Human transmembrane protein 68 links triacylglycerol synthesis to membrane lipid homeostasis

Transmembrane protein 68 (TMEM68) is a recently identified mammalian triacylglycerol (TAG) synthase with high expression in the brain. How TMEM68 regulates cellular lipid metabolism in concert with other enzymatic pathways remains poorly understood. In this study, we assessed TMEM68 function in neuro- and glioblastoma cells by combining genetic gain- and loss-of-function approaches with lipidomics. We found that TMEM68 promotes TAG synthesis and lipid droplet formation independently of canonical acyl-CoA:diacylglycerol acyltransferase (DGAT) 1 and 2 enzymes and contributes a discrete fraction of basal cellular TAG storage. Notably, TMEM68 overexpression increased storage lipids at the expense of membrane lipids, leading to a profound reduction of ether-linked glycerophospholipids (GPLs). Moreover, altered TMEM68 expression levels were associated with diminished prevalence of polyunsaturated GPLs. We conclude that TMEM68, besides its TAG synthesis function, acts as a multifaceted regulator of membrane lipid composition and polyunsaturated fatty acid homeostasis.