Document Detail

Unsaturated fatty acid regulation of peroxisome proliferator-activated receptor alpha activity in rat primary hepatocytes.
MedLine Citation:
PMID:  12853447     Owner:  NLM     Status:  MEDLINE    
Peroxisome proliferator-activated receptors (PPARs alpha, beta, gamma1, and gamma2) 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 PPARalpha 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 PPARalpha 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 PPARalpha 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 PPARalpha-regulated transcript mRNACYP4A. 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 beta-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 PPARalpha. These studies suggest that basal fatty acid levels in the NEFA pool coupled with rates of fatty acid esterification, elongation, desaturation, peroxisomal beta-oxidation, and fatty acyl thioestease activity are important determinants controlling NEFA pool composition and PPARalpha activity.
Anjali Pawar; Donald B Jump
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.; Research Support, U.S. Gov't, P.H.S.     Date:  2003-07-09
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  278     ISSN:  0021-9258     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2003 Sep 
Date Detail:
Created Date:  2003-09-15     Completed Date:  2003-11-20     Revised Date:  2012-05-09    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  35931-9     Citation Subset:  IM    
Department of Physiology, Michigan State University, East Lansing, Michigan 48824, USA.
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MeSH Terms
Blotting, Northern
Cells, Cultured
Chromatography, High Pressure Liquid
Fatty Acids / chemistry,  metabolism
Fatty Acids, Unsaturated / metabolism*
Gene Expression Regulation
Hepatocytes / metabolism*
Lipid Metabolism
Lipids / chemistry
Luciferases / metabolism
Oxygen / metabolism
Peroxisomes / metabolism
Rats, Sprague-Dawley
Receptors, Cytoplasmic and Nuclear / metabolism*
Time Factors
Transcription Factors / metabolism*
Transcription, Genetic
Grant Support
Reg. No./Substance:
0/Fatty Acids; 0/Fatty Acids, Unsaturated; 0/Ligands; 0/Lipids; 0/Receptors, Cytoplasmic and Nuclear; 0/Transcription Factors; 7782-44-7/Oxygen; EC 1.13.12.-/Luciferases

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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