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

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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 5 day, 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.

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Acknowledgements

The authors thank Raymond Wan and Hiroshi Mamitsuka for many useful discussions. C.E.W. was supported by a Japanese Society for the Promotion of Science (JSPS) post-doctoral fellowship and NIH post-doctoral training grant T32 DK07355-22. This work was supported in part by NIH/NIEHS R01 ES013933, NIEHS Grant R37 ES02710, NIEHS Superfund Grant P42 ES04699, and NIEHS Center for Environmental Health Sciences Grant P30 ES05707. The authors thank Alan Buckpitt, Dexter Morin, Ryan Davis, David Lawson and C.J. Dillard for technical assistance.

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  1. Craig E. Wheelock

    Present address: Karolinska Biomics Center, Karolinska University Hospital Solna, Karolinska Institute, Building Z5:02, 17176, Stockholm, Sweden

  2. John W. Newman

    Present address: United States Department of Agriculture, Agricultural Research Service, Western Human Nutrition Research Center, Davis, CA, 95616, USA

Authors and Affiliations

  1. Department of Entomology and Cancer Research Center, University of California, Davis, CA, 95616, USA

    Craig E. Wheelock, Bruce D. Hammock & John W. Newman

  2. Bioinformatics Center, Institute for Chemical Research, Kyoto University, Kyoto, 611-0011, Japan

    Craig E. Wheelock & Susumu Goto

  3. Department of Nutrition, University of California Davis, Davis, CA, 95616, USA

    John W. Newman

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  1. Craig E. Wheelock
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Correspondence to Bruce D. Hammock.

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Wheelock, C.E., Goto, S., Hammock, B.D. et al. Clofibrate-induced changes in the liver, heart, brain and white adipose lipid metabolome of Swiss-Webster mice. Metabolomics 3, 137–145 (2007). https://doi.org/10.1007/s11306-007-0052-8

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  • DOI: https://doi.org/10.1007/s11306-007-0052-8

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