Objective-Sterol regulatory element-binding protein-1 (SREBP-1) is nutritionally regulated and is known to be a key transcription factor regulating lipogenic enzymes. The goal of this study was to evaluate the roles of SREBP-1 in dyslipidemia and atherosclerosis. Methods and Results-Transgenic mice that overexpress SREBP-1c in the liver and SREBP-1-deficient mice were crossed with low-density lipoprotein receptor (LDLR)-deficient mice, and the plasma lipids and atherosclerosis were analyzed. Hepatic SREBP-1c overexpression in LDLR-deficient mice caused postprandial hypertriglyceridemia, increased very-low-density lipoprotein (VLDL) cholesterol, and decreased high-density lipoprotein cholesterol in plasma, which resulted in accelerated aortic atheroma formation. Conversely, absence of SREBP-1 suppressed Western diet-induced hyperlipidemia in LDLR-deficient mice and ameliorated atherosclerosis. In contrast, bone marrow-specific SREBP-1 deficiency did not alter the development of atherosclerosis. The size of nascent VLDL particles secreted from the liver was increased in SREBP-1c transgenic mice and reduced in SREBP-1-deficient mice, accompanied by upregulation and downregulation of phospholipid transfer protein expression, respectively. Key Words: atherosclerosis Ⅲ hyperlipoproteinemia Ⅲ lipids Ⅲ lipoproteins Ⅲ triglycerides S terol regulatory element-binding proteins (SREBPs) are transcription factors that belong to the basic helix-loophelix leucine zipper family. 1,2 Unlike other basic helix-loophelix leucine zipper family transcription factors, SREBPs are synthesized as membrane-bound precursors and embedded in the endoplasmic reticulum membrane. There, they form a complex with SREBP cleavage-activating protein. When cellular cholesterol levels are depleted, SREBP cleavageactivating protein escorts SREBPs to the Golgi apparatus, where SREBPs are cleaved by site-1 and site-2 proteases. After cleavage, SREBPs transfer to the nucleus and activate enzymes involved in lipid synthesis. The SREBP family consists of 3 isoforms: SREBP-1a, SREBP-1c, and SREBP-2. SREBP-1a and SREBP-1c are derived from a single gene through the use of alternative promoters. SREBP-1a has a potent transcriptional activity for genes involved in synthesis of cholesterol, fatty acids, and triglycerides (TGs). 3 In contrast, SREBP-1c has a transcriptional activity for genes involved in fatty acid and TG synthesis. 4,5 SREBP-2 selectively activates transcription of genes involved in cholesterol synthesis. 6 Unlike SREBP-1a, SREBP-1c is regulated by nutritional conditions and therefore plays a central role in nutritional regulation of lipogenesis as a dominant isoform in liver and adipose tissues. 7 Whereas SREBP-1c levels are low in fasting states, they are dramatically increased in refed states in response to higher levels of glucose and insulin. 8 -10 Owing to its activation by overnutrition, SREBP-1c could be the cause of several metabolic disorders. Previous studies revealed that SREBP-1 is involved in hepatic steatosis and insulin resista...

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Background Chronic disseminated intravascular coagulation (DIC) is