Our previous studies in VLCAD-/- mice have shown that compensatory / adaptation mechanisms are up-regulated in tissues and organs to meet the required energy need during higher energy demand but also at rest. Taking advantage of VLCAD-/- mice, and fibroblasts from patients with different lcFAOD we plan to characterize the effects of different dietary interventions (i.e. triheptanoin, protein rich diet) in the regulation of cellular metabolism and on alternative energy producing pathways and how anaplerotic processes can be stimulated to compensate for a defective β-oxidation.
Fat-modified diets, lipidomics of lcFAOD and signaling disturbances
Long-term MCT- and triheptanoin-based diets deeply change membrane fatty acid profiles of tissues from VLCAD-/- mice. In murine fibroblasts we have shown that treatment with octanoate markedly disturbs also the composition of complex lipids. Because MCT and triheptanoin are applied in the treatment of lcFAOD we are addressing the question whether medium chain fatty acids (C7 and C8) redesign the lipidome of fibroblasts from patients with different lcFAOD and how membrane lipid modification affect cell signaling.
Mitochondrial β-oxidation and mtFAS in the regulation of energy metabolism
The malonyl-CoA synthetase (ACSF3) catalyzes the first step of the mitochondrial fatty acid biosynthesis (mFASII) which provides octanoate necessary for the biosynthesis of lipoic acid, an essential cofactor for several mitochondrial enzymes involved in energy metabolism.
Our studies on ACSF3-deficient fibrobrasts have shown a severe impairment of mitochondrial energy metabolism and reduced metabolic flexibility accompanied by the up-regulation of β-oxidation. On the other hand, the metabolic switch and morphologic transdifferentiation of white skeletal muscle of VLCAD-/- mice was associated with a marked up-regulation of mtFAS. How exactly β-oxidation and mtFAS interact and how they regulate each other will be investigated in ACSF3 deficient cells and in cells from patients with different lcFAOD.