Global deletion of the triglyceride-synthesizing enzyme TMEM68 disrupts hepatic lipid homeostasis in mice.

Transmembrane protein 68 (TMEM68) mediates triacylglycerol (TAG) synthesis in mammals independently of canonical diacylglycerol acyltransferase (DGAT) 1 and DGAT2 enzymes. However, the in vivo roles of TMEM68 including its contribution to tissue-specific TAG formation remain largely elusive. In this study, we used a global Tmem68 knockout mouse model to investigate the impact of TMEM68 deficiency on lipid and energy metabolism of the liver. We found that loss of TMEM68 leads to a transient reduction in hepatic TAG storage and circulating ketone bodies approximately 4 weeks after birth. TMEM68-deficient livers exhibited reduced abundance of distinct acylglycerols and fatty acids, altered glycerophospholipid composition, and accumulation of polar ether lipids. Primary TMEM68-deficient hepatocytes also had reduced TAG and lipid droplet contents. RNA sequencing revealed that genes involved in multiple fatty acid metabolic processes and ketogenesis were repressed in Tmem68 knockout livers. Furthermore, Tmem68 ablation reduced hepatic cholesterol esters and modulated bile acid composition. In summary, our study identifies TMEM68 as a positive regulator of hepatic storage lipid levels and demonstrates a multifaceted embedding of the enzyme in hepatic lipid and energy metabolic pathways.