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  • br Acknowledgements br Introduction Serum triglyceride conce

    2019-07-15


    Acknowledgements
    Introduction Serum triglyceride concentrations increase following ingestion of a fat containing meal resulting in postprandial hyperlipidemia. Peak serum triglyceride levels are observed within 2 to 4h of fat consumption and then gradually return to baseline levels within approximately 10h (Cohn et al., 1988). Zilversmit first proposed that the almost continuous exposure to these postprandial triglyceride-containing lipoproteins is the most significant cause of atherosclerosis, and he subsequently termed atherogenesis a “postprandial phenomenon” in the 1970s (Zilversmit, 1979). The recently published Copenhagen City Heart Study (Nordestgaard et al., 2007) and the Women\'s Health Study (Bansal et al., 2007) both corroborated this long-standing UK-5099 by documenting postprandial serum triglycerides as a major, independent risk factor for future cardiovascular events in a fully adjusted analysis. These epidemiological findings have intensified scientific interest in postprandial lipoproteins, and chylomicrons have remerged as a potential therapeutic target to inhibit atherogenesis (Stalenhoef and Watts, 2008). In fact, Redgrave recently advocated that postprandial dyslipidemia should become a focus of drug development (Redgrave, 2008). However, despite recent efforts to establish a standardized oral triglyceride tolerance test to evaluate postprandial lipid metabolism in the clinic (Ridker, 2008, van Oostrom et al., 2009, Warnick and Nakajima, 2008, Weiss et al., 2008), preclinical animal models of postprandial hyperlipidemia to facilitate drug discovery have not been well characterized. There have been sporadic reports on the use of an oral lipid challenge to produce postprandial hyperlipidemia in experimental animals, although methodologies, including the composition and dose of lipid, have been inconsistent (Buhman et al., 2002, Fujinami et al., 2001, Vine et al., 2007). Therefore, the first purpose of this study was to describe and characterize a standardized model of postprandial hyperlipidemia in multiple rodent species to allow evaluation of pharmacological modifiers of postprandial lipoprotein metabolism. Dietary triglycerides are hydrolyzed in the small intestine by pancreatic lipase to monoacylglycerol and fatty acids, which are then absorbed by the enterocytes and recombined into triglycerides by a series of sequential esterification steps, the final of which is catalyzed by acyl CoA:diacylglycerol acyltransferase (DGAT). The re-synthesized triglycerides are then incorporated into chylomicrons and secreted into the circulation via the lymphatic system. DGAT-1 is one of two known DGAT enzymes (Cases et al., 1998). The highest levels of DGAT-1 expression are found in the small intestine (Yen et al., 2008). In addition, DGAT-1 knockout mice have dramatically reduced levels of intestinal triglyceride synthesis and chylomicron secretion following an oral lipid challenge (Buhman et al., 2002). Consequently, DGAT-1 represents a credible target for the treatment of postprandial hyperlipidemia. Therefore, the second purpose of this study was to determine the effect of a potent and selective DGAT-1 inhibitor on the standardized rodent models of postprandial hyperlipidemia described.
    Methods
    Results
    Discussion Postprandial triglyceride-containing lipoproteins have long been hypothesized to play a critical role in the pathogenesis of atherosclerosis by both direct and indirect mechanisms (Zilversmit, 1979). The intra-vascular hydrolysis of the triglyceride content of these particles generates remnant lipoproteins which can directly penetrate the subendothelial space of the arterial wall (Kowala et al., 2000, Proctor et al., 2000). These remnant lipoproteins are then taken up by macrophages to promote foam cell formation, which initiates a proinflammatory and prothrombotic cascade of events (Boyajian and Otis, 2002, Gottsater et al., 2002, Rader and Dugi, 2000, Skalen et al., 2002, Yu and Cooper, 2001). In addition, high concentrations of triglyceride-rich lipoproteins promote the exchange of core lipids between lipoprotein species. This postprandial core lipid exchange and subsequent triglyceride hydrolysis results in the production of atherogenic small dense LDL-cholesterol particles (Caslake et al., 1993, Shepherd, 1993) and enhances the clearance of cardioprotective HDL cholesterol (Lamarche et al., 1999a, Lamarche et al., 1999b, Rashid et al., 2002). Currently available drug therapies for the management of dyslipidemia do not directly target the postprandial response and have only minimal (e.g. statins (Iovine et al., 2006) and niacin (Plaisance et al., 2008)) to moderate (e.g. fenofibrate (Iovine et al., 2006, Kolovou et al., 2008)) effects on postprandial triglycerides in humans, leaving a substantial unmet therapeutic need.