Peroxisomal
fatty acid α-oxidation is an essential pathway for the degradation of β-
carbon methylated
fatty acids such as
phytanic acid. One
enzyme in this pathway is 2-hydroxyacyl
CoA lyase (HACL1), which is responsible for the cleavage of 2-hydroxyphytanoyl-CoA into
pristanal and
formyl-CoA. Hacl1 deficient mice do not present with a severe phenotype, unlike mice deficient in other α-oxidation
enzymes such as
phytanoyl-CoA hydroxylase deficiency (
Refsum disease) in which neuropathy and
ataxia are present. Tissues from wild-type and Hacl1-/- mice fed a high
phytol diet were obtained for proteomic and lipidomic analysis. There was no phenotype observed in these mice. Liver, brain, and kidney tissues underwent
trypsin digestion for untargeted proteomic liquid chromatography-mass spectrometry analysis, while liver tissues also underwent
fatty acid hydrolysis, extraction, and derivatisation for
fatty acid gas chromatography-mass spectrometry analysis. The
liver fatty acid profile demonstrated an accumulation of phytanic and
2-hydroxyphytanic acid in the Hacl1-/- liver and significant decrease in
heptadecanoic acid. The liver
proteome showed a significant decrease in the abundance of Hacl1 and a significant increase in the abundance of
proteins involved in
PPAR signalling, peroxisome proliferation, and omega oxidation, particularly Cyp4a10 and Cyp4a14. In addition, the pathway associated with
arachidonic acid metabolism was affected; Cyp2c55 was upregulated and Cyp4f14 and Cyp2b9 were downregulated. The kidney
proteome revealed fewer significantly upregulated peroxisomal
proteins and the brain
proteome was not significantly different in Hacl1-/- mice. This study demonstrates the powerful insight brought by proteomic and metabolomic profiling of Hacl1-/- mice in better understanding disease mechanism in
fatty acid α-oxidation disorders.