Very long chain fatty acid-containing lipids: a decade of novel insights from the study of ELOVL4

J Lipid Res. 2021:62:100030. doi: 10.1016/j.jlr.2021.100030. Epub 2021 Feb 6.

Abstract

Lipids play essential roles in maintaining cell structure and function by modulating membrane fluidity and cell signaling. The fatty acid elongase-4 (ELOVL4) protein, expressed in retina, brain, Meibomian glands, skin, testes and sperm, is an essential enzyme that mediates tissue-specific biosynthesis of both VLC-PUFA and VLC-saturated fatty acids (VLC-SFA). These fatty acids play critical roles in maintaining retina and brain function, neuroprotection, skin permeability barrier maintenance, and sperm function, among other important cellular processes. Mutations in ELOVL4 that affect biosynthesis of these fatty acids cause several distinct tissue-specific human disorders that include blindness, age-related cerebellar atrophy and ataxia, skin disorders, early-childhood seizures, mental retardation, and mortality, which underscores the essential roles of ELOVL4 products for life. However, the mechanisms by which one tissue makes VLC-PUFA and another makes VLC-SFA, and how these fatty acids exert their important functional roles in each tissue, remain unknown. This review summarizes research over that last decade that has contributed to our current understanding of the role of ELOVL4 and its products in cellular function. In the retina, VLC-PUFA and their bioactive "Elovanoids" are essential for retinal function. In the brain, VLC-SFA are enriched in synaptic vesicles and mediate neuronal signaling by determining the rate of neurotransmitter release essential for normal neuronal function. These findings point to ELOVL4 and its products as being essential for life. Therefore, mutations and/or age-related epigenetic modifications of fatty acid biosynthetic gene activity that affect VLC-SFA and VLC-PUFA biosynthesis contribute to age-related dysfunction of ELOVL4-expressing tissues.

Keywords: Stargardt macular dystrophy; autosomal dominant; erythrokeratodermia variabilis; retinal lipids; spinocerebellar ataxia 34; very long chain polyunsaturated fatty acids; very long chain saturated fatty acids.

Publication types

  • Review

MeSH terms

  • Acetyltransferases / genetics
  • Acetyltransferases / metabolism
  • Animals
  • Eye Proteins* / genetics
  • Eye Proteins* / metabolism
  • Fatty Acids / metabolism
  • Humans
  • Membrane Proteins* / genetics
  • Membrane Proteins* / metabolism

Substances

  • Acetyltransferases
  • ELOVL4 protein, human
  • Eye Proteins
  • Fatty Acids
  • Membrane Proteins