Catalyzes the hydrolysis of acyl-CoAs into free fatty acids and coenzyme A (CoASH), regulating their respective intracellular levels (PubMed:10578051). Preferentially hydrolyzes palmitoyl-CoA, but has a broad specificity acting on other fatty acyl-CoAs with chain-lengths of C8-C18 (PubMed:10578051). May play an important physiological function in brain (PubMed:10578051). H2O + hexadecanoyl-CoA = CoA + H(+) + hexadecanoate H2O + octanoyl-CoA = CoA + H(+) + octanoate dodecanoyl-CoA + H2O = CoA + dodecanoate + H(+) (9Z)-octadecenoyl-CoA + H2O = (9Z)-octadecenoate + CoA + H(+) H2O + tetradecanoyl-CoA = CoA + H(+) + tetradecanoate decanoyl-CoA + H2O = CoA + decanoate + H(+) H2O + octadecanoyl-CoA = CoA + H(+) + octadecanoate Lipid metabolism; fatty acid metabolism. Homohexamer. Isoform 4 is expressed exclusively in brain. Both HotDog ACOT-type hydrolase domains are required for efficient activity. Major isoform.