VLDL hydrolysis by LPL activates PPAR-α through generation of unbound fatty acids
Recent evidence suggests that lipoproteins serve as circulating reservoirs of peroxisomal proliferator activated receptor (PPAR) ligands that are accessible through lipolysis. The present study was conducted to determine the biochemical basis of PPAR-α activation by lipolysis products and their cont...
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doaj-ed87d2e49b4f439dbeebc71875dc5ceb2021-04-28T06:01:42ZengElsevierJournal of Lipid Research0022-22752010-08-0151822752281VLDL hydrolysis by LPL activates PPAR-α through generation of unbound fatty acidsMaxwell A. Ruby0Benjamin Goldenson1Gabriela Orasanu2Thomas P. Johnston3Jorge Plutzky4Ronald M. Krauss5Children's Hospital Oakland Research Institute, 5700 Martin Luther King Jr Way, Oakland, CA 94609Children's Hospital Oakland Research Institute, 5700 Martin Luther King Jr Way, Oakland, CA 94609Cardiovascular Division, Brigham and Women's Hospital, Harvard University, 77 Avenue Louis Pasteur, Boston, MA 02115Division of Pharmaceutical Sciences, University of Missouri-Kansas City, 2464 Charlotte Street, Kansas City, MO 64108Cardiovascular Division, Brigham and Women's Hospital, Harvard University, 77 Avenue Louis Pasteur, Boston, MA 02115To whom correspondence should be addressed; Children's Hospital Oakland Research Institute, 5700 Martin Luther King Jr Way, Oakland, CA 94609Recent evidence suggests that lipoproteins serve as circulating reservoirs of peroxisomal proliferator activated receptor (PPAR) ligands that are accessible through lipolysis. The present study was conducted to determine the biochemical basis of PPAR-α activation by lipolysis products and their contribution to PPAR-α function in vivo. PPAR-α activation was measured in bovine aortic endothelial cells following treatment with human plasma, VLDL lipolysis products, or oleic acid. While plasma failed to activate PPAR-α, oleic acid performed similarly to VLDL lipolysis products. Therefore, fatty acids are likely to be the PPAR-α ligands generated by VLDL lipolysis. Indeed, unbound fatty acid concentration determined PPAR-α activation regardless of fatty acid source, with PPAR-α activation occurring only at unbound fatty acid concentrations that are unachievable under physiological conditions without lipase action. In mice, a synthetic lipase inhibitor (poloxamer-407) attenuated fasting-induced changes in expression of PPAR-α target genes. Apolipoprotein CIII (apoCIII), an endogenous inhibitor of lipoprotein and hepatic lipase, regulated access to the lipoprotein pool of PPAR-α ligands, because addition of exogenous apoCIII inhibited, and removal of endogenous apoCIII potentiated, lipolytic PPAR-α activation. These data suggest that the PPAR-α response is generated by unbound fatty acids released locally by lipase activity and not by circulating plasma fatty acids.http://www.sciencedirect.com/science/article/pii/S0022227520370632peroxisome proliferator activated receptortriglyceride-rich lipoproteinlipoprotein lipaseapolipoprotein CIIInonesterified fatty acidvery low-density lipoprotein |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Maxwell A. Ruby Benjamin Goldenson Gabriela Orasanu Thomas P. Johnston Jorge Plutzky Ronald M. Krauss |
spellingShingle |
Maxwell A. Ruby Benjamin Goldenson Gabriela Orasanu Thomas P. Johnston Jorge Plutzky Ronald M. Krauss VLDL hydrolysis by LPL activates PPAR-α through generation of unbound fatty acids Journal of Lipid Research peroxisome proliferator activated receptor triglyceride-rich lipoprotein lipoprotein lipase apolipoprotein CIII nonesterified fatty acid very low-density lipoprotein |
author_facet |
Maxwell A. Ruby Benjamin Goldenson Gabriela Orasanu Thomas P. Johnston Jorge Plutzky Ronald M. Krauss |
author_sort |
Maxwell A. Ruby |
title |
VLDL hydrolysis by LPL activates PPAR-α through generation of unbound fatty acids |
title_short |
VLDL hydrolysis by LPL activates PPAR-α through generation of unbound fatty acids |
title_full |
VLDL hydrolysis by LPL activates PPAR-α through generation of unbound fatty acids |
title_fullStr |
VLDL hydrolysis by LPL activates PPAR-α through generation of unbound fatty acids |
title_full_unstemmed |
VLDL hydrolysis by LPL activates PPAR-α through generation of unbound fatty acids |
title_sort |
vldl hydrolysis by lpl activates ppar-α through generation of unbound fatty acids |
publisher |
Elsevier |
series |
Journal of Lipid Research |
issn |
0022-2275 |
publishDate |
2010-08-01 |
description |
Recent evidence suggests that lipoproteins serve as circulating reservoirs of peroxisomal proliferator activated receptor (PPAR) ligands that are accessible through lipolysis. The present study was conducted to determine the biochemical basis of PPAR-α activation by lipolysis products and their contribution to PPAR-α function in vivo. PPAR-α activation was measured in bovine aortic endothelial cells following treatment with human plasma, VLDL lipolysis products, or oleic acid. While plasma failed to activate PPAR-α, oleic acid performed similarly to VLDL lipolysis products. Therefore, fatty acids are likely to be the PPAR-α ligands generated by VLDL lipolysis. Indeed, unbound fatty acid concentration determined PPAR-α activation regardless of fatty acid source, with PPAR-α activation occurring only at unbound fatty acid concentrations that are unachievable under physiological conditions without lipase action. In mice, a synthetic lipase inhibitor (poloxamer-407) attenuated fasting-induced changes in expression of PPAR-α target genes. Apolipoprotein CIII (apoCIII), an endogenous inhibitor of lipoprotein and hepatic lipase, regulated access to the lipoprotein pool of PPAR-α ligands, because addition of exogenous apoCIII inhibited, and removal of endogenous apoCIII potentiated, lipolytic PPAR-α activation. These data suggest that the PPAR-α response is generated by unbound fatty acids released locally by lipase activity and not by circulating plasma fatty acids. |
topic |
peroxisome proliferator activated receptor triglyceride-rich lipoprotein lipoprotein lipase apolipoprotein CIII nonesterified fatty acid very low-density lipoprotein |
url |
http://www.sciencedirect.com/science/article/pii/S0022227520370632 |
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