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The Journal of Lipid Research, Vol. 40, 1045-1052, June 1999
Copyright © 1999 by Lipid Research, Inc.

Original Article

Arachidonic acid and PGE₂ regulation of hepatic lipogenic gene expression

Correspondence to: Donald B. Jump

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 PGF₂) 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 ., A. P. Thelen, and D. B. Jump. Arachidonic acid and PGE₂ regulation of hepatic lipogenic gene expression. J. Lipid Res. 1999. 40: 1045–1052.

Supplementary key words: S14 protein, fatty acid synthase, L-pyruvate kinase, cyclooxygenase, gene transcription

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