The metabolism of long chain fatty acids is profoundly altered in diabetes and hyperthyroidism. Carnitine palmitoyltransferase I (CPT-I) regulates the entry of long chain fatty acids into mitochondria and is a rate controlling step in the pathway of fatty acid oxidation. We have examined both the """"""""liver"""""""" (CPT-Ialpha) and """"""""muscle"""""""" (CPT-Ibeta) isoforms of CPT-I in the liver and heart respectively. Studies from our laboratory have demonstrated that CPT-Ialpha activity and gene expression are elevated in diabetes and hyperthyroidism. Our overall goal is to understand the mechanisms by which the expression of CPT-I gene isoforms and mitochondrial fatty acid oxidation are stimulated in these states. The peroxisomal proliferator activated receptor gamma coactivator-1 (PGC-1) is a transcriptional coactivator that promotes mitochondrial biogenesis. PGC-1 is expressed in metabolically active tissues such as the heart and liver. We propose to investigate the role of PGC-1 in the induction of CPT-I genes. Recently we have discovered that PGC-1 enhances CPT-Ialpha gene expression. In the liver, the abundance of PGC- 1 is increased in diabetes and by thyroid hormone (T3). In these studies, we will investigate the role of PGC-1 in regulating fatty acid oxidation and define the mechanisms through which PGC-I stimulates CPT-Ialpha gene expression. T3 is a key regulator of lipid metabolism. We have identified a thyroid hormone response element in the CPT-Ialpha promoter and discovered that elements within the first intron are crucial for liver specific induction by T3. We will define the unique role of the first intron in the T3 induction of CPT-Ialpha gene expression. Fatty acids are a primary source of energy for cardiac myocytes, and fatty acid oxidation is increased at the expense of glucose utilization in the diabetic heart. PGC-1 stimulates CPT-Ibeta gene expression. We will examine the mechanisms by which PGC-1 stimulates CPT-Ibeta gene expression in the heart. Disorders of lipid and glucose metabolism contribute to a number of clinical complications observed in diabetes and altered thyroid states. This proposal will examine novel molecular mechanism underlying alterations in the gene expression of critical enzymes in the mitochondrial pathway of beta-oxidation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK059368-04
Application #
7054670
Study Section
Metabolism Study Section (MET)
Program Officer
Laughlin, Maren R
Project Start
2003-05-01
Project End
2008-04-30
Budget Start
2006-05-01
Budget End
2008-04-30
Support Year
4
Fiscal Year
2006
Total Cost
$235,643
Indirect Cost
Name
University of Tennessee Health Science Center
Department
Pharmacology
Type
Schools of Medicine
DUNS #
941884009
City
Memphis
State
TN
Country
United States
Zip Code
38163
Sharma, Pragya; Levesque, Tania; Boilard, Eric et al. (2014) Thyroid hormone status regulates the expression of secretory phospholipases. Biochem Biophys Res Commun 444:56-62
Wang, Ruishan; Li, Jing Jing; Diao, Shiyong et al. (2013) Metabolic stress modulates Alzheimer's ?-secretase gene transcription via SIRT1-PPAR?-PGC-1 in neurons. Cell Metab 17:685-94
Thakran, Shalini; Sharma, Pragya; Attia, Ramy R et al. (2013) Role of sirtuin 1 in the regulation of hepatic gene expression by thyroid hormone. J Biol Chem 288:807-18
Sharma, Pragya; Thakran, Shalini; Deng, Xiong et al. (2013) Nuclear corepressors mediate the repression of phospholipase A2 group IIa gene transcription by thyroid hormone. J Biol Chem 288:16321-33
Deng, Xiong; Zhang, Wenwei; O-Sullivan, InSug et al. (2012) FoxO1 inhibits sterol regulatory element-binding protein-1c (SREBP-1c) gene expression via transcription factors Sp1 and SREBP-1c. J Biol Chem 287:20132-43
Kashfi, Khosrow; Mynatt, Randall L; Park, Edwards A et al. (2011) Membrane microenvironment regulation of carnitine palmitoyltranferases I and II. Biochem Soc Trans 39:833-7
Attia, Ramy R; Sharma, Pragya; Janssen, Rachel C et al. (2011) Regulation of pyruvate dehydrogenase kinase 4 (PDK4) by CCAAT/enhancer-binding protein beta (C/EBPbeta). J Biol Chem 286:23799-807
Connaughton, Sara; Chowdhury, Farhana; Attia, Ramy R et al. (2010) Regulation of pyruvate dehydrogenase kinase isoform 4 (PDK4) gene expression by glucocorticoids and insulin. Mol Cell Endocrinol 315:159-67
Attia, Ramy R; Connnaughton, Sara; Boone, Lindsey R et al. (2010) Regulation of pyruvate dehydrogenase kinase 4 (PDK4) by thyroid hormone: role of the peroxisome proliferator-activated receptor gamma coactivator (PGC-1 alpha). J Biol Chem 285:2375-85
Song, Shulan; Attia, Ramy R; Connaughton, Sara et al. (2010) Peroxisome proliferator activated receptor alpha (PPARalpha) and PPAR gamma coactivator (PGC-1alpha) induce carnitine palmitoyltransferase IA (CPT-1A) via independent gene elements. Mol Cell Endocrinol 325:54-63

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