Submitted on January 28, 2008
Accepted on June 14, 2008
Expression profiling of hepatic genes associated with lipid metabolism in nephrotic rats
Yunfeng Zhou1, Xiaoyan Zhang1, Lihong Chen1, Jing Wu1, Huaixin Dang1, Ming-Fen Wei1, Yanbo Fan2, Yahua Zhang3, Yi Zhu1, Nanping Wang2, Matthew D Breyer3, and Youfei Guan4*
1 Department of Physiology, Peking (Beijing) University Health Science Center, Beijing, China
2 Institute of Cardiovascular Disease, Beijing, China
3 Division of Nephrology, Vanderbilt University Medical Center, Nashville, Tennessee, United States
4 Department of Physiology, Peking (Beijing) University Health Science Center, Beijing, China; Division of Nephrology, Vanderbilt University Medical Center, Nashville, Tennessee, United States
* To whom correspondence should be addressed. E-mail: youfeiguan{at}bjmu.edu.cn.
Hyperlipidemia is one of the major features of nephrotic syndrome (NS). Although many factors have been implicated in the pathogenesis of NS-related dyslipidemia, the underlying mechanisms remain largely uncharacterized. The present study was designed to examine the gene profile associated with lipid metabolism in the livers of nephrotic rats. NS was created in male Sprague-Dawley rats (n=6) receiving sequential intraperitoneal injections of puromycin aminonucleoside. Analysis by Affymetrix assay, quantitative RT-PCR, and Northern and Western blotting revealed 21 genes associated with cholesterol and fatty acid metabolism. Eight genes involved in cholesterol metabolism, Apo A-I, Acly, Acat, Mpd, Fdps, Ss, Lss, and Nsdhl, were significantly upregulated under NS. Four genes involved in fatty acid biosynthesis, Acc, FAS, ELOVL 2 and 6, and three critical for triglyceride biosynthesis, Gpam, Agpat 3 and Dgat 1, were significantly upregulated, whereas two genes involved in fatty acid oxidation, Dci and MCAD, were downregulated. Expression of several genes in SREBP-1 activation was also aberrantly altered in nephrotic livers. The expression and transcriptional activity of SREBP-1 but not SREBP-2 were increased in nephrotic rats as assessed by real-time PCR, immunoblot and gel shift assays. The upregulation of hepatic genes involved in cholesterol biosynthesis may play an important role in the pathogenesis of hypercholesterolemia, whereas upregulation of genes participating in hepatic fatty acid and triglyceride biosynthesis and downregulation of genes involved in hepatic fatty acid oxidation may contribute to hypertriglyceridemia in nephrotic rats. Activation of SREBP-1 transcription factor may represent an underlying molecular mechanism of hyperlipidemia in NS.
