Avogadro Development Corp, New York, NY, United States.
Front Endocrinol (Lausanne). 2021 Jan 29;11:613639. doi: 10.3389/fendo.2020.613639. eCollection 2020.
Toll-Like Receptor 9 (TLR9) is an ancient receptor integral to the primordial functions of inflammation and metabolism. TLR9 functions to regulate homeostasis in a healthy system under acute stress. The literature supports that overactivation of TLR9 under the chronic stress of obesity is a critical driver of the pathogenesis of NASH and NASH-associated fibrosis. Research has focused on the core contributions of the parenchymal and non-parenchymal cells in the liver, adipose, and gut compartments. TLR9 is activated by endogenous circulating mitochondrial DNA (mtDNA). Chronically elevated circulating levels of mtDNA, caused by the stress of overnutrition, are observed in obesity, metabolic dysfunction-associated fatty liver disease (MAFLD), and NASH. Clinical evidence is supportive of TLR9 overactivation as a driver of disease. The role of TLR9 in metabolism and energy regulation may have an underappreciated contribution in the pathogenesis of NASH. Antagonism of TLR9 in NASH and NASH-associated fibrosis could be an effective therapeutic strategy to target both the inflammatory and metabolic components of such a complex disease.
Toll 样受体 9（TLR9）是一种古老的受体，是炎症和代谢的原始功能所必需的。TLR9 的功能是在急性应激下调节健康系统的内稳态。文献支持肥胖症慢性应激下 TLR9 的过度激活是 NASH 和 NASH 相关纤维化发病机制的关键驱动因素。研究集中在肝脏、脂肪组织和肠道隔室中实质细胞和非实质细胞的核心贡献上。TLR9 被内源性循环线粒体 DNA（mtDNA）激活。肥胖症、代谢功能障碍相关脂肪性肝病（MAFLD）和 NASH 中观察到，由营养过剩引起的慢性升高的循环 mtDNA 水平会导致 TLR9 持续激活。临床证据支持 TLR9 过度激活是疾病的驱动因素。TLR9 在代谢和能量调节中的作用可能在 NASH 的发病机制中具有被低估的贡献。在 NASH 和 NASH 相关纤维化中拮抗 TLR9 可能是针对这种复杂疾病的炎症和代谢成分的有效治疗策略。
