Journal of Biological Chemistry
Volume 280, Issue 37, 16 September 2005, Pages 32317-32325
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Lipids and Lipoproteins
Diet-induced Obesity in C57BL/6J Mice Causes Increased Renal Lipid Accumulation and Glomerulosclerosis via a Sterol Regulatory Element-binding Protein-1c-dependent Pathway*

https://doi.org/10.1074/jbc.M500801200Get rights and content
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Obesity and metabolic syndrome are associated with glomerulosclerosis and proteinuria, but the mechanisms are not known. The purpose of this study was to determine if there is altered renal lipid metabolism and increased expression of sterol regulatory element-binding proteins (SREBPs) in a model of diet-induced obesity. C57BL/6J mice that were fed a high fat, 60 kcal % saturated (lard) fat diet (HFD) developed obesity, hyperglycemia, and hyperinsulinemia compared with those that were fed a low fat, 10 kcal % fat diet (LFD). In contrast, A/J mice were resistant when fed the same diet. C57BL/6J mice with HFD exhibited significantly higher levels of renal SREBP-1 and SREBP-2 expression than those mice with LFD, whereas in A/J mice there were no changes with the same treatment. The increases in SREBP-1 and SREBP-2 expression in C57BL/6J mice resulted in renal accumulation of triglyceride and cholesterol. There were also significant increases in the renal expression of plasminogen activator inhibitor-1 (PAI-1), vascular endothelial growth factor (VEGF), type IV collagen, and fibronectin, resulting in glomerulosclerosis and proteinuria. To determine a role for SREBPs per se in modulating renal lipid metabolism and glomerulosclerosis we performed studies in SREBP-1c–/– mice. In contrast to control mice, in the SREBP-1c–/– mice with HFD the accumulation of triglyceride was prevented, as well as the increases in PAI-1, VEGF, type IV collagen, and fibronectin expression. Our results therefore suggest that diet-induced obesity causes increased renal lipid accumulation and glomerulosclerosis in C57BL/6J mice via an SREBP-1c-dependent pathway.

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This work was supported by National Institutes of Health (NIH) Grants 5R01-DK062209-02 and 7RO3-AG20361-2, Juvenile Diabetes Research Foundation Grant 1-2003-108, and American Heart Association Grant 0350491Z (to M. L.); by NIH National Research Service Award Grant 1F32 DK065407-01 (to S. E. L.); and by NIH GI Training Grant T32 DK-07038-29 (to Z. W.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.