Dgat1-KO Mouse

Dgat1, also known as diacylglycerol-O-acyltransferase 1, is a key enzyme in lipid metabolism. It catalyzes the final step in triglyceride synthesis, which is crucial for the storage of excess fatty acids (FAs) into triglycerides and lipid droplets. This process is integral to maintaining lipid homeostasis and is involved in multiple biological processes like energy storage and cell membrane formation [4,5,6]. Genetic models, such as gene knockout (KO) mouse models, have been valuable in understanding its function.

In glioblastoma (GBM), GBM cells upregulate Dgat1 to avoid lipotoxicity by storing excess FAs. Inhibiting Dgat1 in xenograft models disrupted lipid homeostasis, led to excessive FAs moving into mitochondria, generating high levels of reactive oxygen species (ROS), mitochondrial damage, and apoptosis, suppressing GBM growth [1]. In clear cell renal cell carcinoma (ccRCC), the oncogenic JMJD6-Dgat1 axis was identified. Silencing JMJD6 reduced Dgat1, leading to decreased lipid droplet formation and tumorigenesis. Pharmacological inhibition of Dgat1 also inhibited lipid droplet formation in vitro and ccRCC tumorigenesis in vivo [2]. During starvation-induced autophagy, Dgat1-dependent lipid droplet biogenesis was found to protect mitochondrial function by preventing acylcarnitine accumulation and lipotoxic dysregulation of mitochondria [3].

In conclusion, Dgat1 plays a vital role in maintaining lipid homeostasis, protecting cells from lipotoxicity, and influencing energy-related processes. Model-based research, especially KO/CKO mouse models, has revealed its significance in tumor-related diseases like GBM and ccRCC, providing potential therapeutic targets for these malignancies.

References:

1. Cheng, Xiang, Geng, Feng, Pan, Meixia, Chakravarti, Arnab, Guo, Deliang. 2020. Targeting DGAT1 Ameliorates Glioblastoma by Increasing Fat Catabolism and Oxidative Stress. In Cell metabolism, 32, 229-242.e8. doi:10.1016/j.cmet.2020.06.002. https://pubmed.ncbi.nlm.nih.gov/32559414/

2. Zhou, Jin, Simon, Jeremy M, Liao, Chengheng, Brugarolas, James, Zhang, Qing. 2022. An oncogenic JMJD6-DGAT1 axis tunes the epigenetic regulation of lipid droplet formation in clear cell renal cell carcinoma. In Molecular cell, 82, 3030-3044.e8. doi:10.1016/j.molcel.2022.06.003. https://pubmed.ncbi.nlm.nih.gov/35764091/

3. Nguyen, Truc B, Louie, Sharon M, Daniele, Joseph R, Nomura, Daniel K, Olzmann, James A. . DGAT1-Dependent Lipid Droplet Biogenesis Protects Mitochondrial Function during Starvation-Induced Autophagy. In Developmental cell, 42, 9-21.e5. doi:10.1016/j.devcel.2017.06.003. https://pubmed.ncbi.nlm.nih.gov/28697336/

4. de la Rosa Rodriguez, Montserrat A, Deng, Lei, Gemmink, Anne, Borst, Jan Willem, Kersten, Sander. 2021. Hypoxia-inducible lipid droplet-associated induces DGAT1 and promotes lipid storage in hepatocytes. In Molecular metabolism, 47, 101168. doi:10.1016/j.molmet.2021.101168. https://pubmed.ncbi.nlm.nih.gov/33465519/

5. Oleszycka, Ewa, Kwiecień, Kamila, Grygier, Beata, Cichy, Joanna, Kwiecińska, Patrycja. 2024. The many faces of DGAT1. In Life sciences, 362, 123322. doi:10.1016/j.lfs.2024.123322. https://pubmed.ncbi.nlm.nih.gov/39709166/

6. Khan, Muhammad Zahoor, Ma, Yulin, Ma, Jiaying, Khan, Ibrar Muhammad, Cao, Zhijun. 2021. Association of DGAT1 With Cattle, Buffalo, Goat, and Sheep Milk and Meat Production Traits. In Frontiers in veterinary science, 8, 712470. doi:10.3389/fvets.2021.712470. https://pubmed.ncbi.nlm.nih.gov/34485439/