Mthembu Sinenhlanhla X H, Orlando Patrick, Silvestri Sonia, Ziqubu Khanyisani, Mazibuko-Mbeje Sithandiwe E, Mabhida Sihle E, Nyambuya Tawanda M, Nkambule Bongani B, Muller Christo J F, Basson Albertus K, Tiano Luca, Dludla Phiwayinkosi V
Biomedical Research and Innovation Platform, South African Medical Research Council, Tygerberg, 7505, South Africa; Department of Biochemistry, Mafikeng Campus, Northwest University, Mmabatho, 2735, South Africa.
Department of Life and Environmental Sciences, Polytechnic University of Marche, Ancona, 60131, Italy.
Biochimie. 2023 Jan;204:33-40. doi: 10.1016/j.biochi.2022.08.018. Epub 2022 Sep 5.
Dyslipidemia is one of the major risk factors for the development of cardiovascular disease (CVD) in patients with type 2 diabetes (T2D). This metabolic anomality is implicated in the generation of oxidative stress, an inevitable process involved in destructive mechanisms leading to myocardial damage. Fortunately, commonly used drugs like statins can counteract the detrimental effects of dyslipidemia by lowering cholesterol to reduce CVD-risk in patients with T2D. Statins mainly function by blocking the production of cholesterol by targeting the mevalonate pathway. However, by blocking cholesterol synthesis, statins coincidently inhibit the synthesis of other essential isoprenoid intermediates of the mevalonate pathway like farnesyl pyrophosphate and coenzyme Q (CoQ). The latter is by far the most important co-factor and co-enzyme required for efficient mitochondrial oxidative capacity, in addition to its robust antioxidant properties. In fact, supplementation with CoQ has been found to be beneficial in ameliorating oxidative stress and improving blood flow in subjects with mild dyslipidemia.. Beyond discussing the destructive effects of oxidative stress in dyslipidemia-induced CVD-related complications, the current review brings a unique perspective in exploring the mevalonate pathway to block cholesterol synthesis while enhancing or maintaining CoQ levels in conditions of dyslipidemia. Furthermore, this review disscusses the therapeutic potential of bioactive compounds in targeting the downstream of the mevalonate pathway, more importantly, their ability to block cholesterol while maintaining CoQ biosynthesis to protect against the destructive complications of dyslipidemia.
血脂异常是2型糖尿病（T2D）患者发生心血管疾病（CVD）的主要危险因素之一。这种代谢异常与氧化应激的产生有关，氧化应激是导致心肌损伤的破坏机制中不可避免的过程。幸运的是，常用药物如他汀类药物可以通过降低胆固醇来抵消血脂异常的有害影响，从而降低T2D患者的CVD风险。他汀类药物主要通过靶向甲羟戊酸途径来阻断胆固醇的产生发挥作用。然而，通过阻断胆固醇合成，他汀类药物同时抑制了甲羟戊酸途径中其他必需的类异戊二烯中间体的合成，如法尼基焦磷酸和辅酶Q（CoQ）。辅酶Q除了具有强大的抗氧化特性外，还是有效线粒体氧化能力所需的最重要的辅助因子和辅酶。事实上，已发现补充辅酶Q对改善轻度血脂异常患者的氧化应激和改善血流有益。除了讨论氧化应激在血脂异常诱导的CVD相关并发症中的破坏作用外，本综述还从独特的角度探讨了在血脂异常情况下阻断胆固醇合成同时提高或维持辅酶Q水平的甲羟戊酸途径。此外，本综述讨论了生物活性化合物靶向甲羟戊酸途径下游的治疗潜力，更重要的是，它们在阻断胆固醇的同时维持辅酶Q生物合成以预防血脂异常破坏性并发症的能力。
