Acetyl-CoA acyltransferase 2 (ACAA2) is a key enzyme in the fatty acid oxidation pathway, catalyzing the final step of mitochondrial β-oxidation [3]. It is involved in fatty acid metabolism, the tricarboxylic acid cycle, and ketone body metabolism [5]. ACAA2 also functions as a ligand-dependent coactivator for thyroid hormone receptor β1, potentially influencing how thyroid hormones regulate gene expression [2].

In non-alcoholic fatty liver disease (NAFLD), deficiency of CAND1 enhances the assembly of Cullin1, FBXO42 and ACAA2 complexes, promoting the ubiquitinated degradation of ACAA2. CAND1 mitigates NAFLD by inhibiting this degradation [1]. In the context of kidney injury, proximal tubule-specific knockout of Klf15 reduces the expression of Acaa2, leading to compromised fatty acid β-oxidation (FAO) and exacerbating acute kidney injury and fibrosis [4]. In acetaminophen-induced liver injury, liver-specific Egr1 knockout aggravated the injury, and knockdown of Acaa2 diminished the protective effect of Egr1, which transcriptionally upregulates Acaa2 to improve mitochondrial FAO [6]. In ovarian cancer, ACAA2 overexpression promotes, while knockdown inhibits, the malignant progression of ovarian cancer, suggesting it is an oncogene in this context [3].

In summary, ACAA2 plays essential roles in fatty acid metabolism-related biological processes. Studies using gene knockout models in different disease areas such as NAFLD, kidney injury, liver injury, and ovarian cancer have revealed its significance in disease development, providing insights into potential therapeutic targets.

References:

1. Huang, Xiang, Liu, Xin, Li, Xingda, Yang, Baofeng, Pan, Zhenwei. 2023. Cullin-associated and neddylation-dissociated protein 1 (CAND1) alleviates NAFLD by reducing ubiquitinated degradation of ACAA2. In Nature communications, 14, 4620. doi:10.1038/s41467-023-40327-5. https://pubmed.ncbi.nlm.nih.gov/37528093/

2. Wang, Wesley, Ledee, Dolena. 2021. ACAA2 is a ligand-dependent coactivator for thyroid hormone receptor β1. In Biochemical and biophysical research communications, 576, 15-21. doi:10.1016/j.bbrc.2021.08.073. https://pubmed.ncbi.nlm.nih.gov/34474245/

3. Leng, Yahui, Tian, Tian, Tang, Bingbing, Shen, Li, Zhao, Hongyan. 2024. The oncogenic role and regulatory mechanism of ACAA2 in human ovarian cancer. In Molecular carcinogenesis, 63, 1362-1377. doi:10.1002/mc.23729. https://pubmed.ncbi.nlm.nih.gov/38656551/

4. Piret, Sian E, Attallah, Ahmed A, Gu, Xiangchen, He, John C, Mallipattu, Sandeep K. 2021. Loss of proximal tubular transcription factor Krüppel-like factor 15 exacerbates kidney injury through loss of fatty acid oxidation. In Kidney international, 100, 1250-1267. doi:10.1016/j.kint.2021.08.031. https://pubmed.ncbi.nlm.nih.gov/34634362/

5. Xu, Zhengqi, Jiang, Feng, Wu, Xiaofan, Lin, Li, Li, Sheng. 2025. ACAA2 Protects Against Cardiac Dysfunction and Lipid Peroxidation in Renal Insufficiency with the Treatment of S-Nitroso-L-Cysteine. In Biomolecules, 15, . doi:10.3390/biom15030364. https://pubmed.ncbi.nlm.nih.gov/40149900/

6. Lei, Xiaohong, Xu, Qingling, Li, Chunmin, Li, Xiaobo, Mao, Yimin. 2022. Egr1 confers protection against acetaminophen‑induced hepatotoxicity via transcriptional upregulating of Acaa2. In International journal of biological sciences, 18, 3800-3817. doi:10.7150/ijbs.71781. https://pubmed.ncbi.nlm.nih.gov/35813467/