ACOT9

ACOT9 Full Name

acyl-CoA thioesterase 9

ACOT9 Introduction

Acyl-CoA Thioesterase 9 (ACOT9), also known as acyl-CoA thioesterase BACH or CTE9, is a distinct member of the acyl-CoA thioesterase (ACOT) family, specialized in the regulation of long-chain acyl-CoA ester metabolism within the cytoplasm and peroxisomes. Unlike other ACOT family members with narrow substrate specificity, ACOT9 exhibits a broad range of activity, targeting primarily long-chain acyl-CoA esters (C16-C22) that are involved in lipid storage, membrane synthesis, and energy production. ACOT9 plays a unique role in balancing the intracellular pool of long-chain acyl-CoA esters, preventing their toxic accumulation while ensuring their availability for essential cellular processes. It is predominantly expressed in tissues involved in lipid metabolism and energy homeostasis, including the liver, adipose tissue, and skeletal muscle, where its function is critical for maintaining lipid balance and overall cellular health. Today, ACOT9 is recognized not only as a specialized acyl-CoA thioesterase but also as a key regulator of lipid homeostasis, with profound implications for metabolic biology, obesity research, and related disorders.

Figure 1.The structure of ACOT9.

ACOT9-Related Pathways and Physiological Impact
ACOT9 is a key component of the cellular long-chain acyl-CoA metabolism pathway, which is critical for regulating lipid storage, membrane biosynthesis, and energy production. In the cytoplasm, ACOT9 hydrolyzes long-chain acyl-CoA esters to free fatty acids, which can be either re-esterified into triglycerides for storage in adipose tissue or transported to mitochondria for oxidation and energy generation. In peroxisomes, ACOT9 participates in the processing of long-chain acyl-CoA esters that are not fully degraded in mitochondria, complementing peroxisomal β-oxidation pathways. By regulating the levels of long-chain acyl-CoA esters, ACOT9 also modulates the activity of lipid-sensitive transcription factors (such as PPARs and SREBPs), which control the expression of genes involved in lipid metabolism. Additionally, ACOT9 plays a role in maintaining membrane integrity by regulating the availability of long-chain fatty acids for phospholipid synthesis, ensuring proper cellular membrane structure and function.

ACOT9 in Disease and Therapeutic Relevance
Genetic variations and dysregulation of ACOT9 are associated with metabolic disorders linked to lipid imbalance, particularly obesity, insulin resistance, and non-alcoholic fatty liver disease (NAFLD). Reduced ACOT9 expression or activity leads to the accumulation of long-chain acyl-CoA esters in the cytoplasm, promoting lipotoxicity, insulin resistance, and hepatic lipid deposition—key features of NAFLD and obesity. Conversely, increased ACOT9 activity enhances long-chain acyl-CoA hydrolysis, reducing lipid accumulation and improving insulin sensitivity. While inherited ACOT9 deficiency is rare, common genetic polymorphisms in the ACOT9 gene have been linked to increased susceptibility to obesity and metabolic syndrome in human populations. ACOT9 also holds therapeutic potential for metabolic disorders: modulating its activity could help restore long-chain acyl-CoA homeostasis, reduce lipotoxicity, and alleviate symptoms of obesity and NAFLD. Ongoing research focuses on developing small molecules that target ACOT9 to regulate lipid metabolism and improve metabolic health.

Alternate Names for ACOT9

ACOT9; acyl-CoA thioesterase 9; ACATE2; CGI-16; MTACT48; MT-ACT48; acyl-coenzyme A thioesterase 9, mitochondrial; acyl-CoA thioester hydrolase 9; mitochondrial Acyl-CoA Thioesterase; acyl-Coenzyme A thioesterase 2, mitochondrial;