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  • Traditionally serum triglycerides have been measured


    Traditionally, serum triglycerides have been measured in the clinic in the fasted state in order to reduce variability and also to facilitate the calculation of LDL-cholesterol via the Friedewald equation, which was derived using fasted samples (Warnick and Nakajima, 2008). We have previously reported that chronic administration of DGAT-1 inhibitor A-922500 reduces fasting serum triglyceride levels in both genetic and diet-induced animal models of dyslipidemia (King et al., 2009). However, recent studies have indicated the superiority of postprandial over conventional fasting triglyceride measurements in predicting cardiovascular risk (Bansal et al., 2007, Nordestgaard et al., 2007). Postprandial triglyceride levels are more representative of the usual metabolic state encountered in humans (Warnick and Nakajima, 2008). Therefore, the second purpose of this OPP mg study was to evaluate the effect of a potent and selective DGAT-1 inhibitor on the standardized rodent models of postprandial hyperlipidemia that we had characterized. These findings potentially have more relevance to reducing cardiovascular risk, than the previously reported reductions in fasting serum triglyceride levels (King et al., 2009). In the recently published Women's Health Study, serum triglyceride concentrations measured 2 to 4h after a meal, which corresponds to peak postprandial levels, provided the strongest prediction of future cardiovascular events (Bansal et al., 2007). In addition, a recent study by Weiss established that an abbreviated 4-h postprandial hyperlipidemia test provides a valid surrogate for the complete postprandial time-course in humans (Weiss et al., 2008). Therefore, we assessed the effect of DGAT-1 inhibition on the postprandial triglyceride response in rodents, measured at a time-point to approximate the maximal response, as this may provide the most relevant extrapolation to cardiovascular risk prediction. DGAT-1 inhibition universally attenuated postprandial hyperlipidemia, in a dose-dependent fashion, in all rodent models evaluated. The ability of DGAT-1 inhibitor A-922500 to reduce the serum triglyceride rise in response to an oral fat load was extremely potent, with significant efficacy beginning at 0.03mg/kg in apoE−/−mice and Sprague–Dawley rats and at 0.3mg/kg in all other animals tested. DGAT-1 inhibition completely abolished the postprandial increase in serum triglycerides at the highest dose tested. This suggests that DGAT-1 is the sole enzyme capable of catalyzing the final re-esterifcation step of intestinal triglyceride synthesis in the rodent small intestine. Therefore, it appears that DGAT-2 does not contribute to the intestinal absorption of dietary triglycerides in the mature rodent. The indispensible role of DGAT-1 in postprandial triglyceride excursions documented in the current study is in contrast to observations in DGAT-1 knockout mice (Buhman et al., 2002). While postprandial hyperlipidemia in response to an oral lipid challenge was substantially attenuated in the knockout animals, it was not abolished. This may indicate that during development, DGAT-1 knockout mice adapt to acquire enzyme activity to partially compensate for the complete loss of DGAT-1 activity. DGAT-1 inhibition retained efficacy in attenuating the postprandial response with repeat administration. In fact, compared to a single dose, 7days of treatment with A-922500 appeared to improve efficacy to some extent. Significant inhibition of postprandial hyperlipidemia was observed in CD-1 mice after repeat administration of A-922500 at 0.03mg/kg, whereas significant efficacy after a single dose of A-922500 to CD-1 mice was first observed at 0.3mg/kg. The magnitude of postprandial hyperlipidemia attenuation was then comparable between single and repeat dosing at the higher doses. This feature of DGAT-1 inhibition to retain efficacy with repeat dosing is critical in identifying a therapy capable of producing sustained inhibition of the postprandial response in humans and ultimately improve cardiovascular outcomes with long-term treatment.