Ces1d, also known as carboxylesterase 1d, is a crucial enzyme belonging to the serine hydrolase superfamily. It has a wide range of activities, mainly localizing in the endoplasmic reticulum (ER) [2]. It is involved in metabolizing drugs, pesticides, and lipids, and has been implicated in hepatic triacylglycerol metabolism [3].

In gene knockout studies, Ces1d -deficient mice were protected from high-sucrose diet-induced hepatic lipid accumulation. Mechanistically, Ces1d deficiency led to the activation of AMP-activated protein kinase and inhibitory phosphorylation of acetyl-CoA carboxylase [1]. Adipose tissue-specific Ces1d knockout (FKO) mice showed metabolic dysregulation, including weight gain, impaired glucose and lipid metabolism, and exacerbated liver steatosis [2]. Liver-specific Ces1d-deficient mice did not show any difference in the flux of in vivo HDL-to-feces reverse cholesterol transport nor additional liver CE accumulation after a high-cholesterol diet challenge, challenging its role as a major hepatic cholesteryl ester hydrolase [3]. Deletion of the Ces1d gene in mice markedly reduced the acute ethanol-induced increase of blood fatty acid ethyl esters (FAEEs) levels with a slight but significant reduction of serum aminotransferase levels [4]. Ces1d -/- mice also exhibited augmented lung inflammation in response to lipopolysaccharide (LPS) [5]. Myeloid-specific Ces1d knockout mice had lipid dysregulation in macrophages, triggering pro-inflammatory activation and contributing to worsened metabolic disorders [6].

In conclusion, Ces1d plays a significant role in lipid metabolism, with its deficiency affecting various physiological processes. Gene knockout mouse models have been instrumental in revealing its role in non-alcoholic fatty liver disease (NAFLD), metabolic dysregulation, acute liver injury, and lung inflammation, providing potential pharmacological targets for these disease areas.