Very‐long‐chain‐acyl‐CoA‐dehydrogenase‐deficiency (VLCAD) is the most common defect of long‐chain fatty acid β‐oxidation. The recommended treatment includes the application of medium‐chain‐triglycerides (MCT). However, long‐term treatment of VLCAD‐/‐ mice resulted in the development of a sex specific metabolic syndrome due to the selective activation of the ERK/mTORc1 signaling in females and ERK/PPARγ pathway in males.
In order to investigate a subsequent sex‐specific effect of MCT on the lipid composition of the cellular membranes, we performed lipidomic analysis, SILAC‐based quantitative proteomics and gene expression in fibroblasts from WT and VLCAD‐/‐ mice of both sexes.
Treatment with octanoate (C8) affected the composition of complex lipids resulting in a sex specific signature of the molecular profile. The content of ceramides and sphingomyelins in particular differed significantly under control conditions and increased markedly in cells from mutant female mice but remained unchanged in cells from mutant males. Moreover, we observed a specific upregulation of biosynthesis of plasmalogens only in male mice, whereas in females C8 led to the accumulation of higher concentration of phosphatidylcholines and lysophosphosphatidylcholines.
Our data on membrane lipids in VLCAD‐deficiency after supplementation with C8 provide evidence of a sex specific lipid perturbation. We hypothesize a likely C8‐induced pro‐inflammatory response contributing to the development of a severe metabolic syndrome in female VLCAD‐/‐ mice on long‐term MCT supplementation.