Mevalonic acid

Mevalonic acid is a precursor of cholesterol in the de novo biosynthetic pathway^[1]. it is an important intermediate product of cholesterol and terpenoid synthesis, and plays an important role in regulating cell proliferation and collagen synthesis. Mevalonic acid stimulates HMGR expression and plays a key role in regulating cell growth^[4].

C2C12 myotubes were incubated with simvastatin for 72 h in the absence or presence of increasing amounts of mevalonic acid. Following incubation, cell viability was measured . Control incubations with DMSO or mevalonic acid, but no simvastatin, had no effect on cell viability. C2C12 myotubes incubated with simvastatin manifested the expected decline in cell viability while myotubes incubated with simvastatin plus mevalonic acid showed no decline in cell viability at all mevalonic acid concentrations tested. Thus, it is concluded that mevalonic acid prevents manifestation of the deleterious effects of high-dose simvastatin treatment on C2C12 myotubes^[2]. Mevalonic acid promotes tumor growth and, therefore, an increase in mevalonate synthesis in extrahepatic tissues following cholesterol-lowering therapy may explain the increased risk of cancer observed in some studies^[5,6].Inhibition of the Mevalonic acid metabolic pathway in tumor cells elicits type 1 classical dendritic cells (cDC1) mediated tumor recognition and antigen cross-presentation for antitumor immunity. It demonstrates tumor Mevalonic acid metabolic blockade stimulates a cDC1 response through CLEC9A-mediated immune recognition of tumor cell cytoskeleton^[3]. Mevalonic acid have become a focus area in research on the development of antitumor drugs ^[7].

In the mouse experiment, Xuezhikang inhibited the Fas/FasL apoptosis pathway of myocardial cells in rats with ischemia/reperfusion, and then inhibited the apoptosis of cardiomyocytes, Mevalonic acid can attenuate the protective effect of Xuezhikang^[8].

References:
[1]: Naoumova RP, Marais AD, et,al. Plasma mevalonic acid, an index of cholesterol synthesis in vivo, and responsiveness to HMG-CoA reductase inhibitors in familial hypercholesterolaemia. Atherosclerosis. 1996 Jan 26;119(2):203-13. doi: 10.1016/0021-9150(95)05649-1. PMID: 8808497.
[2]: Moschetti A, Dagda RK, et,al. Coenzyme Q nanodisks counteract the effect of statins on C2C12 myotubes. Nanomedicine. 2021 Oct;37:102439. doi: 10.1016/j.nano.2021.102439. Epub 2021 Jul 10. PMID: 34256063; PMCID: PMC8464493.
[3]: Xu F, Wang Z, et,al. Mevalonate Blockade in Cancer Cells Triggers CLEC9A+ Dendritic Cell-Mediated Antitumor Immunity. Cancer Res. 2021 Sep 1;81(17):4514-4528. doi: 10.1158/0008-5472.CAN-20-3977. Epub 2021 Jul 15. PMID: 34266895.
[4]: Scoppola A, De Paolis P, et,al. Plasma mevalonate concentrations in uremic patients. Kidney Int. 1997 Mar;51(3):908-12. doi: 10.1038/ki.1997.128. PMID: 9067929.
[5]: Melhem MF, Gabriel HF, et,al. Cholestyramine promotes 7,12-dimethylbenzanthracene induced mammary cancer in Wistar rats. Br J Cancer. 1987 Jul;56(1):45-8. doi: 10.1038/bjc.1987.150. PMID: 3113472; PMCID: PMC2001672.
[6]: Rao KN, Melhem MF, et,al. Lipid composition and de novo cholesterogenesis in normal and neoplastic rat mammary tissues. J Natl Cancer Inst. 1988 Oct 5;80(15):1248-53. doi: 10.1093/jnci/80.15.1248. PMID: 3418731.
[7]: Duncan RE, El-Sohemy A, et,al. Mevalonate promotes the growth of tumors derived from human cancer cells in vivo and stimulates proliferation in vitro with enhanced cyclin-dependent kinase-2 activity. J Biol Chem. 2004 Aug 6;279(32):33079-84. doi: 10.1074/jbc.M400732200. Epub 2004 May 20. PMID: 15155733.
[8]: ZUO Hanheng, LI Yinping et,al. Effects of Xuezhikang on Cardiomyocyte Apoptosis.

甲羟戊酸是从头生物合成途径中胆固醇的前体^[1]。它是胆固醇和萜类化合物合成的重要中间产物，对调节细胞增殖和胶原蛋白合成有重要作用。甲羟戊酸刺激HMGR表达并在调节细胞生长中起关键作用^[4]。

C2C12 肌管在不存在或存在增加量的甲羟戊酸的情况下与辛伐他汀一起孵育 72 小时。孵育后，测量细胞活力。使用 DMSO 或甲羟戊酸（但不使用辛伐他汀）进行对照孵育对细胞活力没有影响。用辛伐他汀孵育的 C2C12 肌管表现出预期的细胞活力下降，而用辛伐他汀加甲羟戊酸孵育的肌管在所有测试的甲羟戊酸浓度下均未显示细胞活力下降。因此，可以得出结论，甲羟戊酸可防止大剂量辛伐他汀治疗对 C2C12 肌管的有害作用的表现^[2]。甲羟戊酸促进肿瘤生长，因此，降低胆固醇治疗后肝外组织中甲羟戊酸合成的增加可能解释了一些研究中观察到的癌症风险增加的原因^[5,6]。抑制甲羟戊酸肿瘤细胞中的酸代谢途径引发 1 型经典树突状细胞 (cDC1) 介导的肿瘤识别和抗原交叉呈递以实现抗肿瘤免疫。它表明肿瘤甲羟戊酸代谢阻断通过 CLEC9A 介导的肿瘤细胞骨架的免疫识别刺激 cDC1 反应^[3]。甲羟戊酸已成为抗肿瘤药物开发研究的热点^[7]。

小鼠实验中，血脂康通过抑制大鼠缺血/再灌注心肌细胞Fas/FasL凋亡通路，进而抑制心肌细胞凋亡，甲羟戊酸可减弱血脂康的保护作用^{[8]< /sup>.}