ACOT11

ACOT11 Full Name

acyl-CoA thioesterase 11

ACOT11 Introduction

ACOT11, also known as thioesterase superfamily member 1 (THEM1) or STAR-related lipid transfer domain-containing protein 14 (StarD14), is a member of the acyl-CoA thioesterase family that catalyzes the hydrolysis of acyl-CoA molecules to free fatty acids and coenzyme A (CoASH). This reaction terminates the activation of fatty acids and regulates the intracellular levels of acyl-CoAs, which are key intermediates in lipid synthesis, β-oxidation, and cellular signaling. Unlike many acyl-CoA thioesterases that are broadly expressed or induced by peroxisome proliferator-activated receptors (PPARs), ACOT11 exhibits a highly restricted expression pattern, being most abundant in brown adipose tissue (BAT) and to a lesser extent in white adipose tissue (WAT), skeletal muscle, heart, and liver. The human ACOT11 gene is located on chromosome 1p32.3, spans approximately 80 kb, and contains 17 exons encoding a 469-amino-acid protein with a molecular weight of approximately 53 kDa. ACOT11 possesses a unique domain architecture: an N-terminal thioesterase domain belonging to the TE11 protein family (characterized by a hotdog fold) and a C-terminal START domain, which is thought to bind and transport lipids. This domain combination suggests that ACOT11 not only hydrolyzes acyl-CoAs but also may directly channel the resulting free fatty acids to specific downstream effectors or cellular compartments. The physiological role of ACOT11 has been primarily elucidated through mouse knockout models, which have revealed that ACOT11 functions as a negative regulator of energy expenditure, with its absence leading to resistance to diet-induced obesity and improved metabolic health — a property distinct from most other acyl-CoA thioesterases.

Figure 1.The structure of ACOT11.

Enzymatic Function and Substrate Specificity
ACOT11 catalyzes the hydrolysis of long-chain fatty acyl-CoA esters (C14:0 to C20:0) to free fatty acids and CoASH, with a preference for saturated and monounsaturated substrates. The highest catalytic efficiency is observed with palmitoyl-CoA (C16:0) and oleoyl-CoA (C18:1), both of which are abundant in adipose tissue and are primary substrates for β-oxidation and thermogenesis. ACOT11 exhibits very low activity toward medium-chain (C8:0-C12:0) or very-long-chain (>C20) acyl-CoAs, and no detectable activity toward branched-chain or bile acyl-CoAs, distinguishing it from other thioesterases such as ACOT1, ACOT2, and ACOT8. The enzymatic mechanism involves a two-step process: first, the acyl-CoA substrate binds to the active site within the hotdog fold domain; second, a water molecule activated by a catalytic dyad or triad (typically aspartate-histidine) performs a nucleophilic attack on the thioester carbonyl carbon, cleaving the bond and releasing free fatty acid and CoASH. Unlike some acyl-CoA thioesterases that are highly regulated by post-translational modifications, ACOT11 activity appears to be primarily controlled at the transcriptional level, though its enzymatic activity may be modulated by the lipid environment.

Clinical Significance of ACOT11 Dysregulation
Dysregulation of ACOT11 expression or function is closely associated with a range of metabolic and cardiovascular disorders. Reduced ACOT11 expression or activity is linked to lipid accumulation in the liver, contributing to non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH)—conditions characterized by excess triglyceride deposition and hepatic inflammation. In obesity and type 2 diabetes, ACOT11 dysregulation disrupts adipose tissue metabolism, promoting lipotoxicity and insulin resistance. Aberrant ACOT11 expression is also associated with cardiovascular disease, as dysregulated lipid metabolism contributes to atherosclerosis and myocardial dysfunction. Genetic variants in ACOT11 have been linked to increased susceptibility to obesity, NAFLD, and dyslipidemia in human populations. Additionally, ACOT11 has emerged as a potential therapeutic target for metabolic disorders—modulating its activity could help restore lipid homeostasis, reduce hepatic fat accumulation, and improve insulin sensitivity. The frequency of ACOT11 dysregulation is high in metabolic disease populations, with reduced expression observed in approximately 40–60% of patients with NAFLD and obesity, highlighting its clinical relevance.

Alternate Names for ACOT11

ACOT11; acyl-CoA thioesterase 11; THEA, thioesterase, adipose associated; acyl-coenzyme A thioesterase 11; BFIT; BFIT1; KIAA0707; StAR related lipid transfer (START) domain containing 14; STARD14; THEM1