Hmgcs2, also known as 3-hydroxy-3-methylglutaryl-CoA synthase 2, is the rate-limiting enzyme for ketone body synthesis in mitochondria [5,8]. It is involved in the ketogenesis pathway, which is crucial for energy metabolism, especially during states of carbohydrate restriction. Genetic models, such as gene knockout (KO) and conditional knockout (CKO) mouse models, are valuable for studying its function.

In a high-fat diet-induced NAFLD mouse model, Hmgcs2 knockout led to a spontaneous fatty liver phenotype during postnatal development, which could be rescued by a low-fat diet. Hmgcs2 heterozygous adult mice, with lower ketogenic activity, were more susceptible to diet-induced NAFLD, while HMGCS2 overexpression improved hepatosteatosis and glucose homeostasis [1]. In the context of chronic kidney disease, downregulation of LONP1 caused mitochondrial accumulation of HMGCS2, disrupting mitochondrial function and accelerating disease progression [2]. In septic mouse models, silencing of Hmgcs2 accelerated septic myocardial injury, while Hmgcs2 overexpression protected against septic cardiomyopathy by promoting M2 macrophage polarization [3]. In pancreatic ductal adenocarcinoma models, HMGCS2 was overexpressed in gemcitabine-resistant tumors, and BET inhibitor-mediated decrease in HMGCS2 sensitized these tumors to gemcitabine [4]. Tacrolimus-induced liver lipid deposition was due to decreased HMGCS2-mediated ketogenesis, and liver-specific HMGCS2 overexpression reversed this effect [6]. In diabetic nephropathy, knockdown of HMGCS2 could restrain high-glucose-induced glomerular endothelial cells mitochondrial dysfunction and pyroptosis [7]. In clear cell renal cell carcinoma, upregulation of HMGCS2 inhibited cell proliferation and promoted apoptosis [8].

In conclusion, Hmgcs2 is essential for ketogenesis and energy metabolism. Studies using KO/CKO mouse models have revealed its roles in various disease conditions, including non-alcoholic fatty liver disease, chronic kidney disease, sepsis-induced myocardial injury, pancreatic cancer, tacrolimus-induced hepatic lipid metabolism disorder, diabetic nephropathy, and clear cell renal cell carcinoma. These findings contribute to understanding the mechanisms of these diseases and potentially developing new therapeutic strategies.

References:

1. Asif, Shaza, Kim, Ri Youn, Fatica, Thet, Mulvihill, Erin E, Kim, Kyoung-Han. 2022. Hmgcs2-mediated ketogenesis modulates high-fat diet-induced hepatosteatosis. In Molecular metabolism, 61, 101494. doi:10.1016/j.molmet.2022.101494. https://pubmed.ncbi.nlm.nih.gov/35421611/

2. Bai, Mi, Wu, Mengqiu, Jiang, Mingzhu, Jia, Zhanjun, Zhang, Aihua. 2023. LONP1 targets HMGCS2 to protect mitochondrial function and attenuate chronic kidney disease. In EMBO molecular medicine, 15, e16581. doi:10.15252/emmm.202216581. https://pubmed.ncbi.nlm.nih.gov/36629048/

3. Zou, Xiao-Zheng, Hao, Jun-Feng, Hou, Ming-Xiao. 2023. Hmgcs2 regulates M2 polarization of macrophages to repair myocardial injury induced by sepsis. In Aging, 15, 7794-7810. doi:10.18632/aging.204944. https://pubmed.ncbi.nlm.nih.gov/37561521/

4. Miller, Aubrey L, Fehling, Samuel C, Vance, Rebecca B, Bellis, Susan L, Yoon, Karina J. 2024. BET inhibition decreases HMGCS2 and sensitizes resistant pancreatic tumors to gemcitabine. In Cancer letters, 592, 216919. doi:10.1016/j.canlet.2024.216919. https://pubmed.ncbi.nlm.nih.gov/38704133/

5. Hu, Li-Tian, Xie, Xiao-Yong, Zhou, Gui-Feng, Pan, Qiu-Ling, Chen, Guo-Jun. . HMGCS2-Induced Autophagic Degradation of Tau Involves Ketone Body and ANKRD24. In Journal of Alzheimer's disease : JAD, 91, 407-426. doi:10.3233/JAD-220640. https://pubmed.ncbi.nlm.nih.gov/36442191/

6. Li, Sen-Lin, Zhou, Hong, Liu, Jia, Yang, Ke-Shan, Xiang, Ming. 2024. Restoration of HMGCS2-mediated ketogenesis alleviates tacrolimus-induced hepatic lipid metabolism disorder. In Acta pharmacologica Sinica, 45, 1898-1911. doi:10.1038/s41401-024-01300-0. https://pubmed.ncbi.nlm.nih.gov/38760545/

7. Shen, Yilan, Chen, Wei, Lin, Kanghong, Xu, Youhua, Gui, Dingkun. 2024. Notoginsenoside Fc, a novel renoprotective agent, ameliorates glomerular endothelial cells pyroptosis and mitochondrial dysfunction in diabetic nephropathy through regulating HMGCS2 pathway. In Phytomedicine : international journal of phytotherapy and phytopharmacology, 126, 155445. doi:10.1016/j.phymed.2024.155445. https://pubmed.ncbi.nlm.nih.gov/38412666/

8. Mao, Huajie, Wang, Runzhi, Shao, Fengling, Xia, Hua, Zhao, Ya. 2023. HMGCS2 serves as a potential biomarker for inhibition of renal clear cell carcinoma growth. In Scientific reports, 13, 14629. doi:10.1038/s41598-023-41343-7. https://pubmed.ncbi.nlm.nih.gov/37670031/