Catabolism of (2E)-4-hydroxy-2-nonenal viaω- and ω-1-oxidation stimulated by ketogenic diet

Zhicheng Jin, Jessica M. Berthiaume, Qingling Li, Fabrice Henry, Zhong Huang, Sushabhan Sadhukhan, Peng Gao, Gregory P. Tochtrop, Michelle Puchowicz, Guo Fang Zhang

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Oxidative stress triggers the peroxidation ofω-6-polyunsaturated fatty acids to reactive lipid fragments, including (2E)-4-hydroxy-2-nonenal (HNE). We previously reported two parallel catabolic pathways of HNE. In this study, we report a novel metabolite that accumulates in rat liver perfused with HNE or 4-hydroxynonanoic acid (HNA), identified as 3-(5-oxotetrahydro-2-furanyl)propanoyl-CoA. In experiments using a combination of isotopic analysis and metabolomics studies, three catabolic pathways of HNE were delineated following HNE conversion to HNA. (i) HNA is ω-hydroxylated to 4,9-dihydroxynonanoic acid, which is subsequently oxidized to 4-hydroxynonanedioic acid. This is followed by the degradation of 4-hydroxynonanedioic acid via β-oxidation originating from C-9 of HNA breaking down to 4-hydroxynonanedioyl-CoA, 4-hydroxyheptanedioyl-CoA, or its lactone, 2-hydroxyglutaryl-CoA, and 2-ketoglutaric acid entering the citric acid cycle. (ii) ω-1-hydroxylation of HNA leads to 4,8-dihydroxynonanoic acid (4,8-DHNA), which is subsequently catabolized via two parallel pathways we previously reported. In catabolic pathway A, 4,8-DHNA is catabolized to 4-phospho-8-hydroxynonanoyl-CoA, 3,8-dihydroxynonanoyl-CoA, 6-hydroxyheptanoyl-CoA, 4-hydroxypentanoyl-CoA, propionyl-CoA, and acetyl-CoA. (iii) The catabolic pathway B of 4,8-DHNA leads to 2,6-dihydroxyheptanoyl-CoA, 5-hydroxyhexanoyl-CoA, 3-hydroxybutyryl-CoA, and acetyl-CoA. Both in vivo and in vitro experiments showed that HNE can be catabolically disposed viaω- and ω-1-oxidation in rat liver and kidney, with little activity in brain and heart. Dietary experiments showed thatω- and ω-1-hydroxylation of HNA in rat liver were dramatically up-regulated by a ketogenic diet, which lowered HNE basal level. HET0016 inhibition and mRNA expression level suggested that the cytochrome P450 4A are main enzymes responsible for the NADPH dependent ω- and ω-1-hydroxylation of HNA/HNE.

Original languageEnglish (US)
Pages (from-to)32327-32338
Number of pages12
JournalJournal of Biological Chemistry
Volume289
Issue number46
DOIs
StatePublished - Nov 14 2014

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Ketogenic Diet
Nutrition
Coenzyme A
Oxidation
Acids
Hydroxylation
Liver
Acetyl Coenzyme A
Rats
4-hydroxy-2-nonenal
Metabolomics
Citric Acid Cycle
Oxidative stress
Lactones
Experiments
Unsaturated Fatty Acids
NADP
Metabolites
Cytochrome P-450 Enzyme System

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Jin, Z., Berthiaume, J. M., Li, Q., Henry, F., Huang, Z., Sadhukhan, S., ... Zhang, G. F. (2014). Catabolism of (2E)-4-hydroxy-2-nonenal viaω- and ω-1-oxidation stimulated by ketogenic diet. Journal of Biological Chemistry, 289(46), 32327-32338. https://doi.org/10.1074/jbc.M114.602458

Catabolism of (2E)-4-hydroxy-2-nonenal viaω- and ω-1-oxidation stimulated by ketogenic diet. / Jin, Zhicheng; Berthiaume, Jessica M.; Li, Qingling; Henry, Fabrice; Huang, Zhong; Sadhukhan, Sushabhan; Gao, Peng; Tochtrop, Gregory P.; Puchowicz, Michelle; Zhang, Guo Fang.

In: Journal of Biological Chemistry, Vol. 289, No. 46, 14.11.2014, p. 32327-32338.

Research output: Contribution to journalArticle

Jin, Z, Berthiaume, JM, Li, Q, Henry, F, Huang, Z, Sadhukhan, S, Gao, P, Tochtrop, GP, Puchowicz, M & Zhang, GF 2014, 'Catabolism of (2E)-4-hydroxy-2-nonenal viaω- and ω-1-oxidation stimulated by ketogenic diet', Journal of Biological Chemistry, vol. 289, no. 46, pp. 32327-32338. https://doi.org/10.1074/jbc.M114.602458
Jin, Zhicheng ; Berthiaume, Jessica M. ; Li, Qingling ; Henry, Fabrice ; Huang, Zhong ; Sadhukhan, Sushabhan ; Gao, Peng ; Tochtrop, Gregory P. ; Puchowicz, Michelle ; Zhang, Guo Fang. / Catabolism of (2E)-4-hydroxy-2-nonenal viaω- and ω-1-oxidation stimulated by ketogenic diet. In: Journal of Biological Chemistry. 2014 ; Vol. 289, No. 46. pp. 32327-32338.
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abstract = "Oxidative stress triggers the peroxidation ofω-6-polyunsaturated fatty acids to reactive lipid fragments, including (2E)-4-hydroxy-2-nonenal (HNE). We previously reported two parallel catabolic pathways of HNE. In this study, we report a novel metabolite that accumulates in rat liver perfused with HNE or 4-hydroxynonanoic acid (HNA), identified as 3-(5-oxotetrahydro-2-furanyl)propanoyl-CoA. In experiments using a combination of isotopic analysis and metabolomics studies, three catabolic pathways of HNE were delineated following HNE conversion to HNA. (i) HNA is ω-hydroxylated to 4,9-dihydroxynonanoic acid, which is subsequently oxidized to 4-hydroxynonanedioic acid. This is followed by the degradation of 4-hydroxynonanedioic acid via β-oxidation originating from C-9 of HNA breaking down to 4-hydroxynonanedioyl-CoA, 4-hydroxyheptanedioyl-CoA, or its lactone, 2-hydroxyglutaryl-CoA, and 2-ketoglutaric acid entering the citric acid cycle. (ii) ω-1-hydroxylation of HNA leads to 4,8-dihydroxynonanoic acid (4,8-DHNA), which is subsequently catabolized via two parallel pathways we previously reported. In catabolic pathway A, 4,8-DHNA is catabolized to 4-phospho-8-hydroxynonanoyl-CoA, 3,8-dihydroxynonanoyl-CoA, 6-hydroxyheptanoyl-CoA, 4-hydroxypentanoyl-CoA, propionyl-CoA, and acetyl-CoA. (iii) The catabolic pathway B of 4,8-DHNA leads to 2,6-dihydroxyheptanoyl-CoA, 5-hydroxyhexanoyl-CoA, 3-hydroxybutyryl-CoA, and acetyl-CoA. Both in vivo and in vitro experiments showed that HNE can be catabolically disposed viaω- and ω-1-oxidation in rat liver and kidney, with little activity in brain and heart. Dietary experiments showed thatω- and ω-1-hydroxylation of HNA in rat liver were dramatically up-regulated by a ketogenic diet, which lowered HNE basal level. HET0016 inhibition and mRNA expression level suggested that the cytochrome P450 4A are main enzymes responsible for the NADPH dependent ω- and ω-1-hydroxylation of HNA/HNE.",
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N2 - Oxidative stress triggers the peroxidation ofω-6-polyunsaturated fatty acids to reactive lipid fragments, including (2E)-4-hydroxy-2-nonenal (HNE). We previously reported two parallel catabolic pathways of HNE. In this study, we report a novel metabolite that accumulates in rat liver perfused with HNE or 4-hydroxynonanoic acid (HNA), identified as 3-(5-oxotetrahydro-2-furanyl)propanoyl-CoA. In experiments using a combination of isotopic analysis and metabolomics studies, three catabolic pathways of HNE were delineated following HNE conversion to HNA. (i) HNA is ω-hydroxylated to 4,9-dihydroxynonanoic acid, which is subsequently oxidized to 4-hydroxynonanedioic acid. This is followed by the degradation of 4-hydroxynonanedioic acid via β-oxidation originating from C-9 of HNA breaking down to 4-hydroxynonanedioyl-CoA, 4-hydroxyheptanedioyl-CoA, or its lactone, 2-hydroxyglutaryl-CoA, and 2-ketoglutaric acid entering the citric acid cycle. (ii) ω-1-hydroxylation of HNA leads to 4,8-dihydroxynonanoic acid (4,8-DHNA), which is subsequently catabolized via two parallel pathways we previously reported. In catabolic pathway A, 4,8-DHNA is catabolized to 4-phospho-8-hydroxynonanoyl-CoA, 3,8-dihydroxynonanoyl-CoA, 6-hydroxyheptanoyl-CoA, 4-hydroxypentanoyl-CoA, propionyl-CoA, and acetyl-CoA. (iii) The catabolic pathway B of 4,8-DHNA leads to 2,6-dihydroxyheptanoyl-CoA, 5-hydroxyhexanoyl-CoA, 3-hydroxybutyryl-CoA, and acetyl-CoA. Both in vivo and in vitro experiments showed that HNE can be catabolically disposed viaω- and ω-1-oxidation in rat liver and kidney, with little activity in brain and heart. Dietary experiments showed thatω- and ω-1-hydroxylation of HNA in rat liver were dramatically up-regulated by a ketogenic diet, which lowered HNE basal level. HET0016 inhibition and mRNA expression level suggested that the cytochrome P450 4A are main enzymes responsible for the NADPH dependent ω- and ω-1-hydroxylation of HNA/HNE.

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