Cyp4a14, a member of the cytochrome P450 (Cyp450) enzyme superfamily, possesses NADPH monooxygenase activity. It catalyzes omega-hydroxylation of medium-chain fatty acids and arachidonic acid, and is involved in lipid metabolism, oxidative stress, and bile acid synthesis pathways [1,2,4]. Genetic models, such as knockout mice, have been crucial in studying its functions.

In the context of disease, Cyp4a14-knockout (KO) mice showed a higher number of goblet cells in the colon and were more resistant to dextran sulfate sodium-induced colitis, with lower levels of oxidative stress markers and pro-inflammatory cytokines [4]. In another study, KO mice had hypertension driven by excessive fluid reabsorption in the proximal tubule, secondary to overexpression of sodium-hydrogen exchanger 3 [5]. Additionally, in a non-alcoholic steatohepatitis (NASH) model, Gsdmd -/- mice showed lower steatosis, partly due to upregulated expression of Cyp4a14 along with other lipolytic genes [3].

In summary, Cyp4a14 plays important roles in lipid metabolism, oxidative stress response, and inflammation. Studies using KO mouse models have revealed its implications in diseases like colitis, hypertension, and NASH, contributing to a better understanding of the underlying disease mechanisms and potentially identifying it as a therapeutic target for these conditions.

References:

1. Zhou, Fei, Yang, Linquan, Sun, Wenwen, Ma, Huijuan, Yang, Linlin. 2023. The PPARα/CYP4A14 bile acid pathway is associated with lipid metabolism disorders caused by low birth weight with high-fat diet. In Food & nutrition research, 67, . doi:10.29219/fnr.v67.8994. https://pubmed.ncbi.nlm.nih.gov/36794015/

2. Sobocanec, Sandra, Balog, Tihomir, Sarić, Ana, Kusić, Borka, Marotti, Tanja. . Cyp4a14 overexpression induced by hyperoxia in female CBA mice as a possible contributor of increased resistance to oxidative stress. In Free radical research, 44, 181-90. doi:10.3109/10715760903390820. https://pubmed.ncbi.nlm.nih.gov/19905990/

3. Xu, Bing, Jiang, Mingzuo, Chu, Yi, Wu, Kaichun, Liang, Jie. 2017. Gasdermin D plays a key role as a pyroptosis executor of non-alcoholic steatohepatitis in humans and mice. In Journal of hepatology, 68, 773-782. doi:10.1016/j.jhep.2017.11.040. https://pubmed.ncbi.nlm.nih.gov/29273476/

4. Xuan, Qingxia, Zhou, Yunfeng, Tan, Binbin, Chu, Fong-Fong, Gao, Qiang. 2018. Mice Deficient in Cyp4a14 Have An Increased Number of Goblet Cells and Attenuated Dextran Sulfate Sodium-Induced Colitis. In Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology, 50, 2272-2282. doi:10.1159/000495087. https://pubmed.ncbi.nlm.nih.gov/30423565/

5. Quigley, Raymond, Chakravarty, Sumana, Zhao, Xueying, Imig, John D, Capdevila, Jorge H. 2009. Increased renal proximal convoluted tubule transport contributes to hypertension in Cyp4a14 knockout mice. In Nephron. Physiology, 113, p23-8. doi:10.1159/000235774. https://pubmed.ncbi.nlm.nih.gov/19713718/