Acox3, acyl-CoA oxidase 3, is a key enzyme in lipid metabolism, specifically involved in peroxisomal fatty acid β-oxidation. It converts acyl-CoAs to 2-trans-enoyl-CoAs, playing a crucial role in lipid homeostasis [5,6]. Its function is significant in various biological processes related to lipid management, and genetic models can help in understanding its precise role.

In a study on two dizygotic Korean twin brothers with recurrent spontaneous vasospasm of the extracranial internal carotid artery (RSV-eICA), two compound heterozygous missense variants in Acox3 were identified. In vitro assays showed practically no enzyme activity in the mutants, and knockdown of Acox3 in human aortic smooth muscle cells (HASMC) using siRNA significantly repressed carbachol-induced HASMC contraction. This indicates that Acox3 dysfunction may lead to a prolonged loss of basal aortic myogenic tone, making the internal carotid artery smooth muscles hypersensitive to sympathomimetic stimuli and causing recurrent vasospasm [1]. In other studies, treatment with recombinant Sirt1 downregulated Acox3 both in vitro and in vivo in a model of metabolic cardiomyopathy, and semaglutide treatment in obese mice reduced the expression of Acox3 involved in lipid metabolism, accompanied by beneficial effects on adipose tissues [2,3]. In hypothyroid rats, a temporary decrease in Acox3 levels was observed, and its localization and colocalization patterns contributed to peroxisomal functional compartmentalization in brown adipocytes [4]. In brown trout, estrogenic stimulus caused an up-regulation of Acox3, which may impact hepatic lipid mobilization to the gonads [5]. Treatment with atorvastatin in juvenile brown trout led to a significant down-regulation of acox3 [7].

In conclusion, Acox3 is essential for lipid metabolism, with its dysfunction potentially causing diseases like RSV-eICA. Studies using various models, including those related to metabolic cardiomyopathy, obesity, hypothyroidism, and in fish models, have provided insights into its role in different biological processes and disease conditions. These findings contribute to understanding the importance of Acox3 in maintaining normal physiological functions and its implications in disease development.

References:

1. Kim, Joon-Tae, Won, So Yeon, Kang, KyungWook, Choi, Seok-Yong, Kim, Myeong-Kyu. 2020. ACOX3 Dysfunction as a Potential Cause of Recurrent Spontaneous Vasospasm of Internal Carotid Artery. In Translational stroke research, 11, 1041-1051. doi:10.1007/s12975-020-00779-z. https://pubmed.ncbi.nlm.nih.gov/31975215/

2. Costantino, Sarah, Mengozzi, Alessandro, Velagapudi, Srividya, Luscher, Thomas Felix, Paneni, Francesco. 2023. Treatment with recombinant Sirt1 rewires the cardiac lipidome and rescues diabetes-related metabolic cardiomyopathy. In Cardiovascular diabetology, 22, 312. doi:10.1186/s12933-023-02057-2. https://pubmed.ncbi.nlm.nih.gov/37957697/

3. Zhu, Ruiyi, Chen, Shuchun. 2023. Proteomic analysis reveals semaglutide impacts lipogenic protein expression in epididymal adipose tissue of obese mice. In Frontiers in endocrinology, 14, 1095432. doi:10.3389/fendo.2023.1095432. https://pubmed.ncbi.nlm.nih.gov/37025414/

4. Aleksic, Marija, Golic, Igor, Jankovic, Aleksandra, Cvoro, Aleksandra, Korac, Aleksandra. 2023. ACOX-driven peroxisomal heterogeneity and functional compartmentalization in brown adipocytes of hypothyroid rats. In Royal Society open science, 10, 230109. doi:10.1098/rsos.230109. https://pubmed.ncbi.nlm.nih.gov/37153362/

5. Madureira, Tânia Vieira, Castro, L Filipe C, Rocha, Eduardo. 2015. Acyl-coenzyme A oxidases 1 and 3 in brown trout (Salmo trutta f. fario): Can peroxisomal fatty acid β-oxidation be regulated by estrogen signaling? In Fish physiology and biochemistry, 42, 389-401. doi:10.1007/s10695-015-0146-6. https://pubmed.ncbi.nlm.nih.gov/26508171/

6. Kim, Sangwoo, Kim, Kyung-Jin. . Crystal Structure of Acyl-CoA Oxidase 3 from Yarrowia lipolytica with Specificity for Short-Chain Acyl-CoA. In Journal of microbiology and biotechnology, 28, 597-605. doi:10.4014/jmb.1711.11032. https://pubmed.ncbi.nlm.nih.gov/29429324/

7. Lourenço, Tiago, Rocha, Eduardo, Gonçalves, José Fernando, Rocha, Maria João, Madureira, Tânia Vieira. 2024. A Proof-of-Concept for a Hypolipidemic Brown Trout Model. In Toxics, 12, . doi:10.3390/toxics12030219. https://pubmed.ncbi.nlm.nih.gov/38535952/