biostudies-literatureCho YKNational Research Foundation of Korea (NRF)NIDDK NIH HHSNational Research Foundation of Korea1113https://www.ebi.ac.uk/biostudies/studies/S-EPMC12855804biostudies-literatureUnknown17(1)Efficient fatty acid (FA) re-esterification is essential for lipid homeostasis in adipocytes, yet the mechanisms coordinating Coenzyme A (CoA) availability at the endoplasmic reticulum (ER)-a major site of lipid synthesis-remain unclear. Here, we identify TMEM120A as an ER-resident CoA-binding protein that regulates intracellular FA metabolism. TMEM120A interacts with the ER-localized acyl-CoA synthetase ACSL1 and ACSL3 to promote long-chain acyl-CoA synthesis and channeling into the ER, thereby facilitating FA re-esterification and lipid cycling during lipolysis. By relieving acyl-CoA-mediated feedback inhibition of lipolysis, TMEM120A enhances lipid turnover while protecting against ER stress and lipotoxicity. Adipocyte-specific deletion of Tmem120a in mice impairs lipolysis-induced energy expenditure and exacerbates inflammation and metabolic dysfunction under high-fat diet conditions. These findings establish TMEM120A as a critical regulator of ER CoA handling and lipid flux, revealing a previously unrecognized mechanism that links intracellular CoA dynamics to systemic energy balance and metabolic health.Nature communicationsTMEM120A maintains adipose tissue lipid homeostasis through ER CoA channeling.PMC12855804R01 DK062292RS-2023-00213572, RS-2024-00400118, RS-2025-16063709Jung CWJung YSKim JKLee JMottillo EPCho YKGranneman JGShim MSeomoon CKwon SWPark SLee YHMai XLNamgoong SJeong YLChoi YHSeong JKLee DKfalseTMEM120A maintains adipose tissue lipid homeostasis through ER CoA channeling.Efficient fatty acid (FA) re-esterification is essential for lipid homeostasis in adipocytes, yet the mechanisms coordinating Coenzyme A (CoA) availability at the endoplasmic reticulum (ER)-a major site of lipid synthesis-remain unclear. Here, we identify TMEM120A as an ER-resident CoA-binding protein that regulates intracellular FA metabolism. TMEM120A interacts with the ER-localized acyl-CoA synthetase ACSL1 and ACSL3 to promote long-chain acyl-CoA synthesis and channeling into the ER, thereby facilitating FA re-esterification and lipid cycling during lipolysis. By relieving acyl-CoA-mediated feedback inhibition of lipolysis, TMEM120A enhances lipid turnover while protecting against ER stress and lipotoxicity. Adipocyte-specific deletion of Tmem120a in mice impairs lipolysis-induced energy expenditure and exacerbates inflammation and metabolic dysfunction under high-fat diet conditions. These findings establish TMEM120A as a critical regulator of ER CoA handling and lipid flux, revealing a previously unrecognized mechanism that links intracellular CoA dynamics to systemic energy balance and metabolic health.2025-01-01T00:00:00Z2025 Dec2026-06-16T07:09:25.85Z2026-06-16T03:09:51.974ZS-EPMC128558044142363310.1038/s41467-025-67870-7