Arachidonic acid and PGE2 regulation of hepatic lipogenic gene expression.
N-6 polyunsaturated fatty acids (PUFA) suppress hepatic and adipocyte de novo lipogenesis by inhibiting the transcription of genes encoding key lipogenic proteins. In cultured 3T3-L1 adipocytes, arachidonic acid (20:4,n-6) suppression of lipogenic gene expression requires cyclooxygenase (COX) activity. In this study, we found no evidence to support a role for COX-1 or -2 in the 20:4,n-6 inhibition of hepatocyte lipogenic gene expression. In contrast to L1 preadipocytes, adipocytes and rat liver, RT-PCR and Western analyses did not detect COX-1 or COX-2 expression in cultured primary hepatocytes. Moreover, the COX inhibitor, flurbiprofen, did not affect the 20:4,n-6 regulation of lipogenic gene expression in primary hepatocytes. Despite the absence of COX-1 and -2 expression in primary hepatocytes, prostaglandins (PGE2 and PGF2alpha) suppressed fatty acid synthase, l-pyruvate kinase, and the S14 protein mRNA, while having no effect on acyl-CoA oxidase or CYP4A2 mRNA. Using PGE2 receptor agonist, the PGE2 effect on lipogenic gene expression was linked to EP3 receptors. PGE2 inhibited S14CAT activity in transfected primary hepatocytes and targeted the S14 PUFA-response region located -220 to -80 bp upstream from the transcription start site. Taken together, these studies show that COX-1 and COX-2 do not contribute to the n-6 PUFA suppression of hepatocyte lipogenic gene expression. However, cyclooxygenase products from non-parenchymal cells can act on parenchymal cells through a paracrine process and mimic the effects of n-6 PUFA on lipogenic gene expression.
Mater
M K
MK
Departments of Physiology and Biochemistry, Michigan State University, East Lansing, MI 48824, USA.
Thelen
A P
AP
Jump
D B
DB
D042962:Acyl-CoA Oxidase; D017667:Adipocytes / Q000201:enzymology; D000818:Animals; D016718:Arachidonic Acid / Q000494:pharmacology*; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D042926:Cytochrome P-450 CYP4A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D015232:Dinoprostone / Q000494:pharmacology*; D064429:Fatty Acid Synthases / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects*; D007527:Isoenzymes / Q000235:genetics; D008055:Lipids / Q000096:biosynthesis* / Q000235:genetics*; D008099:Liver / Q000201:enzymology*; D008297:Male; D008565:Membrane Proteins; D006899:Mixed Function Oxygenases / Q000235:genetics; D009687:Nuclear Proteins; D010088:Oxidoreductases / Q000235:genetics; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics; D011506:Proteins / Q000235:genetics; D011770:Pyruvate Kinase / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors
D007527:Isoenzymes; D008055:Lipids; D008565:Membrane Proteins; D009687:Nuclear Proteins; D011506:Proteins; D012333:RNA, Messenger; C051065:THRSP protein, human; C501478:Thrsp protein, rat; D014157:Transcription Factors; D016718:Arachidonic Acid; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D010088:Oxidoreductases; D042926:Cytochrome P-450 CYP4A; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; C496513:Ptgs1 protein, rat; D042962:Acyl-CoA Oxidase; D064429:Fatty Acid Synthases; D011770:Pyruvate Kinase; D015232:Dinoprostone