Fraction of hepatic cytosolic acetyl-CoA derived from glucose in vivo: Relation to PDH phosphorylation state

S. Kaempfer, M. Blackham, M. Christiansen, K. Wu, D. Cesar, T. Vary, M. K. Hellerstein

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19 Scopus citations

Abstract

We measured the contribution of glucose to hepatic cytosolic acetyl-CoA in vivo in rats and compared it with the phosphorylation state of a potentially regulatory enzyme complex [pyruvate dehydrogenase (PDH)]. Xenobiotic probes were used to sample hepatic cytosolic acetyl-CoA [acetylated sulfamethoxazole (SMX)] and UDP-glucose (glucuronidated acetaminophen) in vivo during [U-14C]glucose infusions. Percent active (dephosphorylated) form of PDH (PDH(a)) was determined on freeze-clamped liver. First, we confirmed using liver cell elutriation that acetylation of SMX occurs in parenchymal hepatocytes. Next, the fraction of cytosolic acetyl-CoA derived from [14C]glucose in vivo was shown to depend on dietary state. Specific activity of acetyl-CoA relative to plasma glucose or hepatic UDP-glucose was lower after 48 h fasting than after overnight fasting, and glucose refeeding (25 mg·kg-1·min-1 iv) maximally increased [14C]- glucose fractional contribution to acetyl-CoA within 2 h in the overnight-fasted but not in the prolonged fasted group. Hepatic PDH(a) demonstrated a similar but not identical pattern. The isotopic and enzymatic parameters showed significant correlations (r2 = 0.61 in 48-h fasted-refed group, r2 = 0.28 in over-night-fasted refed group), although [14C]glucose contribution to acetyl-CoA increased disproportionately compared with PDH(a) as refeeding progressed. The indirect pathway of UDP-glucose synthesis correlated inversely with the fractional contribution of glucose to acetyl-CoA. In summary, the fraction of hepatic acetyl-CoA derived from glucose in vivo is influenced by acute and chronic dietary factors and is only partially explained by PDH(a). Regulation of the carbon source of hepatic acetyl-CoA in vivo and interactions suggested by these results (e.g., glucose-fatty acid cycle; branch-point regulation of glucose recycling) can be addressed in a quantitative fashion using this experimental framework.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Endocrinology and Metabolism
Volume260
Issue number6 23/6
StatePublished - 1991
Externally publishedYes

Keywords

  • Acetyl-coenzyme A
  • Branch-point control
  • Liver metabolism
  • Metabolic probes
  • Parenchymal hepatocytes
  • Pyruvate dehydrogenase
  • Xenobiotic conjugation

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology
  • Physiology

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    Kaempfer, S., Blackham, M., Christiansen, M., Wu, K., Cesar, D., Vary, T., & Hellerstein, M. K. (1991). Fraction of hepatic cytosolic acetyl-CoA derived from glucose in vivo: Relation to PDH phosphorylation state. American Journal of Physiology - Endocrinology and Metabolism, 260(6 23/6).