title: Catabolism of (2E)-4-hydroxy-2-nonenal via ω- and ω-1-oxidation stimulated by ketogenic diet.
abstract: Oxidative stress triggers the peroxidation of ω-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 via ω- and ω-1-oxidation in rat liver and kidney, with little activity in brain and heart. Dietary experiments showed that ω- 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.
authors.affiliation: Departments of Nutrition, Case Western Reserve University, Cleveland, Ohio 44106.
authors.forename: Zhicheng
authors.initials: Z
authors.lastname: Jin
authors.affiliation: Departments of Nutrition, Case Western Reserve University, Cleveland, Ohio 44106; Departments of Physiology and Biophysics, and Case Western Reserve University, Cleveland, Ohio 44106.
authors.forename: Jessica M
authors.initials: JM
authors.lastname: Berthiaume
authors.affiliation: Departments of Nutrition, Case Western Reserve University, Cleveland, Ohio 44106.
authors.forename: Qingling
authors.initials: Q
authors.lastname: Li
authors.affiliation: Departments of Nutrition, Case Western Reserve University, Cleveland, Ohio 44106.
authors.forename: Fabrice
authors.initials: F
authors.lastname: Henry
authors.affiliation: Departments of Nutrition, Case Western Reserve University, Cleveland, Ohio 44106.
authors.forename: Zhong
authors.initials: Z
authors.lastname: Huang
authors.affiliation: Departments of Chemistry, Case Western Reserve University, Cleveland, Ohio 44106.
authors.forename: Sushabhan
authors.initials: S
authors.lastname: Sadhukhan
authors.affiliation: Departments of Chemistry, Case Western Reserve University, Cleveland, Ohio 44106.
authors.forename: Peng
authors.initials: P
authors.lastname: Gao
authors.affiliation: Departments of Chemistry, Case Western Reserve University, Cleveland, Ohio 44106.
authors.forename: Gregory P
authors.initials: GP
authors.lastname: Tochtrop
authors.affiliation: Departments of Nutrition, Case Western Reserve University, Cleveland, Ohio 44106.
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Puchowicz
authors.affiliation: Departments of Nutrition, Case Western Reserve University, Cleveland, Ohio 44106. Electronic address: gxz35@case.edu.
authors.forename: Guo-Fang
authors.initials: GF
authors.lastname: Zhang
mesh_terms: D000214:Acyl Coenzyme A / Q000378:metabolism; D000447:Aldehydes / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism; D042926:Cytochrome P-450 CYP4A / Q000378:metabolism; D055423:Diet, Ketogenic; D005227:Fatty Acids / Q000737:chemistry / Q000378:metabolism; D006900:Hydroxylation; D007668:Kidney / Q000378:metabolism; D015227:Lipid Peroxidation; D008099:Liver / Q000201:enzymology*; D008297:Male; D013058:Mass Spectrometry; D008660:Metabolism; D009206:Myocardium / Q000378:metabolism; D018384:Oxidative Stress; D010100:Oxygen / Q000378:metabolism*; D010477:Perfusion; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000214:Acyl Coenzyme A; D000447:Aldehydes; D005227:Fatty Acids; C009061:propionyl-coenzyme A; D042926:Cytochrome P-450 CYP4A; C027576:4-hydroxy-2-nonenal; D010100:Oxygen
keywords: Coenzyme A (CoA); Cytochrome P450; Diet; Fatty Acid Oxidation; Isotopic Tracer; Lipid Peroxidation; Mass Spectrometry (MS); Metabolism; Metabolomics; beta-Oxidation