Diet, especially a high-fat diet, is of great concern to Americans for it has far-reaching effects on their health and well being. Obesity is a major health factor that affects the body's susceptibility to a variety of diseases such as heart attack, stroke, and diabetes. Obesity is a measure of the fat deposited in the adipose in consequence to food intake, fatty acid and triglyceride synthesis and fatty acid oxidation and energy consumption. Excess food provides not only the timely energy needs of the body, but promotes glycogen synthesis and storage in liver and muscle and fatty acid and triglyceride synthesis and storage in the fat tissues. Calorie restriction or starvation promotes glycogenolysis that supplies glucose where needed and lipolysis that supplies fatty acids for oxidation and energy production. Insulin and glucagon are the hormones that coordinate these processes. Malonyl-CoA, the key intermediate in fatty acid synthesis, has recently assumed an additional role as a second messenger that regulates energy levels (ATP) through fatty acid oxidation, which in turn affects fatty acid synthesis and carbohydrate metabolism. The acetyl-CoA carboxylases, ACC1 and ACC2, catalyze malonyl-CoA synthesis, through the carboxylation of acetyl-C0A, the product of pyruvate dehydrogenase. Hence, studies of the carboxylases interrelate three major metabolic pathways-carbohydrate metabolism, fatty acid synthesis, and fatty acid oxidation. The differential expression of ACC1 and ACC2 in various tissues suggests that they may have differential functions. We showed that ACC2 is associated with the mitochondria, and through its product malonyl-CoA, it may be involved in the regulation of fatty acid oxidation. ACC 1 is localized in the cytosol and generates malonyl-C0A for the synthesis of fatty acids. Results from knockout mouse models of ACC 1 and ACC2 support the hypothesis that ACC1 and ACC2 play distinct and different roles in animal physiology and energy metabolism. A mutation in ACC1 led to embryonic lethality. Acc2-/- mutant mice had normal life span, higher fatty acid oxidation rate, and accumulated less fat in their livers and adipose tissues than the wild-type mice fed the same normal diet. We plan to study the biochemical and physiological implications of these observations as they relate to our understanding of the hormonal and dietary regulation of fatty acid metabolism in normal and disease states, especially those of diabetes and obesity.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM063115-03
Application #
6723766
Study Section
Medical Biochemistry Study Section (MEDB)
Program Officer
Jones, Warren
Project Start
2002-04-01
Project End
2006-03-31
Budget Start
2004-04-01
Budget End
2005-03-31
Support Year
3
Fiscal Year
2004
Total Cost
$316,050
Indirect Cost
Name
Baylor College of Medicine
Department
Biochemistry
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
Jung, Dongju; Abu-Elheiga, Lutfi; Ayuzawa, Rie et al. (2012) Mislocalization and inhibition of acetyl-CoA carboxylase 1 by a synthetic small molecule. Biochem J 448:409-16
Abu-Elheiga, Lutfi; Wu, Hongmei; Gu, Ziwei et al. (2012) Acetyl-CoA carboxylase 2-/- mutant mice are protected against fatty liver under high-fat, high-carbohydrate dietary and de novo lipogenic conditions. J Biol Chem 287:12578-88
Kamisuki, Shinji; Shirakawa, Takashi; Kugimiya, Akira et al. (2011) Synthesis and evaluation of diarylthiazole derivatives that inhibit activation of sterol regulatory element-binding proteins. J Med Chem 54:4923-7
Zhang, Wei; Chakravarty, Bornali; Zheng, Fei et al. (2011) Crystal structure of FAS thioesterase domain with polyunsaturated fatty acyl adduct and inhibition by dihomo-gamma-linolenic acid. Proc Natl Acad Sci U S A 108:15757-62
Mao, Jianqiang; Yang, Tao; Gu, Ziwei et al. (2009) aP2-Cre-mediated inactivation of acetyl-CoA carboxylase 1 causes growth retardation and reduced lipid accumulation in adipose tissues. Proc Natl Acad Sci U S A 106:17576-81
Kamisuki, Shinji; Mao, Qian; Abu-Elheiga, Lutfi et al. (2009) A small molecule that blocks fat synthesis by inhibiting the activation of SREBP. Chem Biol 16:882-92
Wakil, Salih J; Abu-Elheiga, Lutfi A (2009) Fatty acid metabolism: target for metabolic syndrome. J Lipid Res 50 Suppl:S138-43
Essop, M Faadiel; Camp, Heidi S; Choi, Cheol Soo et al. (2008) Reduced heart size and increased myocardial fuel substrate oxidation in ACC2 mutant mice. Am J Physiol Heart Circ Physiol 295:H256-65
Choi, Cheol Soo; Savage, David B; Abu-Elheiga, Lutfi et al. (2007) Continuous fat oxidation in acetyl-CoA carboxylase 2 knockout mice increases total energy expenditure, reduces fat mass, and improves insulin sensitivity. Proc Natl Acad Sci U S A 104:16480-5
Mao, Jianqiang; DeMayo, Francesco J; Li, Huiguang et al. (2006) Liver-specific deletion of acetyl-CoA carboxylase 1 reduces hepatic triglyceride accumulation without affecting glucose homeostasis. Proc Natl Acad Sci U S A 103:8552-7

Showing the most recent 10 out of 18 publications