Acot12-KO Mouse

Acot12, acyl-CoA thioesterase 12, is an enzyme that hydrolyzes acetyl-CoA to acetate in the liver cytosol [6]. It is involved in multiple pathways such as peroxisome proliferator-activated receptor α (PPARα)-mediated de novo lipogenesis, and plays a role in maintaining cellular lipid metabolism homeostasis [1,2,5]. Genetic models, especially knockout mouse models, have been crucial in understanding its functions.

In Ppara-/-mice, ACOT12 was identified as a key regulatory factor in cartilage homeostasis, with its suppressed level observed in OA patient and OA-induced animal cartilages. Acot12-/-mice showed severe cartilage degradation due to increased de novo lipogenesis (DNL) via acetyl-CoA accumulation, stimulating matrix MMPs and chondrocyte apoptosis [2]. In hepatocellular carcinoma (HCC), ACOT12 expression is down-regulated in HCC tissues. Gain-and loss-of-function studies in vitro and in vivo demonstrated that ACOT12 suppresses HCC metastasis by regulating cellular acetyl-CoA levels and histone acetylation [4]. Similarly, in intrahepatic cholangiocarcinoma (ICC), ACOT12 expression is significantly down-regulated, and in vitro and in vivo studies showed that it suppresses ICC cells metastasis, with its down-regulation promoting metastasis by inducing Slug expression and epithelial-mesenchymal transition (EMT) [3]. In non-alcoholic fatty liver disease (NAFLD), Acot12-/-mice had acetyl-CoA accumulation, stimulating DNL and cholesterol biosynthesis in the liver [5]. In kidney fibrosis, Acot12 deficiency in mice subjected to unilateral ureteral obstruction (UUO) induced lipid accumulation and fibrosis [7].

In conclusion, Acot12 is essential for maintaining lipid metabolism-related homeostasis in various tissues. Studies using Acot12 knockout mouse models have revealed its significant roles in diseases such as osteoarthritis, liver cancers, NAFLD, and kidney fibrosis, providing potential targets for therapeutic strategies in these disease areas.

References:

1. Han, S. 2022. Osteoarthritis year in review 2022: biology. In Osteoarthritis and cartilage, 30, 1575-1582. doi:10.1016/j.joca.2022.09.003. https://pubmed.ncbi.nlm.nih.gov/36150676/

2. Park, Sujeong, Baek, In-Jeoung, Ryu, Ji Hyun, Chun, Churl-Hong, Jin, Eun-Jung. 2022. PPARα-ACOT12 axis is responsible for maintaining cartilage homeostasis through modulating de novo lipogenesis. In Nature communications, 13, 3. doi:10.1038/s41467-021-27738-y. https://pubmed.ncbi.nlm.nih.gov/34987154/

3. Zhou, Xu, Zhou, Yu, Shao, Weiqing, Lu, Ming, Zhu, Wenwei. 2022. ACOT12-mediated acetyl-CoA hydrolysis suppresses intrahepatic cholangiocarcinoma metastasis by inhibiting epithelial-mesenchymal transition. In Journal of Cancer, 13, 1734-1744. doi:10.7150/jca.62169. https://pubmed.ncbi.nlm.nih.gov/35399720/

4. Lu, Ming, Zhu, Wen-Wei, Wang, Xuan, Lu, Jian-Quan, Qin, Lun-Xiu. 2019. ACOT12-Dependent Alteration of Acetyl-CoA Drives Hepatocellular Carcinoma Metastasis by Epigenetic Induction of Epithelial-Mesenchymal Transition. In Cell metabolism, 29, 886-900.e5. doi:10.1016/j.cmet.2018.12.019. https://pubmed.ncbi.nlm.nih.gov/30661930/

5. Park, Sujeong, Song, Jinsoo, Baek, In-Jeoung, Raught, Brian, Jin, Eun-Jung. 2021. Loss of Acot12 contributes to NAFLD independent of lipolysis of adipose tissue. In Experimental & molecular medicine, 53, 1159-1169. doi:10.1038/s12276-021-00648-1. https://pubmed.ncbi.nlm.nih.gov/34285335/

6. He, Haiyue, Sugiyama, Akiko, Snyder, Nathaniel W, Acuña, Mariana, Cohen, David E. 2023. Acyl-CoA thioesterase 12 suppresses YAP-mediated hepatocarcinogenesis by limiting glycerolipid biosynthesis. In Cancer letters, 565, 216210. doi:10.1016/j.canlet.2023.216210. https://pubmed.ncbi.nlm.nih.gov/37150501/

7. Kim, Ee Hyun, Kim, Mi Kyung, Choe, MiSun, Ha, Hunjoo, Jin, Eun-Jung. 2025. ACOT12, a novel factor in the pathogenesis of kidney fibrosis, modulates ACBD5. In Experimental & molecular medicine, 57, 478-488. doi:10.1038/s12276-025-01406-3. https://pubmed.ncbi.nlm.nih.gov/39939783/