Lipotoxicity plays a significant role in the development of type 2 diabetes, with the ectopic deposition of lipids in cells causing chronic organ damage and dysfunction, which is an important mechanism for diabetic complications. Clinically, lipid-lowering and lipid control are important strategies in the prevention and treatment of diabetes and its complications. The latest guidelines for the prevention and treatment of type 2 diabetes from the Chinese Medical Association and the American Diabetes Association explicitly recommend that diabetic patients should receive statin drugs for lipid-lowering treatment.

However, clinical research data suggests the complexity of "lipid-lowering" in diabetic patients. On one hand, long-term use of statin drugs can affect blood sugar levels, leading to increased blood sugar and insulin resistance. Our institute's Professor Cai Weibin's team, in previous research (Nat Commun. 2023 Jan 24;14(1):390.), used a diabetic mouse model to observe the effects of statin drug use over 40 weeks, providing long-term research data that is difficult to achieve clinically. The study confirmed that long-term use of statin drugs in the context of diabetes can lead to lipid deposition and lipotoxicity in the kidneys, exacerbating the progression of diabetic nephropathy, preliminarily confirming that lipid-lowering does not equate to reducing organ lipids. On the other hand, even after intensive statin therapy for diabetic patients, 77% of cardiovascular events cannot be avoided, meaning that there is still residual risk of cardiovascular events. Whether there is ectopic lipid deposition in myocardial cells in the context of diabetes that exacerbates myocardial lipotoxicity has not yet been confirmed. Clarifying this key scientific question is related to the long-term prognosis of myocardial damage in diabetic patients.

On October 30, 2024, Professor Cai Weibin's research group from Sun Yat-sen University's School of Medicine published a research paper titled "SREBP1 induction mediates long-term statins therapy related myocardial lipid peroxidation and lipid deposition in TIIDM mice" in the journal Redox Biol. The study confirmed that under the context of diabetes, long-term statin therapy for lipid-lowering treatment abnormally activates the transcriptional regulatory factor SREBP1, which is important for lipid synthesis in myocardial cells, leading to increased myocardial lipid deposition and lipid peroxidation, ultimately accelerating the progression of diabetic cardiomyopathy.

The study used three classic type 2 diabetes mouse models: db/db mice, KKay mice, and streptozotocin (STZ)-induced type 2 diabetes mice, to establish a comparative medical model that simulates the long-term statin therapy for lipid-lowering treatment in type 2 diabetic patients. The study found that after long-term statin therapy, all three types of diabetic mice showed明显的下降 in cardiac function, increased myocardial damage, accompanied by lipid deposition and lipid peroxidation. The research team further used SREBP1 knockdown mice, constructed TIIDM mice through a high-fat diet (HFD)/STZ, to study the role of SREBP1 in myocardial lipid metabolism after statin treatment. Mechanistically, statin drugs promote the cleavage of SREBP1 into the nucleus of myocardial cells, and SREBP1 knockdown can reverse the lipid deposition caused by long-term statin therapy in myocardial cells.

It is worth noting that in a cohort of people with diabetes and myocardial injury, the research team found significant activation of SREBP1, which is negatively correlated with myocardial lipid peroxidation and myocardial fibrosis, emphasizing the potential of SREBP1 as a therapeutic target for reducing lipid deposition in the myocardium of diabetic patients.

The study was supported by the National Key R&D Program, the National Natural Science Foundation of China, the Guangdong Basic and Applied Basic Research Fund, and the Guangzhou Science and Technology Program. Huang Tongsheng, a 2019 Ph.D. student, and Wu Teng, a 2020 Ph.D. student, are the co-first authors of the paper. Professor Cai Weibin from our institute, Professor Ren Meng from Sun Yat-sen Memorial Hospital of Sun Yat-sen University, and Professor Wang Hong from Temple University School of Medicine are the co-corresponding authors of the paper. The study received strong support from Professor Zhang Yuling from Sun Yat-sen Memorial Hospital, Professor Yang Xiaofeng from Temple University School of Medicine, and the assistance of teachers from the Experimental Animal Center of Sun Yat-sen University and the Scientific Research Instrument Platform of the School of Medicine.

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