Allosteric regulation of Thioesterase Superfamily Member 1 by free fatty acids and lysophosphatidylcholine

Non-shivering thermogenesis occurs in brown adipose tissue to generate heat in response to cold temperatures. Thioesterase superfamily member 1 (Them1) is transcriptionally upregulated in brown adipose tissue upon cold exposure and suppresses thermogenesis to conserve energy reserves. Them1 hydrolyzes long-chain fatty acyl-CoAs, preventing their use as fuel for thermogenesis. Them1 contains a C-terminal StAR-related lipid transfer domain (StarD) with unknown ligand or function. By complementary biophysical approaches, we show that StarD binds to long-chain fatty acids, products of Them1s enzymatic reaction, as well lysophosphatidylcholine (LPC), which activate thermogenesis in brown adipocytes. Certain fatty acids stabilize the StarD and allosterically enhance Them1 catalysis of acyl-CoA, whereas 18:1 LPC destabilizes and inhibits activity, which we verify in cell culture. Additionally, we demonstrate that the StarD functions to localize Them1 near lipid droplets. These findings define the role of the StarD as a lipid sensor that allosterically regulates Them1 activity and localization.