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J. Biol. Chem., Vol. 278, Issue 38, 35931-35939, September 19, 2003

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Unsaturated Fatty Acid Regulation of Peroxisome Proliferator-activated Receptor Activity in Rat Primary Hepatoctes^*

Anjali Pawar and Donald B. Jump 

From the Departments of Physiology, Biochemistry and Molecular Biology, Michigan State University, East Lansing, Michigan 48824

Peroxisome proliferator-activated receptors (PPARs , , 1, and 2) are widely regarded as monitors of intracellular nonesterified fatty acid (NEFA) levels. As such, fatty acid binding to PPAR leads to changes in the transcription of many genes involved in lipid metabolism and storage. Although the composition of the intracellular NEFA pool is likely an important factor controlling PPAR activity, little information is available on factors affecting its composition. Accordingly, we have examined the effects of exogenous fatty acids on PPAR activity and NEFA pool composition in rat primary hepatocytes. Prior to the addition of fatty acids to primary hepatocytes, nonesterified unsaturated fatty acid levels are very low, representing 0.5% of the total fatty acid in the cell. The relative abundance of putative PPAR ligands in the NEFA pool is 20:4n-6 = 18:2n-6 = 18:1n-9 > 22:6n-3 > 18:3n-3/6 = 20:5n-3. Of these fatty acids, only 20:5n-3 and 22:6n-3 consistently induced PPAR activity. Metabolic labeling of primary hepatocytes indicated that both ¹⁴C-18:1n-9 and ¹⁴C-20:5n-3 are rapidly assimilated into neutral and polar lipids. Although the addition of 18:1n-9 had no effect on NEFA pool composition, 20:5n-3 mass increased >15-fold within 90 min. Changes in NEFA pool 20:5n-3 mass correlated with dynamic changes in the PPAR-regulated transcript mRNA_CYP4A. Metabolic labeling also indicated that a significant fraction of ¹⁴C-20:5n-3 was elongated to 22:5n-3. Cells treated with 22:5n-3 or 22:6n-3 led to a significant accumulation of 20:5n-3 in the NEFA pool through a process that requires peroxisomal -oxidation and fatty acyl CoA thioesterase activity. Further analyses suggest that 20:5n-3 and 22:6n-3, but not 22:5n-3, are active ligands for PPAR. These studies suggest that basal fatty acid levels in the NEFA pool coupled with rates of fatty acid esterification, elongation, desaturation, peroxisomal -oxidation, and fatty acyl thioestease activity are important determinants controlling NEFA pool composition and PPAR activity.

Received for publication, June 12, 2003 , and in revised form, June 25, 2003.

^* This work was supported by National Institutes of Health Grant DK43220, United States Department of Agriculture Grant 98-35200-6064, and funds from the Michigan Agriculture Experiment Station. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Department of Physiology, 3165 Biomedical and Physical Science Bldg., Michigan State University, East Lansing, MI 48824. Tel.: 517-355-6475 (ext. 1133); Fax: 517-355-5125; E-mail: Jump{at}msu.edu.

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