Abstract:
:Previous studies have demonstrated that pyruvate dehydrogenase kinase (PDHK) activity in extracts of rat cardiac mitochondria is increased @two-fold by providing a high-fat diet for 28 days. The present study sought to establish the factor(s) that might underlie the response of cardiac PDHK to the provision of a high-fat diet. ELISA assays of PDHKII, conducted over a range of PDHK activities, demonstrated that the increase in cardiac PDHK activity was not due to an increase in mitochondrial immunoreactive PDHKII concentration. The pyruvate concentration giving 50% active PDHC (PDHa) in mitochondria incubated with respiratory substrates was unaffected by high-fat feeding, demonstrating a dissociation between increased PDHK activity and altered sensitivity of PDHK to suppression by pyruvate. In cardiac myocytes cultured (25 h) with n-octanoate (1 mm) plus dibutyryl cAMP (50 microM), insulin at 12.5 microU/ml, 25 microU/ml and 75 microU/ml, suppressed PDHK activities in cells prepared from control rats, but insulin at concentrations <100 microU/ml failed to suppress PDHK activities in cardiac myocytes prepared from high-fat-fed rats. In vivo, cardiac insulin sensitivity (assessed by euglycaemic hyperinsulinaemic clamp in combination with 2-[3H] deoxyglucose administration) was suppressed after high-fat feeding. A sustained (24 h) two- to four-fold elevation in plasma insulin concentration (achieved by insulin infusion via osmotic pumps) did not affect PDHK activity in hearts of control rats. In contrast, PDHK activity in hearts of high-fat-fed rats was suppressed to values not significantly different from (insulin-infused) control rats. Basal and agonist-stimulated cAMP concentrations were unaffected by high-fat-feeding or insulin. Furthermore, rates of palmitate oxidation (to CO2) in cardiac myocytes (in the absence or presence of insulin or adrenergic agonists) were not statistically significantly affected by high-fat-feeding. The results indicate that an impaired action of insulin to suppress PDHK participates in the mechanism by which increased PDHK activity is achieved in response to high-fat feeding, but insulin does not act through decreasing cAMP concentrations or suppressing fatty acid oxidation.
journal_name
J Mol Cell Cardioljournal_title
Journal of molecular and cellular cardiologyauthors
Sugden MC,Orfali KA,Fryer LG,Holness MJ,Priestman DAdoi
10.1006/jmcc.1997.0425subject
Has Abstractpub_date
1997-07-01 00:00:00pages
1867-75issue
7eissn
0022-2828issn
1095-8584pii
S0022-2828(97)90425-9journal_volume
29pub_type
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journal_title:Journal of molecular and cellular cardiology
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journal_title:Journal of molecular and cellular cardiology
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journal_title:Journal of molecular and cellular cardiology
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journal_title:Journal of molecular and cellular cardiology
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journal_title:Journal of molecular and cellular cardiology
pub_type: 杂志文章
doi:10.1006/jmcc.1996.0105
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journal_title:Journal of molecular and cellular cardiology
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pub_type: 杂志文章
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journal_title:Journal of molecular and cellular cardiology
pub_type: 杂志文章
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journal_title:Journal of molecular and cellular cardiology
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journal_title:Journal of molecular and cellular cardiology
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