A conserved ER protein prevents lipotoxicity by stimulating the key enzyme in glycerolipid synthesis.

The synthesis of glycerolipid is essential to prevent the toxic effects of excess fatty acids. Glycerolipids are generated by the sequential attachment of acyl-CoA to glycerol by endoplasmic reticulum (ER)-localized acyltransferases, ultimately yielding non-toxic triacylglycerol that can be stored in lipid droplets. The key acyltransferase GPAT4 associates with the CHP1 protein, but the regulation of GPAT4 remains poorly understood. Here, we have used genetic, biochemical, and imaging techniques to identify TMEM120A as GPAT4-activating protein. We show that ER-localized TMEM120A and CHP1 synergistically activate GPAT4 and promote the incorporation of medium and long chain acyl-CoA into glycerolipid. C. elegans mutants of TMEM120A or CHP1 ortholog are susceptible to high-fat diet induced sterility, in part due to their deficiency in lipid droplet expansion. In mammalian cells, fatty acid supplementation and myristoylated CHP1 enhance the association of TMEM120A with GPAT4. Together, our results reveal an unexpected mechanism that alleviates lipotoxicity.