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Carnitine Palmitoyl Transferase-I (CAT-I)

New Exercise Hormone That Potentially Converts White Fat into Brown Fat

Carnitine palmitoyl transferase-I inhibition prevents ventricular remodeling and delays decompensation in pacing-induced heart failure:

OBJECTIVE: Experimental evidence suggests that modulation of myocardial substrate metabolism can markedly affect the progression of chronic heart failure (HF). We tested whether the inhibition of carnitine palmitoyl transferase-I (CPT-I), the enzyme regulating mitochondrial fatty acid oxidation, slows left ventricular remodeling and deterioration of function in pacing-induced HF.
METHODS: Normal dogs (n=9) were compared to untreated dogs with pacing-induced HF (n=9) and HF dogs treated with 65 mg/kg/day of oxfenicine (HF+Oxf, n=9), a CPT-I inhibitor.
RESULTS: HF+Oxf reached terminal failure (LV end-diastolic pressure=25 mm Hg) 6 days later than untreated HF (P<0.05). At 28 days of pacing, hemodynamic alterations and LV dilation were significantly attenuated and the 25% decrease in LV wall thickness was completely prevented in HF+Oxf vs. untreated HF, as was the activation of matrix metalloproteinase-2 and -9, markers of tissue remodeling. Oxfenicine also prevented HF-induced transcriptional down-regulation of CPT-I, medium chain acyl-CoA dehydrogenase, GAPDH and citrate synthase, key enzymes of cardiac energy metabolism. In addition, mRNA, but not protein levels of the nuclear receptor peroxisome proliferator-activated receptor-alpha were reduced in untreated HF, while they did not change significantly in HF+Oxf, as compared to control.
CONCLUSIONS: CPT-I inhibition early in the development of HF prevented LV wall thinning and delayed the time to end-stage failure. While these results are limited to an experimental model of disease, they nevertheless suggest that CPT-I inhibition might be effective for slowing the progression of clinical HF.

Lionetti V, et al. Cardiovasc Res. 2005 Jun 1;66(3):454-61. Epub 2005 Mar 3.

 

Carnitine palmitoyl transferase I and the control of beta-oxidation in heart mitochondria:

Mitochondrial beta-oxidation provides much of the fuel requirements of heart and skeletal muscle despite the malonyl-CoA concentration greatly exceeding the IC(50) of carnitine palmitoyl transferase for malonyl-CoA. To try to explore the relationship between inhibition of carnitine palmitoyl transferase I activity and beta-oxidation flux, we measured the flux control coefficient of carnitine palmitoyl transferase I over beta-oxidation carbon flux in suckling rat heart mitochondria. The flux control coefficient was found to be 0.08 +/- 0.05 and 50% of carnitine palmitoyl transferase I activity could be inhibited before beta-oxidation flux was affected. These observations may help to explain the presence of high rates of beta-oxidation despite the high concentration of malonyl-CoA in rat heart; we hypothesize that although not rate-limiting in vitro, carnitine palmitoyl transferase is rate-limiting in vivo because of the high malonyl-CoA concentration in heart and muscle.

Eaton S, et al. Biochem Biophys Res Commun. 2001 Jul 13;285(2):537-9.

 

Differential effects of neonatal endotoxemia on heart and kidney carnitine palmitoyl transferase I:

BACKGROUND/PURPOSE: The heart and kidney are both affected in sepsis-related multiple organ failure. Both utilize fatty acid substrates during the neonatal period, and impairment of oxidative metabolism during sepsis could lead to bioenergetic failure. The enzyme carnitine palmitoyl transferase I (CPT I) is important in the control of fat oxidation in the neonatal period. The aim of this study was to determine the effects of sepsis on neonatal cardiac and renal CPT I.
METHODS: Suckling rats received 300 microgram/kg lipopolysaccharide intraperitoneally. Mitochondria were isolated from the heart and kidney after 2 hours. CPT I and II activity were measured radiochemically. Protein levels of M- and L- isoforms of CPT I, both of which are present in heart, were determined by Western blotting.
RESULTS: CPT I activity was decreased significantly in the heart but not in the kidney by endotoxemia, whereas CPT II activity was the same in each organ. To investigate the mechanism of this decrease, we carried out Western blotting of the CPT I isoforms in heart mitochondria. Neither M- nor L- isoform was decreased in amount. To determine whether free-radical attack could directly inhibit CPT I activity, control heart mitochondria were incubated with free-radical generating systems. Although hydrogen peroxide had no effect on CPT I activity, the reactive oxygen species nitric oxide, superoxide, and peroxynitrite, all of which are generated in the heart during sepsis, significantly inhibited CPT I activity.
CONCLUSIONS: The activity of CPT I, a rate-controlling step of fat oxidation, is significantly impaired in heart but not in kidney during neonatal sepsis. This may be caused by direct attack by free radicals, suggesting that antioxidant strategies could be of use in preventing sepsis-related cardiac damage.

Fukumoto K., et al. J Pediatr Surg. 2002 May;37(5):723-6.

Western Blot Analysis using CPT-IC (769-798) (Mouse) (H-002-87)


Sequence

%002-87%


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