Biosynthesis of very long-chain polyunsaturated fatty acids in hepatocytes expressing ELOVL4

Abstract

Elongation of Very Long chain fatty acids-4 (ELOVL4) is a fatty acid condensing enzyme that mediates biosynthesis of very long chain polyunsaturated fatty acids (VLC-PUFA; ≥ C28) in a limited number of tissues. Depletion of VLCPUFA in retinal photoreceptors leads to retinal dysfunction and likely contributes to autosomal dominant Stargardt-like macular dystrophy (STGD3) pathology. In addition, depletion of VLC-PUFA in rodent testicular tissues leads to sterility. These results suggest that VLC-PUFA synthesized in situ play a unique role that cannot be compensated for by other fatty acid species. Though liver is the major fatty acid biosynthetic organs, it does not express the ELOVL4 protein; hence, no VLC-PUFA are detected in the blood and plasma. Thus, delivery of these VLC-PUFA to target tissues to compensate for their reduction caused by disease presents a challenge. We hypothesized that expression of ELOVL4 in the liver will result in the biosynthesis of VLC-PUFA that could be transported via the bloodstream to target tissues such as retina, brain and testis. Hence, we evaluated the ability of rat hepatoma (4HIIE) and human hepatocyte (HepG2) cells to synthesize VLC-PUFA by expressing ELOVL4 in these cells. We showed that, in the presence of ELOVL4, both 4HIIE and HepG2 cells are capable of VLC-PUFA biosynthesis. We propose that transgenic expression of ELOVL4 in the liver will result in the biosynthesis of VLC-PUFA that can be transported to target.