Clofibrate-induced changes in the liver, heart, brain and white adipose lipid metabolome of Swiss-Webster mice

Craig E. Wheelock, Susumu Goto, Bruce D. Hammock, John W. Newman

Research output: Contribution to journalArticle

16 Scopus citations

Abstract

Peroxisome proliferator activated receptor alpha (PPARα) agonists are anti-hyperlipidemic drugs that influence fatty acid combustion, phospholipid biosynthesis and lipoprotein metabolism. To evaluate impacts on other aspects of lipid metabolism, we applied targeted metabolomics to liver, heart, brain and white adipose tissue samples from male Swiss-Webster mice exposed to a 5day, 500 mg/kg/day regimen of i.p. clofibrate. Tissue concentrations of free fatty acids and the fatty acid content of sphingomyelin, cardiolipin, cholesterol esters, triglycerides and phospholipids were quantified. Responses were tissue-specific, with changes observed in the liver > heart > > brain > adipose. These results indicate that liver saturated fatty acid-rich triglycerides feeds clofibrate-induced monounsaturated fatty acid (MUFA) synthesis, which were incorporated into hepatic phospholipids and sphingomyelin. In addition, selective enrichment of docosahexeneoic acid in the phosphatidylserine of liver (1.7-fold), heart (1.6-fold) and brain (1.5-fold) suggests a clofibrate-dependent systemic activation of phosphatidylserine synthetase 2. Furthermore, the observed ∼20% decline in cardiac sphingomyelin is consistent with activation of a sphingomeylinase with a substrate preference for polyunsaturate-containing sphingomyelin. Finally, perturbations in the liver, brain, and adipose cholesterol esters were observed, with clofibrate exposure elevating brain cholesterol arachidonyl-esters ∼20-fold. Thus, while supporting previous findings, this study has identified novel impacts of PPARα agonist exposure on lipid metabolism that should be further explored.

Original languageEnglish (US)
Pages (from-to)137-145
Number of pages9
JournalMetabolomics
Volume3
Issue number2
DOIs
StatePublished - Jun 2007

Keywords

  • Clofibrate
  • Extra-hepatic
  • Lipid metabolism
  • Metabolomics
  • PPAR-alphaagonist
  • Sphingomyelin

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology

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