Akr1a1, also known as aldo-keto reductase family 1 member A1, is a key enzyme in the aldo-keto reductase superfamily. It catalyzes the reduction of aldehyde groups to corresponding alcohols in an NADPH-dependent manner. It is involved in multiple biological processes, such as the transformation of D-glucuronate to L-gulonate in vitamin C synthesis [2], and acts as a S-nitroso-glutathione reductase, regulating protein S-nitrosylation [1]. It also participates in the metabolic activation of benzo(a)pyrene [3].

In animal models, Akr1a1 knockout (KO) mice with vitamin C deficiency exhibit aberrant bone formation and osteoporosis, and kefir peptides can ameliorate this condition by promoting osteoblastogenesis and inhibiting osteoclastogenesis [2]. In alcohol-associated liver disease, Akr1a1-/-mice on a 5% alcohol-fed diet show a lower survival rate and more severe liver injury, with increased pro-inflammatory cytokines, oxidative stress, lipid accumulation, and fibrosis, suggesting that Akr1a1 plays a protective role by reducing 4-HNE accumulation and p53 activation [4]. In addition, deletion of Akr1a1 in mice increases protein S-nitrosylation, protects against acute kidney injury, and improves survival, mediated by inhibitory S-nitrosylation of pyruvate kinase M2 [5].

In conclusion, Akr1a1 plays essential roles in multiple biological processes and diseases. KO mouse models have been crucial in revealing its protective functions in osteoporosis, alcohol-associated liver disease, and acute kidney injury. Understanding Akr1a1 functions helps in uncovering disease mechanisms and may offer new therapeutic directions for these conditions.

References:

1. Stomberski, Colin T, Anand, Puneet, Venetos, Nicholas M, Premont, Richard T, Stamler, Jonathan S. 2019. AKR1A1 is a novel mammalian S-nitroso-glutathione reductase. In The Journal of biological chemistry, 294, 18285-18293. doi:10.1074/jbc.RA119.011067. https://pubmed.ncbi.nlm.nih.gov/31649033/

2. Chang, Gary Ro-Lin, Lin, Wei-Yu, Fan, Hueng-Chuen, Chen, Wei, Chen, Chuan-Mu. 2022. Kefir peptides ameliorate osteoporosis in AKR1A1 knockout mice with vitamin C deficiency by promoting osteoblastogenesis and inhibiting osteoclastogenesis. In Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie, 156, 113859. doi:10.1016/j.biopha.2022.113859. https://pubmed.ncbi.nlm.nih.gov/36252352/

3. Osorio-Yáñez, Citlalli, García-Tavera, José Luis, Pérez-Núñez, Maria Teresa, Zapata-Pérez, Omar, Albores, Arnulfo. 2012. Benzo(a)pyrene induces hepatic AKR1A1 mRNA expression in tilapia fish (Oreochromis niloticus). In Toxicology mechanisms and methods, 22, 438-44. doi:10.3109/15376516.2012.666684. https://pubmed.ncbi.nlm.nih.gov/22394341/

4. Lan, Ying-Wei, Chen, Wan-Ru, Chang, Gary Ro-Lin, Chen, Ming-Shan, Chen, Chuan-Mu. 2024. Aldo-keto reductase family 1 member A1 (AKR1A1) exerts a protective function in alcohol-associated liver disease by reducing 4-HNE accumulation and p53 activation. In Cell & bioscience, 14, 18. doi:10.1186/s13578-024-01200-0. https://pubmed.ncbi.nlm.nih.gov/38308335/

5. Zhou, Hua-Lin, Zhang, Rongli, Anand, Puneet, Karumanchi, S Ananth, Stamler, Jonathan S. 2018. Metabolic reprogramming by the S-nitroso-CoA reductase system protects against kidney injury. In Nature, 565, 96-100. doi:10.1038/s41586-018-0749-z. https://pubmed.ncbi.nlm.nih.gov/30487609/