title: Glucocorticoids and cyclic AMP selectively increase hepatic lipin-1 expression, and insulin acts antagonistically.
abstract: Glucocorticoids (GCs) increase hepatic phosphatidate phosphatase (PAP1) activity. This is important in enhancing the liver's capacity for storing fatty acids as triacylglycerols (TAGs) that can be used subsequently for beta-oxidation or VLDL secretion. PAP1 catalyzes the conversion of phosphatidate to diacylglycerol, a key substrate for TAG and phospholipid biosynthesis. PAP1 enzymes in liver include lipin-1A and -1B (alternatively spliced isoforms) and two distinct gene products, lipin-2 and lipin-3. We determined the mechanisms by which the composite PAP1 activity is regulated using rat and mouse hepatocytes. Levels of lipin-1A and -1B mRNA were increased by dexamethasone (dex; a synthetic GC), and this resulted in increased lipin-1 synthesis, protein levels, and PAP1 activity. The stimulatory effect of dex on lipin-1 expression was enhanced by glucagon or cAMP and antagonized by insulin. Lipin-2 and lipin-3 mRNA were not increased by dex/cAMP, indicating that increased PAP1 activity is attributable specifically to enhanced lipin-1 expression. This work provides the first evidence for the differential regulation of lipin activities. Selective lipin-1 expression explains the GC and cAMP effects on increased hepatic PAP1 activity, which occurs in hepatic steatosis during starvation, diabetes, stress, and ethanol consumption.
authors.affiliation: Signal Transduction Research Group, Department of Biochemistry, University of Alberta, Edmonton, Alberta T6G 2S2, Canada.
authors.forename: Boripont
authors.initials: B
authors.lastname: Manmontri
authors.forename: Meltem
authors.initials: M
authors.lastname: Sariahmetoglu
authors.forename: Jimmy
authors.initials: J
authors.lastname: Donkor
authors.forename: Maroun
authors.initials: M
authors.lastname: Bou Khalil
authors.forename: Meenakshi
authors.initials: M
authors.lastname: Sundaram
authors.forename: Zemin
authors.initials: Z
authors.lastname: Yao
authors.forename: Karen
authors.initials: K
authors.lastname: Reue
authors.forename: Richard
authors.initials: R
authors.lastname: Lehner
authors.forename: David N
authors.initials: DN
authors.lastname: Brindley
mesh_terms: D000818:Animals; D018929:Cell Culture Techniques; D000242:Cyclic AMP / Q000494:pharmacology*; D004435:Eating; D005215:Fasting; D005786:Gene Expression Regulation / Q000187:drug effects; D005938:Glucocorticoids / Q000494:pharmacology*; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D009687:Nuclear Proteins / Q000235:genetics*; D000073718:Pancreatitis-Associated Proteins; D017856:Phosphotransferases (Phosphate Group Acceptor) / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D005938:Glucocorticoids; C530902:Lpin1 protein, rat; D009687:Nuclear Proteins; D000073718:Pancreatitis-Associated Proteins; C000612141:REG3A protein, human; D012333:RNA, Messenger; D011994:Recombinant Proteins; D000242:Cyclic AMP; D017856:Phosphotransferases (Phosphate Group Acceptor); C099834:phosphatidic acid kinase