Abstract：
:In recent years the short-chain fatty acid, 4-phenylbutyrate (PB), has emerged as a promising drug for various clinical conditions. In fact, PB has been Food and Drug Administration-approved for urea cycle disorders since 1996. PB is more potent and less toxic than its metabolite, phenylacetate (PA), and is not just a pro-drug for PA, as was initially assumed. The metabolic pathway of PB, however, has remained unclear. Therefore, we set out to identify the enzymes involved in the β-oxidation of PB. We used cells deficient in specific steps of fatty acid β-oxidation and ultra-HPLC to measure which enzymes were able to convert PB or its downstream products. We show that the first step in PB oxidation is catalyzed solely by the enzyme, medium-chain acyl-CoA dehydrogenase. The second (hydration) step can be catalyzed by all three mitochondrial enoyl-CoA hydratase enzymes, i.e., short-chain enoyl-CoA hydratase, long-chain enoyl-CoA hydratase, and 3-methylglutaconyl-CoA hydratase. Enzymes involved in the third step include both short- and long-chain 3-hydroxyacyl-CoA dehydrogenase. The oxidation of PB is completed by only one enzyme, i.e., long-chain 3-ketoacyl-CoA thiolase. Taken together, the enzymatic characteristics of the PB degradative pathway may lead to better dose finding and limiting the toxicity of this drug.
journal_name
J Lipid Resjournal_title
Journal of lipid researchauthors
Palir N,Ruiter JPN,Wanders RJA,Houtkooper RHdoi
10.1194/jlr.M075317subject
Has Abstractpub_date
2017-05-01 00:00:00pages
955-961issue
5eissn
0022-2275issn
1539-7262pii
jlr.M075317journal_volume
58pub_type
杂志文章abstract：:LPL is an enzyme involved in the breakdown and uptake of lipoprotein triglycerides. In the present study, we examined how the transgenic (Tg) overexpression of human LPL in mouse skeletal muscle affected tolerance to cold temperatures, cold-induced thermogenesis, and fuel utilization during this response. Tg mice and ...
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journal_title：Journal of lipid research
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doi：10.1194/jlr.M059469
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journal_title：Journal of lipid research
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doi：
更新日期：1978-08-01 00:00:00
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journal_title：Journal of lipid research
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journal_title：Journal of lipid research
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journal_title：Journal of lipid research
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doi：10.1194/jlr.M600130-JLR200
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journal_title：Journal of lipid research
pub_type： 杂志文章
doi：
更新日期：1989-06-01 00:00:00
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journal_title：Journal of lipid research
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doi：
更新日期：1993-05-01 00:00:00
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doi：10.1194/jlr.P900032-JLR200
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journal_title：Journal of lipid research
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更新日期：1996-04-01 00:00:00
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journal_title：Journal of lipid research
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doi：
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doi：10.1194/jlr.M092486
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journal_title：Journal of lipid research
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doi：
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doi：
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doi：
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journal_title：Journal of lipid research
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journal_title：Journal of lipid research
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doi：
更新日期：1984-09-01 00:00:00
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journal_title：Journal of lipid research
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更新日期：1991-12-01 00:00:00
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doi：10.1194/jlr.M400412-JLR200
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journal_title：Journal of lipid research
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更新日期：1998-01-01 00:00:00
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journal_title：Journal of lipid research
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