Ghada Abdel-Fattah

Bio: Ghada Abdel-Fattah is an academic researcher from Baylor College of Medicine. The author has contributed to research in topics: Hypertriglyceridemia & Sirolimus. The author has an hindex of 3, co-authored 3 publications receiving 349 citations. Previous affiliations of Ghada Abdel-Fattah include University of Texas Health Science Center at Houston.

Sirolimus changes lipid concentrations and lipoprotein metabolism in kidney transplant recipients

Abstract: Background Sirolimus (Rapammune, rapamycin, RAPA) is a strong immunosuppressive agent that reduces kidney transplant rejection Hyperlipidemia is a significant side effect of sirolimus treatment and often leads to vascular disease We have studied the repeatability, reversibility, and dose dependence of the plasma lipid and apoprotein changing effects of sirolimus and attempted to determine the mechanism by which sirolimus induces hypertriglyceridemia in some kidney transplant recipients Methods Six patients with renal allografts maintained on cyclosporine A and prednisone were selected on the basis of their previous hyperlipidemic response to short-term (14 days) sirolimus administration For longer-term treatment, each patient was started on 10 mg/d sirolimus and continued as tolerated for 42 days to reinduce hyperlipidemia Timed blood samples were analyzed for lipid, apoprotein, and sirolimus levels Results During sirolimus administration, mean total plasma cholesterol increased from 214 to 322 mg/dL (+50%); low density lipoprotein-cholesterol levels changed in a similar pattern Mean triglyceride level rose from 227 to 432 mg/dL (+95%) ApoB-100 concentration rose from 124 to 160 mg/dL (+28%) ApoC-III level increased from 289 to 555 mg/dL (+92%) These lipid and apoprotein changes were found to be repeatable, reversible, and dose dependent [13C4]-palmitate metabolic studies in four patients with hypertriglyceridemia indicated that the free fatty acid pool was expanded by sirolimus treatment (mean = 423%) Incorporation of [13C4]-palmitate into triglycerides of very low density lipoprotien, intermediate density lipoprotein, low density lipoproteins was decreased 383%, 421%, and 384%, respectively, by sirolimus treatment of these patients Conclusions These results suggest that sirolimus alters the insulin signaling pathway so as to increase adipose tissue lipase activity, decrease lipoprotein lipase activity, or both, resulting in increased hepatic synthesis of triglyceride, increased secretion of VLDL, and increased hypertriglyceridemia

Regulation of cell apoptosis by insulin-like growth factor I.

Abstract: Correct temporal and spatial regulation of apoptosis is critical for normal mammary gland development and lactation. Previous work with a strain of trans-genic mice that overexpress des(1-3)hIGF-I during pregnancy and lactation suggested that this growth factor inhibits apoptosis. The hypothesis tested within these studies is that overexpression of des(1-3)hIGF-I within the mammary gland inhibits apoptosis and the expression of apoptosis-associated genes that are known to be activated by the transcription factor AP-1. This inhibition of apoptosis was further posited to predispose the tissue to carcinogenesis. TUNEL analysis of mammary tissue from transgenic mice that overexpress des(1-3)hIGF-I under control of the rat whey acidic protein promoter showed only 25% (P < 0.05) of the number of apoptotic cells found in nontransgenic mice at the same stage of lactation. Northern analysis of RNA from these animals showed a 75% (P = 0.08) reduction in c-Jun mRNA abundance. Histological analysis of mammary tissue from nonlactating multiparous WAP-DES mice ranging in age from 13 to 25 months showed a variety of hyper-plastic lesions. These lesions aberrantly expressed the transgene. At 23 months of age 50% of the transgenic mice within this study developed adenocarcinomas. These results support the conclusion that inhibition of apoptosis within the mammary gland by IGF-I involves decreased activity of AP-1 and predisposes the tissue to tumors.

mTOR controls mitochondrial oxidative function through a YY1–PGC-1α transcriptional complex

Abstract: Transcriptional complexes that contain peroxisome-proliferator-activated receptor coactivator (PGC)-1alpha control mitochondrial oxidative function to maintain energy homeostasis in response to nutrient and hormonal signals. An important component in the energy and nutrient pathways is mammalian target of rapamycin (mTOR), a kinase that regulates cell growth, size and survival. However, it is unknown whether and how mTOR controls mitochondrial oxidative activities. Here we show that mTOR is necessary for the maintenance of mitochondrial oxidative function. In skeletal muscle tissues and cells, the mTOR inhibitor rapamycin decreased the gene expression of the mitochondrial transcriptional regulators PGC-1alpha, oestrogen-related receptor alpha and nuclear respiratory factors, resulting in a decrease in mitochondrial gene expression and oxygen consumption. Using computational genomics, we identified the transcription factor yin-yang 1 (YY1) as a common target of mTOR and PGC-1alpha. Knockdown of YY1 caused a significant decrease in mitochondrial gene expression and in respiration, and YY1 was required for rapamycin-dependent repression of those genes. Moreover, mTOR and raptor interacted with YY1, and inhibition of mTOR resulted in a failure of YY1 to interact with and be coactivated by PGC-1alpha. We have therefore identified a mechanism by which a nutrient sensor (mTOR) balances energy metabolism by means of the transcriptional control of mitochondrial oxidative function. These results have important implications for our understanding of how these pathways might be altered in metabolic diseases and cancer.