Polyunsaturated Fatty Acid Suppression of Hepatic Fatty Acid Synthase and S14 Gene Expression Does Not Require Peroxisome Proliferator-activated Receptor α

Bing Ren,Annette P Thelen,Jeffrey M Peters,Frank J Gonzalez,Donald B Jump

doi:10.1074/jbc.272.43.26827

Bing Ren, Annette P Thelen + Show 3 more

Open Access

https://doi.org/10.1074/jbc.272.43.26827

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Abstract

Dietary polyunsaturated fatty acids (PUFA) induce hepatic peroxisomal and microsomal fatty acid oxidation and suppress lipogenic gene expression. The peroxisome proliferator-activated receptor alpha (PPARalpha) has been implicated as a mediator of fatty acid effects on gene transcription. This report uses the PPARalpha-deficient mouse to examine the role of PPARalpha in the PUFA regulation of mRNAs encoding hepatic lipogenic (fatty acid synthase (FAS) and the S14 protein (S14)), microsomal (cytochrome P450 4A2 (CYP4A2)), and peroxisomal (acyl-CoA oxidase (AOX)) enzymes. PUFA ingestion induced mRNAAOX (2.3-fold) and mRNACYP4A2 (8-fold) and suppressed mRNAFAS and mRNAS14 by >/=80% in wild type mice. In PPARalpha-deficient mice, PUFA did not induce mRNAAOX or mRNACYP4A2, indicating a requirement for PPARalpha in the PUFA-mediated induction of these enzymes. However, PUFA still suppressed mRNAFAS and mRNAS14 in the PPARalpha-deficient mice. Studies in rats provided additional support for the differential regulation of lipogenic and peroxisomal enzymes by PUFA. These studies provide evidence for two distinct pathways for PUFA control of hepatic lipid metabolism. One requires PPARalpha and is involved in regulating peroxisomal and microsomal enzymes. The other pathway does not require PPARalpha and is involved in the PUFA-mediated suppression of lipogenic gene expression.

Highlights

Polyunsaturated Fatty Acid Suppression of Hepatic Fatty Acid Synthase and S14 Gene Expression Does Not Require Peroxisome Proliferator-activated Receptor ␣*
Fish oil did not significantly induce mRNAAOX and mRNACYP4A2 in the peroxisome proliferator-activated receptor (PPAR)␣ null (Ϫ/Ϫ) mice. These results indicate that PPAR␣ is required for the PUFAmediated induction of acyl-CoA oxidase (AOX) and cytochrome P450A2 (CYP4A2) mRNAs
PPAR␣ is the predominant PPAR subtype expressed in rat liver and it plays a central role in the induction of hepatic

Summary

Introduction

Polyunsaturated Fatty Acid Suppression of Hepatic Fatty Acid Synthase and S14 Gene Expression Does Not Require Peroxisome Proliferator-activated Receptor ␣*. Dietary polyunsaturated fatty acids (PUFA) induce hepatic peroxisomal and microsomal fatty acid oxidation and suppress lipogenic gene expression. The peroxisome proliferator-activated receptor ␣ (PPAR␣) has been implicated as a mediator of fatty acid effects on gene transcription. Dietary polyunsaturated fatty acids (PUFAs), in particular highly unsaturated n-3 fatty acids, suppress hepatic lipogenesis and triglyceride synthesis/secretion while inducing peroxisomal and microsomal fatty acid oxidation (1–12). These effects on lipid metabolism are due to changes in gene expression leading to induction or suppression of mRNAs encoding key metabolic enzymes (4, 13–19). PPAR␣ has been shown to interfere with thyroid hormone action by sequestering RXR␣, a factor required for thyroid hormone receptor binding to DNA (36 –38)

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