Acads-KO Mouse

Acads, encoding short-chain acyl-CoA dehydrogenase (SCAD), functions in the mitochondrial β -oxidation of saturated short-chain fatty acids, regulating energy homeostasis and participating in lipid metabolism pathways [6]. Genetic models, such as cell lines with altered Acads expression, are valuable for studying its gene-regulatory effects on cellular phenotypes [5].

Loss-of-function analyses in hepatocellular carcinoma (HCC) cells showed that Acads was involved in the proliferation and metastasis of HCC. DNA methylation downregulated Acads expression in HCC, and the knockdown of DNA methyltransferase (DMNT) increased Acads expression, indicating it could be a potential therapeutic target [1]. In an unselected adult population, clinically relevant Acads variants were not associated with evidence of metabolic disease, suggesting that short-chain acyl CoA dehydrogenase deficiency (SCADD) may be a biochemical entity without clinical correlate, especially when caused by common variants [2]. In a Chinese Han population, polymorphisms in the Acads gene, like rs2239686 and rs487915, were associated with chronic obstructive pulmonary disease (COPD) risk, and certain haplotypes were protective or increased susceptibility [3]. Depletion of the Acads gene in HCC cells significantly inhibited HCC proliferation and metastasis, and gut microbial metabolite butyrate, which activates the calcium signaling pathway, had a similar effect [4].

In conclusion, Acads is essential for mitochondrial fatty acid β -oxidation and energy homeostasis. Model-based research has revealed its roles in diseases like HCC, SCADD-related metabolic conditions, and COPD. These findings contribute to understanding the molecular mechanisms underlying these diseases and may offer potential targets for therapeutic intervention.

References:

1. Chen, Diyu, Feng, Xiaode, Lv, Zhen, Chen, Jianzhong, Wu, Jian. 2019. ACADS acts as a potential methylation biomarker associated with the proliferation and metastasis of hepatocellular carcinomas. In Aging, 11, 8825-8844. doi:10.18632/aging.102292. https://pubmed.ncbi.nlm.nih.gov/31652420/

2. Breilyn, Margo S, Kenny, Eimear E, Abul-Husn, Noura S. 2022. Diverse and unselected adults with clinically relevant ACADS variants lack evidence of metabolic disease. In Molecular genetics and metabolism, 138, 106971. doi:10.1016/j.ymgme.2022.106971. https://pubmed.ncbi.nlm.nih.gov/36549199/

3. Yuan, Yiming, Yang, Shanshan, Deng, Dan, Zhou, Ruixue, Su, Zhiguang. 2020. Effects of genetic variations in Acads gene on the risk of chronic obstructive pulmonary disease. In IUBMB life, 72, 1986-1996. doi:10.1002/iub.2336. https://pubmed.ncbi.nlm.nih.gov/32593204/

4. Che, Yibin, Chen, Guoyu, Guo, Qianqian, Feng, Haizhong, Xia, Qiang. 2023. Gut microbial metabolite butyrate improves anticancer therapy by regulating intracellular calcium homeostasis. In Hepatology (Baltimore, Md.), 78, 88-102. doi:10.1097/HEP.0000000000000047. https://pubmed.ncbi.nlm.nih.gov/36947402/

5. Matejka, Kerstin, Stückler, Ferdinand, Salomon, Michael, Hauner, Hans, Laumen, Helmut. 2019. Dynamic modelling of an ACADS genotype in fatty acid oxidation - Application of cellular models for the analysis of common genetic variants. In PloS one, 14, e0216110. doi:10.1371/journal.pone.0216110. https://pubmed.ncbi.nlm.nih.gov/31120904/

6. Chen, Yulong, Su, Zhiguang. 2015. Reveal genes functionally associated with ACADS by a network study. In Gene, 569, 294-302. doi:10.1016/j.gene.2015.05.069. https://pubmed.ncbi.nlm.nih.gov/26045367/