2. Academic Validation
  3. TLR4 mediates glucolipotoxicity-induced mitochondrial dysfunction in osteoblasts by enhancing NLRP3-MAVS expression and interaction

TLR4 mediates glucolipotoxicity-induced mitochondrial dysfunction in osteoblasts by enhancing NLRP3-MAVS expression and interaction

  • Int Immunopharmacol. 2025 Mar 17:153:114438. doi: 10.1016/j.intimp.2025.114438.
Ximei Shen 1,  Xiaoyuan Chen 2,  Shuai Zhong 2,  Yongze Zhang 1,  Xuan Zhou 2,  Chao Lan 2,  Jiebin Lin 2,  Lifeng Zheng 3,  Sunjie Yan 4
Affiliations

Affiliations

  • 1 Deprtment of Endocrinology, the First Affiliated Hospital, Fujian Medical University, Fuzhou, 350005, China; Department of Endocrinology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou 350212, China; Clinical Research Center for Metabolic Diseases of Fujian Province, the First Affiliated Hospital, Fujian Medical University, Fuzhou, 350005, China; Fujian Key Laboratory of Glycolipid and Bone Mineral Metabolism, the First Affiliated Hospital, Fujian Medical University, Fuzhou, 350005, China; Diabetes Research Institute of Fujian Province, the First Affiliated Hospital, Fujian Medical University, Fuzhou, 350005, China; Metabolic Diseases Research Institute, the First Affiliated Hospital, Fujian Medical University, Fuzhou, 350005, China.
  • 2 Deprtment of Endocrinology, the First Affiliated Hospital, Fujian Medical University, Fuzhou, 350005, China.
  • 3 Department of Orthopedics, the First Affiliated Hospital of Fujian Medical University, Fuzhou 350005, China.
  • 4 Deprtment of Endocrinology, the First Affiliated Hospital, Fujian Medical University, Fuzhou, 350005, China; Department of Endocrinology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou 350212, China; Clinical Research Center for Metabolic Diseases of Fujian Province, the First Affiliated Hospital, Fujian Medical University, Fuzhou, 350005, China; Fujian Key Laboratory of Glycolipid and Bone Mineral Metabolism, the First Affiliated Hospital, Fujian Medical University, Fuzhou, 350005, China; Diabetes Research Institute of Fujian Province, the First Affiliated Hospital, Fujian Medical University, Fuzhou, 350005, China; Metabolic Diseases Research Institute, the First Affiliated Hospital, Fujian Medical University, Fuzhou, 350005, China. Electronic address: fjyansunjie@163.com.
PMID: 40101421 DOI: 10.1016/j.intimp.2025.114438
Abstract

Mitochondrial dysfunction is a critical mechanism underlying diabetic bone loss, which is driven by the inhibition of osteoblast differentiation due to glucolipotoxicity. The molecular mechanisms through which glucolipotoxicity induces mitochondrial dysfunction remain poorly understood. In this study, we observed an upregulation of Toll-like Receptor 4 (TLR4) expression in osteoblasts subjected to glycolipotoxic conditions, which was associated with mitochondrial dysfunction. Proteomic analysis revealed that TLR4 plays a crucial role in glucolipotoxicity and is closely linked to mitochondrial function in osteoblasts. Knockdown of TLR4 was found to alleviate osteoblast differentiation disorders and mitochondrial dysfunction as well as mitochondria-mediated Apoptosis induced by glucolipotoxicity. In contrast, overexpression of TLR4 exacerbated the detrimental effects of glucolipotoxicity. Mechanistically, glucolipotoxicity activates TLR4, resulting in increased expression of NLRP3 (NOD-like Receptor protein 3) and MAVS (Mitochondrial Antiviral signaling protein), which promotes the interaction between NLRP3 and MAVS. This cascade leads to increased intracellular Reactive Oxygen Species, decreased ATP levels, elevated expression of Caspase-1, GSDMD, Bax, and reduced expression of the anti-apoptotic protein Bcl-2. Furthermore, TLR4 knockout was shown to mitigate bone loss in diabetic rats. Proteomic analysis revealed that the improvement in the expression of proteins related to mitochondrial function and osteogenic function in diabetic rats is associated with TLR4 knockout. Diabetic osteoporosis may be associated with increased TLR4 expression and disturbed Oxidative Phosphorylation. In conclusion, glucolipotoxicity activates TLR4, which subsequently induces the expression and interaction of NLRP3-MAVS, leading to mitochondrial dysfunction and inhibition of osteoblast differentiation. This process contributes to bone mass loss in diabetes.

Keywords

Glucolipotoxicity; MAVS; Mitochondrial function; NLRP3; TLR4.

Figures
Products