Hacd2, short for 3-Hydroxyacyl-CoA dehydratase 2, is an enzyme-encoding gene involved in very long chain fatty acid (C≥18) synthesis [1,4,5,6]. It participates in fatty acid elongation pathways, with HACD1 and HACD2 showing functional redundancy in saturated to polyunsaturated fatty acid elongation, and HACD2 being a major 3-hydroxyacyl-CoA dehydratase [5]. This gene is also associated with lipid metabolism-related pathways in various organisms [7,8,9,10].

Mouse models have been crucial in understanding Hacd2's functions. A partial knockdown of Hacd2 expression in mice leads to death within 1-4 weeks after birth, marked by growth arrest, cachexia, and lethargy, while total knockout results in embryonic lethality around E9.5 with developmental arrest and cardiovascular malformations. Mechanistically, Hacd2 deficiency causes mitochondrial inefficiency, ultrastructure alteration, and oxidized cardiolipin accumulation, indicating its essential role in energetic metabolism during development [1]. In addition, in pancreatic cancer, HACD2 promotes cancer cell proliferation through a dehydratase-independent mechanism by enhancing PKM2 dissociation from PRKN [2]. Also, in diet-induced obesity studies, loss of Hacd2 expression in the liver protected mice against obesity, fatty liver disease, and diabetes, suggesting it could be a therapeutic target for obesity-related metabolic diseases [3].

In summary, Hacd2 is essential for energetic metabolism during embryonic and postnatal development, acting through mitochondrial regulation. Its study using knockout mouse models has provided insights into mitochondrial diseases, pancreatic cancer progression, and obesity-related metabolic diseases, highlighting its potential as a therapeutic target in these disease areas.

References:

1. Khadhraoui, Nahed, Prola, Alexandre, Vandestienne, Aymeline, Tiret, Laurent, Pilot-Storck, Fanny. 2023. Hacd2 deficiency in mice leads to an early and lethal mitochondrial disease. In Molecular metabolism, 69, 101677. doi:10.1016/j.molmet.2023.101677. https://pubmed.ncbi.nlm.nih.gov/36693621/

2. Chu, Xuanning, Zhao, Jinyu, Shen, Yuting, Ma, Lingman, Zhou, Yiran. 2025. HACD2 Promotes Pancreatic Cancer Progression by Enhancing PKM2 Dissociation From PRKN in a Dehydratase-Independent Manner. In Advanced science (Weinheim, Baden-Wurttemberg, Germany), 12, e2407942. doi:10.1002/advs.202407942. https://pubmed.ncbi.nlm.nih.gov/39836601/

3. Wei, Lengyun, Weng, Shengmei, Lu, Xuyang, Yang, Qin, Chen, Yong Q. 2022. 3-Hydroxyacyl-CoA dehydratase 2 deficiency confers resistance to diet-induced obesity and glucose intolerance. In Biochemical and biophysical research communications, 605, 134-140. doi:10.1016/j.bbrc.2022.03.057. https://pubmed.ncbi.nlm.nih.gov/35325655/

4. Zhou, Youli, Lv, Rui, Ye, Richard D, Ren, Ruobing, Yu, Leiye. 2024. The 3-hydroxyacyl-CoA dehydratase 1/2 form complex with trans-2-enoyl-CoA reductase involved in substrates transfer in very long chain fatty acid elongation. In Biochemical and biophysical research communications, 704, 149588. doi:10.1016/j.bbrc.2024.149588. https://pubmed.ncbi.nlm.nih.gov/38422897/

5. Sawai, Megumi, Uchida, Yukiko, Ohno, Yusuke, Sassa, Takayuki, Kihara, Akio. 2017. The 3-hydroxyacyl-CoA dehydratases HACD1 and HACD2 exhibit functional redundancy and are active in a wide range of fatty acid elongation pathways. In The Journal of biological chemistry, 292, 15538-15551. doi:10.1074/jbc.M117.803171. https://pubmed.ncbi.nlm.nih.gov/28784662/

6. Lei, Gaoke, Zhou, Huiling, Chen, Yanting, You, Minsheng, You, Shijun. 2023. A very long-chain fatty acid enzyme gene, PxHacd2 affects the temperature adaptability of a cosmopolitan insect by altering epidermal permeability. In The Science of the total environment, 891, 164372. doi:10.1016/j.scitotenv.2023.164372. https://pubmed.ncbi.nlm.nih.gov/37236474/

7. Lin, Ruiyi, Li, Huihuang, Lin, Weilong, Lai, Lianjie, Lin, Weimin. 2024. Whole-genome selection signature differences between Chaohu and Ji'an red ducks. In BMC genomics, 25, 522. doi:10.1186/s12864-024-10339-6. https://pubmed.ncbi.nlm.nih.gov/38802792/

8. Yu, Hengwei, Wang, Jianfang, Zhang, Ke, Mei, Chugang, Zan, Linsen. 2023. Integrated multi-omics analysis reveals variation in intramuscular fat among muscle locations of Qinchuan cattle. In BMC genomics, 24, 367. doi:10.1186/s12864-023-09452-9. https://pubmed.ncbi.nlm.nih.gov/37391702/

9. Jiang, Ping, Iqbal, Ambreen, Cui, Zhiqian, Yu, Haibin, Zhao, Zhihui. 2022. Bta-miR-33a affects gene expression and lipid levels in Chinese Holstein mammary epithelial cells. In Archives animal breeding, 65, 357-370. doi:10.5194/aab-65-357-2022. https://pubmed.ncbi.nlm.nih.gov/36304442/

10. Liu, Tianyi, Feng, Hui, Yousuf, Salsabeel, Xie, Lingli, Miao, Xiangyang. 2022. Differential regulation of mRNAs and lncRNAs related to lipid metabolism in Duolang and Small Tail Han sheep. In Scientific reports, 12, 11157. doi:10.1038/s41598-022-15318-z. https://pubmed.ncbi.nlm.nih.gov/35778462/