Polyunsaturated fatty acid suppression of hepatic fatty acid synthase and S14 gene expression does not require peroxisome proliferator-activated receptor alpha.
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.
Ren
B
B
Departments of Biochemistry and Physiology, Michigan State University, East Lansing, Michigan 48824, USA.
Thelen
A P
AP
Peters
J M
JM
Gonzalez
F J
FJ
Jump
D B
DB
D042962:Acyl-CoA Oxidase; D000818:Animals; D002478:Cells, Cultured; D042926:Cytochrome P-450 CYP4A; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis; D004042:Dietary Fats, Unsaturated / Q000494:pharmacology*; D019587:Dietary Supplements; D064429:Fatty Acid Synthases / Q000096:biosynthesis*; D005395:Fish Oils / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects*; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D008830:Microbodies / Q000201:enzymology; D008862:Microsomes, Liver / Q000201:enzymology; D006899:Mixed Function Oxygenases / Q000096:biosynthesis; D009687:Nuclear Proteins / Q000378:metabolism; D000069463:Olive Oil; D010088:Oxidoreductases / Q000096:biosynthesis; D010938:Plant Oils / Q000494:pharmacology; D014176:Protein Biosynthesis; D011506:Proteins; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects*
D004042:Dietary Fats, Unsaturated; D005395:Fish Oils; D009687:Nuclear Proteins; D000069463:Olive Oil; D010938:Plant Oils; D011506:Proteins; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; C051065:THRSP protein, human; C501477:Thrsp protein, mouse; C501478:Thrsp protein, rat; D014157:Transcription Factors; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D010088:Oxidoreductases; D042926:Cytochrome P-450 CYP4A; D042962:Acyl-CoA Oxidase; D064429:Fatty Acid Synthases