1 in Huh-7 cells. The intracellular accumulation of estrone-3-sulphate was reduced by 30% in cells overexpressing miR-206. The repressive effect of miR-206 on the activity of the firefly luciferase gene 2 under the control of the OATP1B1 3' untranslated region was lost upon deletion of the predicted miR-206 binding site. Hepatic miR-206 level negatively correlated with OATP1B1 mRNA and protein levels extracted from normal human liver tissues. CONCLUSIONS: miR-206 exerts a suppressive effect on OATP1B1 expression by an epigenetic mechanism. Individuals with high hepatic levels of miR-206 appear to display lower level of OATP1B1.

Sex-specific effects of leisure-time physical activity on cause-specific mortality in NHANES III.

Associations between leisure time physical activity (LTPA) and all-cause mortality seem quite strong, however, less is known about the association of LTPA and cause-specific mortality. To examine this association data from the Third National Health and Nutrition Examination Survey (NHANES III), including 15,307 individuals of the non-institutionalized civilian United States population, were used. Data were collected from 1988 to 1994 with a mortality follow-up until 2006. LTPA was assessed during home interviews in which participants specified their LTPA and the performed frequency during the past month. Cox proportional hazards regression models were applied to analyze the risk of cause-specific mortality regarding LTPA. Hazard ratios (HRs) and 95% confidence intervals (CIs) were computed. An inverse association of LTPA with CVD mortality was observed for men and women combined for irregular (HR 0.66; 95% CI 0.51-0.85), and for regular activity (HR 0.58; 95% CI 0.47-0.72). An inverse association of LTPA with CVD mortality was observed only in women for irregular (HR 0.64; 95% CI 0.49-0.84) and for regular activity (HR 0.55; 95% CI 0.43-0.72). In men, no significant associations were seen. For mortality caused by respiratory diseases, a decreased mortality was also observed in the combined group (men and women) but after separating according to sex a decreased mortality was only observed in women. No statistically significant association of LTPA with cancer mortality was observed. Our data support an inverse association between LTPA and CVD and respiratory disease mortality in women, but not in men, and no associations with cancer.