TY - JOUR
T1 - SREBP1 induction mediates long-term statins therapy related myocardial lipid peroxidation and lipid deposition in TIIDM mice
AU - Huang, Tong-Sheng
AU - Wu, Teng
AU - Fu, Xin-Lu
AU - Ren, Hong-Lin
AU - He, Xiao-Dan
AU - Zheng, Ding-Hao
AU - Tan, Jing
AU - Shen, Cong-Hui
AU - Xiong, Shi-Jie
AU - Qian, Jiang
AU - Zou, Yan
AU - Wan, Jun-Hong
AU - Ji, Yuan-Jun
AU - Liu, Meng-Ying
AU - Wu, Yan-di
AU - Li, Xing-Hui
AU - Li, Hui
AU - Zheng, Kai
AU - Yang, Xiao-Feng
AU - Wang, Hong
AU - Ren, Meng
AU - Cai, Wei-Bin
N1 - Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.
PY - 2024/12
Y1 - 2024/12
N2 - Statins therapy is efficacious in diminishing the risk of major cardiovascular events in diabetic patients. However, our research has uncovered a correlation between the prolonged administration of statins and an elevated risk of myocardial dysfunction in patients with type II diabetes mellitus (TIIDM). Here, we report the induction of sterol regulatory element-binding protein 1 (SREBP1) activation, associated lipid peroxidation, and the consequent diabetic myocardial dysfunction after statin treatment and explored the underlying mechanisms. In db/db mice, we observed that 40 weeks atorvastatin (5 and 10 mg/kg) and rosuvastatin (20 mg/kg) administration exacerbated diabetic myocardial dysfunction by echocardiography and cardiomyocyte contractility assay, increased myocardial inflammation and fibrosis as shown by CD68, IL-1β, Masson's staining and Collagen1A1 immunohistochemistry (IHC) staining, increased respiratory exchange ratio (RER) by metabolic cage system assessment, exacerbated mitochondrial structural pathological changes by transmission electron microscopy (TEM) examination, increased deposition of lipid and glycogen by TEM, Oil-red and periodic acid-schiff stain (PAS) staining, which were corresponded with augmented levels of myocardial SREBP1 protein and lipid peroxidation marked by 4-hydroxynonenal (4-HNE) staining. Comparable myocardial fibrosis was also observed in KK-ay and low-dose streptozotocin (STZ)-induced TIIDM mice. Elevated SREBP1 levels were observed in the heart tissues from diabetic patients, which was positively correlated with their myocardial dysfunction. To elucidate the role of statin induced SREBP1 in lipid peroxidation and lipid deposition and related mechanism, we cultured neonatal mouse primary cardiomyocytes (NMPCs) and treated them with atorvastatin (10 μM, 24 h), tracing with [U-13C]-glucose and evaluating for SREBP1 expression and localization. We found that statin treatment elevated de novo lipogenesis (DNL) and the levels of SREBP1 cleavage-activating protein (SCAP), reduced the interaction of SCAP with insulin-induced gene 1 (Insig1), and enhance SCAP/SREBP1 translocation to the Golgi, which facilitate SREBP1 cleavage leading to its nuclear trans-localization and activation in NMPCs. Ultimately, SREBP1 knockdown or l-carnitine mitigated long-term statins therapy induced lipid peroxidation and myocardial fibrosis in low-dose STZ treated SREBP1+/- mice and l-carnitine treated db/db mice. In conclusion, we demonstrated that statin therapy may augment DNL by activating SREBP1, resulting in myocardial lipid peroxidation and lipid deposition.
AB - Statins therapy is efficacious in diminishing the risk of major cardiovascular events in diabetic patients. However, our research has uncovered a correlation between the prolonged administration of statins and an elevated risk of myocardial dysfunction in patients with type II diabetes mellitus (TIIDM). Here, we report the induction of sterol regulatory element-binding protein 1 (SREBP1) activation, associated lipid peroxidation, and the consequent diabetic myocardial dysfunction after statin treatment and explored the underlying mechanisms. In db/db mice, we observed that 40 weeks atorvastatin (5 and 10 mg/kg) and rosuvastatin (20 mg/kg) administration exacerbated diabetic myocardial dysfunction by echocardiography and cardiomyocyte contractility assay, increased myocardial inflammation and fibrosis as shown by CD68, IL-1β, Masson's staining and Collagen1A1 immunohistochemistry (IHC) staining, increased respiratory exchange ratio (RER) by metabolic cage system assessment, exacerbated mitochondrial structural pathological changes by transmission electron microscopy (TEM) examination, increased deposition of lipid and glycogen by TEM, Oil-red and periodic acid-schiff stain (PAS) staining, which were corresponded with augmented levels of myocardial SREBP1 protein and lipid peroxidation marked by 4-hydroxynonenal (4-HNE) staining. Comparable myocardial fibrosis was also observed in KK-ay and low-dose streptozotocin (STZ)-induced TIIDM mice. Elevated SREBP1 levels were observed in the heart tissues from diabetic patients, which was positively correlated with their myocardial dysfunction. To elucidate the role of statin induced SREBP1 in lipid peroxidation and lipid deposition and related mechanism, we cultured neonatal mouse primary cardiomyocytes (NMPCs) and treated them with atorvastatin (10 μM, 24 h), tracing with [U-13C]-glucose and evaluating for SREBP1 expression and localization. We found that statin treatment elevated de novo lipogenesis (DNL) and the levels of SREBP1 cleavage-activating protein (SCAP), reduced the interaction of SCAP with insulin-induced gene 1 (Insig1), and enhance SCAP/SREBP1 translocation to the Golgi, which facilitate SREBP1 cleavage leading to its nuclear trans-localization and activation in NMPCs. Ultimately, SREBP1 knockdown or l-carnitine mitigated long-term statins therapy induced lipid peroxidation and myocardial fibrosis in low-dose STZ treated SREBP1+/- mice and l-carnitine treated db/db mice. In conclusion, we demonstrated that statin therapy may augment DNL by activating SREBP1, resulting in myocardial lipid peroxidation and lipid deposition.
KW - Myocardial lipid peroxidation
KW - Statins
KW - Sterol regulatory element-binding protein 1
KW - Type 2 diabetes mellitus
KW - Myocytes, Cardiac/metabolism
KW - Humans
KW - Lipid Metabolism/drug effects
KW - Male
KW - Sterol Regulatory Element Binding Protein 1/metabolism
KW - Diabetes Mellitus, Experimental/metabolism
KW - Lipid Peroxidation/drug effects
KW - Animals
KW - Myocardium/metabolism
KW - Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology
KW - Diabetes Mellitus, Type 2/metabolism
KW - Mice
KW - Disease Models, Animal
UR - http://www.scopus.com/inward/record.url?scp=85207340308&partnerID=8YFLogxK
U2 - 10.1016/j.redox.2024.103412
DO - 10.1016/j.redox.2024.103412
M3 - Article
C2 - 39476450
SN - 2213-2317
VL - 78
SP - 103412
JO - Redox Biology
JF - Redox Biology
M1 - 103412
ER -