Sterol Regulatory Element–Binding Protein-1 Determines Plasma Remnant Lipoproteins and Accelerates Atherosclerosis in Low-Density Lipoprotein Receptor–Deficient Mice

Abstract

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...

Molecular Biology of Atherosclerosis

“…The cholesterol content of chylomicrons and VLDL was markedly reduced. In the same study, hepatic over-expression of SREBP-1 increased atherosclerosis 140% while BMT studies had no effect (882).…”

“…These animals suffered increased atherosclerosis. Conversely, double KO of SREBP-1 and LDLR resulted in lower VLDL and less atherosclerosis compared with LDLR KO controls (882). Other genes that may affect lipoprotein size and composition due to effects on synthesis or residence time are apo CI, apo CIII, and CETP with proatherogenic effects demonstrated for all these except CETP, which showed mixed effects (see TABLE 8).…”

Role of Nrf2 in the pathogenesis of atherosclerosis

“…These lipogenic genes affect atherosclerosis development through systemic lipid metabolism. Actually, Srebp-1c overexpression accelerates atheroma formation in LDLR KO mice, and conversely, Srebp-1 knockout ameliorates atherosclerosis in LDLR KO mice [62]. SHP deficiency shows a protective effect against atherosclerosis development in ApoE KO mice [63].…”

Lack of association between SREBF-1c gene polymorphisms and risk of non-alcoholic fatty liver disease in a Chinese Han population

“…Overexpression of SREBP-1c induced insulin resistance, diabetes, non-alcoholic fatty liver disease (NAFLD), and accelerated atherosclerosis in mice9101112. Given the mediating role of SREBF-1c in the transcription of genes involved in de novo lipogenesis and triglyceride-rich lipoprotein metabolism, the SREBF-1c gene could be considered as a good candidate indicator to predict metabolic syndromes disorders.…”