The stable isotope dilution measurement of bile acid pool sizes and turnover rates in humans has involved the collection of nine blood samples over four days. This precludes widespread application... Show moreThe stable isotope dilution measurement of bile acid pool sizes and turnover rates in humans has involved the collection of nine blood samples over four days. This precludes widespread application to larger population studies. This study describes a two time-point approach for blood sampling without loss of statistical power. Isotopic decay curves of cholic acid, chenodeoxycholic acid and deoxycholic acid acquired in three recent human studies were analysed. The optimal combination of two time-points was determined. Time-points around 12 and 72h after administration allowed for the most accurate description of the decay curves and prediction of kinetic parameters. Analyses of 39 statistical comparisons of kinetic parameters based upon the two time-points and all time-points approaches exhibited only one slightly discrepant result. In conclusion, for group comparison of bile acid kinetics in humans, a two time-point blood collection approach at time-points near 12 and 72h provides statistically reliable data. Show less
BACKGROUND: Liver-selective thyromimetics have been reported to efficiently reduce plasma cholesterol through the hepatic induction of both, the low-density lipoprotein receptor (LDLr) and the... Show moreBACKGROUND: Liver-selective thyromimetics have been reported to efficiently reduce plasma cholesterol through the hepatic induction of both, the low-density lipoprotein receptor (LDLr) and the high-density lipoprotein (HDL) receptor; the scavenger receptor class B type I (SR-BI). Here, we investigated the effect of the thyromimetic T-0681 on reverse cholesterol transport (RCT) and atherosclerosis, and studied the underlying mechanisms using different mouse models, including mice lacking LDLr, SR-BI, and apoE, as well as CETP transgenic mice. METHODOLOGY/PRINCIPAL FINDINGS: T-0681 treatment promoted bile acid production and biliary sterol secretion consistently in the majority of the studied mouse models, which was associated with a marked reduction of plasma cholesterol. Using an assay of macrophage RCT in mice, we found T-0681 to significantly increase fecal excretion of macrophage-derived neutral and acidic sterols. No positive effect on RCT was found in CETP transgenic mice, most likely due to the observed decrease in plasma CETP mass. Studies in SR-BI KO and LDLr KO mice suggested hepatic LDLr to be necessary for the action of T-0681 on lipid metabolism, as the compound did not have any influence on plasma cholesterol levels in mice lacking this receptor. Finally, prolonged treatment with T-0681 reduced the development of atherosclerosis by 60% in apoE KOs on Western type diet. In contrast, at an earlier time-point T-0681 slightly increased small fatty streak lesions, in part due to an impaired macrophage cholesterol efflux capacity, when compared to controls. CONCLUSIONS/SIGNIFICANCE: The present results show that liver-selective thyromimetics can promote RCT and that such compounds may protect from atherosclerosis partly through induction of bile acid metabolism and biliary sterol secretion. On-going clinical trials will show whether selective thyromimetics do prevent atherosclerosis also in humans. Show less
