Regulation of phosphatidic acid phosphohydrolase 1 by fatty acids.
In the starved state and during metabolic stress, free fatty acids (FFA) are the principal hepatic energy supply, undergoing beta-oxidation. Accordingly, it appears paradoxical that FFA have been reported to increase the liver's esterification capacity by translocating the rate-limiting enzyme phosphatidic acid phosphohydrolase (PAP-1) from the cytosol to the endoplasmic reticulum. We have therefore investigated the regulation of rat liver PAP-1. Oleic acid inhibited PAP activity in all subcellular fractions, with PAP-1 activity in cytosol being the most sensitive. Inhibition was also observed with oleoyl-CoA, linoleate, and palmitate. Fatty acids and their derivatives show detergent effects at high concentrations, and such effects can lead to enzyme inhibition. Inhibition by oleate, however, was reversed by phosphatidic acid and albumin and exhibited sigmoidal kinetics. These results demonstrate that PAP-1 is reversibly inhibited by FFA and their CoA esters, which may play a role in directing hepatic FFA to beta-oxidation during times of increased energy demand.
Elabbadi
Noureddine
N
School of Biochemistry and Genetics, Medical School, University of Newcastle upon Tyne, United Kingdom.
Day
Christopher P
CP
Virden
Richard
R
Yeaman
Stephen J
SJ
D000214:Acyl Coenzyme A / Q000494:pharmacology; D000818:Animals; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005227:Fatty Acids / Q000494:pharmacology*; D005230:Fatty Acids, Nonesterified / Q000378:metabolism; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D007700:Kinetics; D019787:Linoleic Acid / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008297:Male; D019301:Oleic Acid / Q000494:pharmacology; D019308:Palmitic Acid / Q000494:pharmacology; D000073718:Pancreatitis-Associated Proteins; D010711:Phosphatidate Phosphatase / Q000037:antagonists & inhibitors*; D051381:Rats; D017208:Rats, Wistar
D000214:Acyl Coenzyme A; D004791:Enzyme Inhibitors; D005227:Fatty Acids; D005230:Fatty Acids, Nonesterified; D007527:Isoenzymes; D000073718:Pancreatitis-Associated Proteins; C000612141:REG3A protein, human; C017585:oleoyl-coenzyme A; D019301:Oleic Acid; D019308:Palmitic Acid; D019787:Linoleic Acid; D010711:Phosphatidate Phosphatase