Effect of norepinephrine on ketogenesis, fatty acid oxidation, and esterification in isolated rat hepatocytes.
Recent studies in man demonstrated a marked ketogenic effect of increased plasma norepinephrine concentrations as observed in diabetic ketoacidosis. Since this effect may have been due either to increased substrate supply for ketogenesis (lipolysis) or to direct hepatic activation of ketogenesis, the latter mechanism was examined in isolated rat hepatocytes. Incubation of hepatocytes with norepinephrine (10(-7) to 10(-4) M) resulted in a dose-dependent increase in conversion of the long-chain fatty acid [1-14C]palmitate into ketone bodies and CO2. Norepinephrine decreased [1-14C]palmitate conversion into triglycerides without affecting fatty acid uptake. Norepinephrine enhanced ketogenesis from [1-14C]palmitate in a physiologic range of fatty acid concentrations (0.5-2.5 mM), but failed to affect fatty acid esterification to phospholipids or mono- and diglycerides. In contrast to long-chain fatty acids, oxidation of the medium-chain fatty acid [1-14C]octanoate to ketone bodies was not enhanced by norepinephrine, whereas CO2 production increased. The effect of norepinephrine on [1-14C]fatty acid oxidation was blocked by the alpha 1 receptor blocker prazosin. The results demonstrate that norepinephrine diverts long-chain fatty acids into the pathways of oxidation and ketogenesis away from esterification, suggesting enhanced carnitine-dependent mitochondrial fatty acid uptake. The studies using octanoate indicated that norepinephrine also enhanced fatty acid oxidation by increasing the flux of acetyl-CoA through the Krebs cycle. The data suggest that stress-associated sympathetic activation and norepinephrine discharge, as observed in diabetic ketoacidosis, result in direct activation of ketogenesis in the liver.
Oberhaensli
R D
RD
Schwendimann
R
R
Keller
U
U
D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D002210:Caprylates / Q000378:metabolism; D002245:Carbon Dioxide / Q000378:metabolism; D004951:Esterification; D005227:Fatty Acids / Q000378:metabolism*; D066298:In Vitro Techniques; D007657:Ketone Bodies / Q000096:biosynthesis*; D008099:Liver / Q000378:metabolism*; D008297:Male; D009638:Norepinephrine / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D010084:Oxidation-Reduction; D019308:Palmitic Acid; D010169:Palmitic Acids / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains
D000317:Adrenergic alpha-Antagonists; D000319:Adrenergic beta-Antagonists; D002210:Caprylates; D005227:Fatty Acids; D007657:Ketone Bodies; D010169:Palmitic Acids; D002245:Carbon Dioxide; D019308:Palmitic Acid; C031492:octanoic acid; D009638:Norepinephrine