Effect of Mitochondrial Ca2+ on Hepatic Aspartate Formation and Gluconeogenic Flux
According to current evidence, the mechanism of action of many gluconeogenic hormones involves a rise in intracellular free Ca2+ (Charestet al., 1983; Sistareet al., 1985). There is general agreement that hepatic gluconeogenesis is controlled at several sites in the pathway by Ca2+ -and cAMP-mediated phosphorylations of cytosolic enzymes (Hers and Hue, 1983; Pilkiset al., 1986). Nevertheless, there is a perception that other Ca2+ -linked sites of action may be important; in particular, those which involve mitochondrial enzymes (Leverveet al., 1986; McCormack, 1985; Staddon and Hansford, 1987). The purpose of the study was to evaluate the significance of the stimulation by Ca2+ ofα-ketoglutarate dehydrogenase (McCormack, 1985) and pyruvate dehydrogenase (Oviasu and Whitton, 1984) which occurs following exposure of the liver to glucagon or phenylephrine. The dramatic decrease inα-toglutarate caused by these hormones (Siesset al., 1977) is rather convincingly due to the stimulation ofα-ketoglutarate dehydrogenase. Studies from this laboratory (LaNoueet al., 1983; Schoolwerth and LaNoue, 1983) showed thatα-ketoglutarate is a potent and physiologically important inhibitor of glutamate dehydrogenase. Stimulation ofα-ketoglutarate dehydrogenase relieves inhibition of glutamate dehydrogenase byα-ketoglutarate and, thereby, may stimulate gluconeogenesis from amino acids. Glucagon and phenylephrine are also known to stimulate gluconeogenesis from lactate (Hutsonet al., 1976; Kneeret al., 1979), and to stimulate alcohol oxidation (Ochs and Lardy, 1981) and the malate-aspartate cycle (Kneeret al., 1979; Leverveet al., 1986). These processes do not involve glutamate dehydrogenase but rather aspartate aminotransferase and the glutamate aspartate translocase (Rognstad and Katz, 1970; Williamsonet al., 1971).
KeywordsPyruvate Kinase Phorbol Ester Pyruvate Dehydrogenase Glutamate Dehydrogenase Perfuse Liver
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- LaNoue, K. F., Sterniczuk, A., Strzelecki, T., Hreniuk, S., Scaduto, R., Jr., 1987, The effect of mitochondrial Ca2+ on hepatic aspartate formation and gluconeogenic flux. In: Integration of Mitochondrial Function (J. J. Lemasters, C. R. Hackenbrock, R. G. Thurman, and H. V. Esterhoff, eds.), in press.Google Scholar
- Trinder, P., 1969, Ann. Clin. Biochem. 6:24.Google Scholar