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Title:   Author  item
                                            WHEELOCK, C - UCD ENTOMOLOGY & KYOTO UNitem
                                            GOTO, S - KYOTO UNIV. CHEM. RES.item
                                            HAMMOCK, B - UCD DEPT. ENTOMOLOGYitem
                                            Newman, John
  Submitted to: Trade Journal Publication
                                    Publication Type: Peer Reviewed Journal
                                    Publication Acceptance Date: 3/1/2007
                                    Publication  Date: 3/1/2007
                                    Citation: Wheelock, C.S., Goto, S., Hammock, B.D., Newman, J.W. Clofibrate-induced changes in the liver, heart, brain and white adipose lipid metabolome of swiss-webster mice. Metabolomics 3(2):137-145, 2007.Interpretive Summary: Peroxisome proliferator activated receptor alpha (PPAR') agonists are widely prescribed anti-hyperlipidemic drugs that influence fatty acid combustion, phospholipid biosynthesis and lipoprotein metabolism in various tissues. Here we apply targeted metabolomics to evaluate impacts on other aspects of lipid metabolism.  Specifically, the effect of a 5 day, 500 mg/kg/day regimen of i.p. clofibrate on liver, heart, brain and white adipose was evaluated in male Swiss-Webster mice. Tissue levels of free fatty acids and the fatty acid content of sphingomyelin, cardiolipin, cholesterol esters, triglycerides and phospholipids were quantified.  Responses were tissue-specific, with the number of changes observed in the liver > heart >> brain > adipose.  Among the wealth of information produced in this study were a series of novel observations. In the liver, saturated fatty acid-rich triglycerides fed 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, heart and brain suggests systemic phosphatidylserine synthetase 2 activation with clofibrate treatment. A ~20% decline in cardiac sphingomyelin was observed 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. While supporting previous findings, this study has identified a series novel and potentially fruitful research questions to be explored concerning the impact of PPAR' agonist exposure on lipid metabolism.
                                Technical Abstract: Peroxisome proliferator activated receptor alpha (PPAR') agonists are drugs which effect lipid metabolism. Using a metabolomics approach focusing on lipids, we searched for novel effects of the prototypical PPAR' agonists clofibrate on the liver, heart, brain and white adipose of male mice.  Responses were tissue-specific, with the number of changes observed in the liver > heart >> brain > adipose. Among the wealth of information produced (~1,500 data points per animal) were a series of novel observations.  First, in the liver, saturated fatty acid-rich triglycerides were used to synthesize monounsaturated fatty acids, which were then incorporated into hepatic phospholipids and sphingomyelin.  Second, a ~20% decline in cardiac sphingomyelin was observed consistent with activation of a sphingomeylinase with a substrate preference for polyunsaturate-containing sphingomyelin. Third, perturbations in the liver, brain, and adipose cholesterol esters were observed. Finally, selective enrichment of docosahexeneoic acid in the phosphatidylserine of liver, heart and brain suggests systemic phosphatidylserine synthetase 2 activation with clofibrate treatment. Therefore, this study has identified a series novel and potentially fruitful research questions to be explored concerning the impact of PPAR' agonist exposure on lipid metabolism.


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