Catabolism of 4-hydroxy-2 (E/I)-nonenal via omega- and omega-1 oxidation: Stimulated by ketogenic diet [Lipids]

October 1st, 2014 by Jin, Z., Berthiaume, J. M., Li, Q., Henry, F., Huang, Z., Sadhukhan, S., Gao, P., Tochtrop, G. P., Puchowicz, M. A., Zhang, G.-F.

Oxidative stress triggers the peroxidation of omega-6 polyunsaturated fatty acids (n-6 PUFAs) to reactive lipid fragments including 4-hydroxy-2(E)-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, OTHFPA-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) omega-hydroxylation to 4,9-dihydroxynonanoic acid (4,9-DHNA), which is subsequently oxidized to 4-hydroxynonanedioic acid. This is followed by the degradation of 4-hydroxynoanedioic acid via beta oxidation originating from C-9 of HNA breaking down to: 4-hydroxynonanedioyl-CoA, 4-hydroxyheptanedioyl-CoA or its lactone, 2-hydroxyglutaryl-CoA, and 2-ketoglutarate entering citric acid cycle; (ii) omega-1 hydroxylation of HNA led 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 omega- and omega-1 oxidation in rat liver and kidney, with little activity in brain and heart. Dietary experiments showed that omega- and omega-1 hydroxylation of HNA in rat liver was 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 omega- and omega-1 hydroxylation of HNA/HNE.