br Conclusions Recently Cohn advocated for a prospective stu

Conclusions Recently, Cohn advocated for a prospective study to investigate the role of postprandial lipoproteins in cardiovascular disease (Cohn, 2008). However, he indicated that unlike LDL-cholesterol that can be easily modified by drugs, the levels of chylomicrons and their remnants are less easily altered (Cohn, 2008). The results of the current study indicate that a selective DGAT-1 inhibitor potently attenuates postprandial hyperlipidemia in multiple rodent models. Therefore DGAT-1 inhibitors may finally provide the tool to definitely test the Zilversmit 8-pCPT-2-O-Me-cAMP-AM that atherogenesis is a “postprandial phenomenon” (Zilversmit, 1979) and answer the call for a prospective study on the role of postprandial lipoproteins in cardiovascular disease (Cohn, 2008). Furthermore, the standardized oral triglyceride tolerance test described in rodents in this study may serve as the foundation for further preclinical evaluation of pharmacologic modifiers of the postprandial response.
Acknowledgments All work was funded by Abbott Laboratories. All authors are employees of Abbott Laboratories. We would like to acknowledge Mary Tyrrell, Irina Skarzhin and Nateeh Pedroza from Clinical Chemistries at Abbott Laboratories for running the lipid assays.
Introduction Obesity is often accompanied by the excessive accumulation of lipids in nonadipose tissues (Friedman, 2002, Schaffer, 2003, Unger, 2002). One such process, hepatic steatosis, the accumulation of lipids in the liver, is increasing in prevalence, with current estimates ranging from 14% to 34% of the general population (Kim et al., 2004, Seppala-Lindroos et al., 2002, Szczepaniak et al., 2005, Wieckowska and Feldstein, 2005). Hepatic steatosis is part of the spectrum of nonalcoholic fatty liver diseases, which include the serious consequences of steatohepatitis and cirrhosis (Browning and Horton, 2004). Because hepatic steatosis is an increasing concern for public health, a better understanding of its pathophysiology and its consequences is of great importance. Hepatic steatosis is strongly associated with insulin resistance. Numerous studies in humans and animals have shown that insulin-resistant states are often accompanied by hepatic steatosis (Angulo and Lindor, 2001, Marchesini et al., 1999, Marchesini et al., 2005, Petersen and Shulman, 2006, Seppala-Lindroos et al., 2002, Yki-Jarvinen, 2005). For example, leptin-deficient ob/ob mice, lipodystrophic mice, and mice fed a high-fat diet all develop severe insulin resistance and hepatic steatosis (Browning and Horton, 2004, den Boer et al., 2004, Halaas et al., 1995, Koteish and Mae Diehl, 2002, Shimomura et al., 1999a, Shimomura et al., 1999b). However, the causal relationship between hepatic steatosis and insulin resistance is uncertain. On the one hand, it seems clear that systemic insulin resistance may lead to steatosis. Insulin resistance is often accompanied by hyperinsulinemia, which can activate hepatic signaling pathways and sterol regulatory element binding protein 1c (SREBP-1c), which in turn activates the transcription of genes involved in fatty acid biosynthesis (Farese et al., 2005a, Matsumoto et al., 2003, Shimomura et al., 2000). On the other hand, whether hepatic steatosis is sufficient to cause hepatic insulin resistance is less clear. Acute intravenous infusions of lipids or chronic high-fat feeding can result in hepatic steatosis that is accompanied by insulin resistance (Boden et al., 1994, Boden et al., 2002, Collins et al., 2004, Gauthier et al., 2003, Winzell and Ahren, 2004). However, models of lipid administration are complex and may be accompanied by alterations not restricted to the liver, making it difficult to determine the contribution of steatosis to insulin resistance.