Decreased triglyceride turnover in PGC1αKO mice during adrenergic stress

ABSTRACTS / Journal of Molecular and Cellular Cardiology 42 (2007) S55–S71

In vivo administration of tetradecylthioacetic acid (TTA) in mice causes cardiac inefficiency and reduced post-ischemic ventricular function Anne D. Hafstad1, Ahmed M. Khalid1, Ole-Jakob How, Rolf Berge 2, Terje S. Larsen1, Ellen Aasum1. 1Institute of Medical Biology, University of Tromsø, Norway. 2Institute of Medicine, University of Bergen, Norway Myocardial fatty acid (FA) oxidation is regulated acutely by the FA supply and chronically by changes at the gene transcriptional level via the PPAR family. The aim of the present study was to examine the effects of tetradecylthioacetic acid (TTA, a pan PPAR agonist) on myocardial metabolism and ventricular function. Balb/c mice were treated for 8 days with TTA (0.5%, added to the diet). Using the isolated working heart we examined myocardial FA and glucose oxidation, cardiac efficiency, i.e. the relationship between myocardial work (pressure–volume area, PVA) and myocardial oxygen consumption (MVO2), as well as functional recovery following 40 min low-flow ischemia. In contrast to previous reports showing only minor changes in cardiac metabolism following PPAR treatment of normal mice, TTA treatment caused a 2.4 fold increase in myocardial FA oxidation with a concomitant reduction in glucose oxidation. Hearts from TTA-treated mice showed a marked reduction in cardiac efficiency, due to a near two-fold increase in the oxygen used for non-contractile processes (i.e. unloaded MVO2). These hearts also showed decreased recovery of ventricular function following low-flow ischemia. We conclude that TTA have a direct and strong stimulatory effect on FA oxidation in the normal mouse heart. This elevation of myocardial FA oxidation leads to a marked increase in MVO2 which could contribute to the reduced ischemic tolerance. Keywords: PPAR; Cardiac metabolism; Cardiac efficiency doi:10.1016/j.yjmcc.2007.03.784

Decreased triglyceride turnover in PGC1αKO mice during adrenergic stress Natasha Banke1, Teresa C. Leone2, John Lehman2, Daniel P. Kelly2, E. Douglas Lewandowski1. 1UIC, Chicago, IL, USA. 2 Washington University, St. Louis, MO, USA PPARγ coactivator-1α (PGC-1α) is an inducible transcription coactivator that promotes expression of genes associated with myocardial fatty acid oxidation and mitochondrial respiration. This study examines the impact of generalized PGC-1α deficiency (PGCKO) on triglyceride (TG) turnover rates in intact beating hearts and the balance between lipid storage and oxidation. Hearts from PGCKO and wild type (WT) littermates were perfused in a 14.1 T NMR magnet with buffer containing 0.4 mM [2,4,6,8,10,12,14,16]-13C palmitate and 10 mM glucose at baseline workload (PGCKO, n = 11; WT, n = 16) and during stress (10− 7 M isoproterenol,

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ISO) (PGCKO ISO, n = 7; WT ISO, n = 5). TG enrichment and turnover rates were determined by dynamic-mode 13C NMR. PGCKO hearts contained 30% more TG than WT (P < 0.05). ISO reduced TG in PGCKO by 14% with a 84% decrease in TG 13C enrichment. TG content in WT remained unchanged, but with a 66% drop in enrichment. With increased oxidative rates in both groups diverting palmitate away from TG during ISO, accounting for reduced TG enrichment, the relative contribution of palmitate to oxidative metabolism dropped in PGCKO by 17% with a shift toward glucose oxidation. These shifts with ISO reduced TG turnover in PGCKO from 2006 ± 684 to 867 ± 444 nmol/mg prot/ min. The dynamic balance between lipid storage and oxidation diverged between PGCKO and WT under adrenergic stress, as PGCKO shifted from palmitate to glucose oxidation with reduced storage of palmitate into TG. PGC-1α deficiency in the stressed heart reduces mobilization of myocardial TG for energy synthesis. Keywords: Metabolism; Fatty acid; Nuclear magnetic resonance doi:10.1016/j.yjmcc.2007.03.785

Fenofibrate exacerbates aberrant cardiolipin profile and mitochondrial dysfunction in the failing SHHF rat heart Adam J. Chicco, Sylvia A. McCune, Meredith L. Rees, Ryan T. Gardner, Russell L. Moore, Genevieve C. Sparagna. University of CO, Boulder, USA Cardiolipin (CL) is a dimeric phospholipid located in the mitochondrial inner membrane where it is essential for optimal mitochondrial energy metabolism. Studies in our laboratory indicate that tetra-linoleoyl CL (L4CL), the predominant CL species found in the healthy mammalian heart, progressively decreases in cardiac mitochondria during the pathogenesis of heart failure (HF). Peroxisome proliferator activated receptor-alpha (PPARα) is a nuclear transcription factor that regulates fatty acid metabolism and is downregulated during the pathogenesis of HF. In the present study, male spontaneously hypertensive HF (SHHF) rats were administered the PPARα-agonist fenofibrate (150 mg/kg/d; FENO), a diet supplemented with 10% linoleic acid (LA), or both for 4 weeks beginning at 22 months of age when animals present with early decompensated LV hypertrophy. FENO significantly reduced levels of L4CL, while CL species with alternate acyl configurations were increased (P < 0.01). FENO also decreased state III mitochondrial respiratory rate (mVO2) and impaired LV systolic function compared to untreated control animals (P < 0.05). LA alone increased L4CL levels, improved mVO2 and attenuated the decline in LV systolic function compared to FENO and control animals (P < 0.05). LA also attenuated the detrimental effects of FENO on these parameters. This study demonstrates for the first time that both PPARα and LA independently regulate CL composition and mitochondrial function in the hypertrophied