George A Cook1, Eduard N Lavrentyev2, Kevin Pham3, Edwards A Park4. 1. Department of Pharmacology, College of Medicine, The University of Tennessee Health Science Center, Memphis, TN 38163, United States. Electronic address: gcook@uthsc.edu. 2. Department of Pharmacology, College of Medicine, The University of Tennessee Health Science Center, Memphis, TN 38163, United States. 3. Department of Veterans Affairs Medical Center, 1030 Jefferson Avenue, Memphis, TN 38104, United States. 4. Department of Pharmacology, College of Medicine, The University of Tennessee Health Science Center, Memphis, TN 38163, United States; Department of Veterans Affairs Medical Center, 1030 Jefferson Avenue, Memphis, TN 38104, United States.
Abstract
BACKGROUND: Diabetic cardiomyopathy develops in insulin-dependent diabetic patients who have no hypertension, cardiac hypertrophy or vascular disease. Diabetes increases cardiac fatty acid oxidation, but cardiac hypertrophy limits fatty acid oxidation. Here we examined effects of diabetes on gene expression in rat hearts. METHODS: We used oligonucleotide microarrays to examine effects of insulindependent diabetes in the rat heart. RTQ PCR confirmed results of microarrays. Specific antibodies were used to examine changes in the mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2). RESULTS: A surprising result of diabetes was increased mRNA encoding all enzymes of the ketone body synthesis pathway. Increased mRNA expression for these enzymes was confirmed by RTQ PCR. The mRNA encoding HMGCS2, the rate-controlling enzyme, was 27 times greater in diabetic hearts. Total HMGCS2 protein increased 8-fold in diabetic hearts, but no difference was found in HMGCS2 protein in control vs. diabetic liver. CONCLUSIONS: Insulin-dependent diabetes induced the enzymes of ketone body synthesis in the heart, including HMGCS2, as well as increasing enzymes of fatty acid oxidation. GENERAL SIGNIFICANCE: The mammalian heart does not export ketone bodies to other tissues, but rather is a major consumer of ketone bodies. Induction of HMGCS2, which is normally expressed only in the fetal and newborn heart, may indicate an adaptation by the heart to combat "metabolic inflexibility" by shifting the flux of excess intramitochondrial acetyl-CoA derived from elevated fatty acid oxidation into ketone bodies, liberating free CoA to balance the acetyl-CoA/CoA ratio in favor of increased glucose oxidation through the pyruvate dehydrogenase complex.
BACKGROUND:Diabetic cardiomyopathy develops in insulin-dependent diabeticpatients who have no hypertension, cardiac hypertrophy or vascular disease. Diabetes increases cardiac fatty acid oxidation, but cardiac hypertrophy limits fatty acid oxidation. Here we examined effects of diabetes on gene expression in rat hearts. METHODS: We used oligonucleotide microarrays to examine effects of insulindependent diabetes in the rat heart. RTQ PCR confirmed results of microarrays. Specific antibodies were used to examine changes in the mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2). RESULTS: A surprising result of diabetes was increased mRNA encoding all enzymes of the ketone body synthesis pathway. Increased mRNA expression for these enzymes was confirmed by RTQ PCR. The mRNA encoding HMGCS2, the rate-controlling enzyme, was 27 times greater in diabetic hearts. Total HMGCS2 protein increased 8-fold in diabetic hearts, but no difference was found in HMGCS2 protein in control vs. diabetic liver. CONCLUSIONS:Insulin-dependent diabetes induced the enzymes of ketone body synthesis in the heart, including HMGCS2, as well as increasing enzymes of fatty acid oxidation. GENERAL SIGNIFICANCE: The mammalian heart does not export ketone bodies to other tissues, but rather is a major consumer of ketone bodies. Induction of HMGCS2, which is normally expressed only in the fetal and newborn heart, may indicate an adaptation by the heart to combat "metabolic inflexibility" by shifting the flux of excess intramitochondrial acetyl-CoA derived from elevated fatty acid oxidation into ketone bodies, liberating free CoA to balance the acetyl-CoA/CoA ratio in favor of increased glucose oxidation through the pyruvate dehydrogenase complex.
Authors: C Des Rosiers; J A Montgomery; M Garneau; F David; O A Mamer; P Daloze; G Toffolo; C Cobelli; B R Landau; H Brunengraber Journal: Am J Physiol Date: 1990-03
Authors: Brian N Finck; John J Lehman; Teresa C Leone; Michael J Welch; Michael J Bennett; Attila Kovacs; Xianlin Han; Richard W Gross; Ray Kozak; Gary D Lopaschuk; Daniel P Kelly Journal: J Clin Invest Date: 2002-01 Impact factor: 14.808
Authors: Feike R van der Leij; Keith B Cox; Vicky N Jackson; Nicolette C A Huijkman; Beatrijs Bartelds; Jaap R G Kuipers; Trijnie Dijkhuizen; Peter Terpstra; Philip A Wood; Victor A Zammit; Nigel T Price Journal: J Biol Chem Date: 2002-05-15 Impact factor: 5.157
Authors: Deborah M Muoio; Robert C Noland; Jean-Paul Kovalik; Sarah E Seiler; Michael N Davies; Karen L DeBalsi; Olga R Ilkayeva; Robert D Stevens; Indu Kheterpal; Jingying Zhang; Jeffrey D Covington; Sudip Bajpeyi; Eric Ravussin; William Kraus; Timothy R Koves; Randall L Mynatt Journal: Cell Metab Date: 2012-05-02 Impact factor: 27.287
Authors: Leroy C Joseph; Jianting Shi; Quynh N Nguyen; Victoria Pensiero; Chris Goulbourne; Robert C Bauer; Hanrui Zhang; John P Morrow Journal: iScience Date: 2022-04-01