Role of Sterol Regulatory Element-binding Protein 1 in Regulation of Renal Lipid Metabolism and Glomerulosclerosis in Diabetes Mellitus

Moshe Levi,Lijun Sun,Weiping Zhang,Nabil Halaihel,Thomas Rogers

doi:10.1074/jbc.m110650200

Abstract

Diabetic renal disease is associated with lipid deposits in the kidney. The purpose of our study was to determine whether there is altered regulation of the sterol regulatory element-binding proteins (SREBPs) in the diabetic kidney and whether SREBPs mediate the abnormal renal lipid metabolism and diabetic renal disease. In streptozotocin-induced diabetes in the rat, there were marked increases in SREBP-1 and fatty acid synthase (FAS) expression, resulting in increased triglyceride (TG) accumulation. Treatment of diabetic rats with insulin prevented the increased renal expression of SREBP-1 and the accumulation of TG. The role of hyperglycemia in the up-regulation of SREBP-1 was confirmed in renal cells cultured in a high glucose media. High glucose induced increased expression of SREBP-1a and -1c mRNA, SREBP-1 protein, and FAS, resulting in increased TG content. To determine a direct role for SREBP in mediating the increase in renal lipids and glomerulosclerosis, we studied SREBP-1a transgenic mice with increased renal expression of SREBP-1. The increase in SREBP-1 was associated with increased expression of FAS and acetyl CoA carboxylase, resulting in increased TG content, increased expression of transforming growth factor beta1 and vascular endothelial growth factor, mesangial expansion, glomerulosclerosis, and proteinuria. Our study therefore indicates that renal SREBP-1 expression is increased in diabetes and that SREBP-1 plays an important role in the increased lipid synthesis, TG accumulation, mesangial expansion, glomerulosclerosis, and proteinuria by increasing the expression of transforming growth factor beta and vascular endothelial growth factor.

Highlights

From the Departments of ‡Medicine and §Pathology, The University of Texas Southwestern Medical Center, Veterans Affairs Medical Center, Dallas, Texas 75216
Since the description by Kimmelstiel and Wilson [4] of the classical nodular glomerulosclerosis and presence of lipid deposits in the diabetic kidney, several investigators have shown the presence of lipid deposits in the kidneys of diabetic humans and experimental animals, and they have proposed that these deposits may play an important role in the pathogenesis of diabetic kidney disease [5, 6]
We found that in streptozotocin-induced diabetes, a type I diabetes model characterized by hyperglycemia and no changes in serum lipids, sterol regulatory element-binding proteins (SREBPs)-1 expression was increased in the kidney cortex, resulting in up-regulation of enzymes responsible for fatty acid synthesis and, as a consequence, high renal triglyceride content, and was associated with mesangial expansion and glomerulosclerosis

Summary

Introduction

From the Departments of ‡Medicine and §Pathology, The University of Texas Southwestern Medical Center, Veterans Affairs Medical Center, Dallas, Texas 75216. The purpose of our study was to determine whether there is altered regulation of the sterol regulatory element-binding proteins (SREBPs) in the diabetic kidney and whether SREBPs mediate the abnormal renal lipid metabolism and diabetic renal disease. In streptozotocin-induced diabetes in the rat, there were marked increases in SREBP-1 and fatty acid synthase (FAS) expression, resulting in increased triglyceride (TG) accumulation. Our study indicates that renal SREBP-1 expression is increased in diabetes and that SREBP-1 plays an important role in the increased lipid synthesis, TG accumulation, mesangial expansion, glomerulosclerosis, and proteinuria by increasing the expression of transforming growth factor ␤ and vascular endothelial growth factor. The Ϸ500-amino acid NH2-terminal segment of SREBP is released from the membrane and translocated to the nucleus, where it binds to enhancer regions of target genes to activate transcription. SREBP-1 preferentially activates genes involved in fatty acid synthesis, including acetyl CoA carboxylase and

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