Department of Endocrinology, Endocrinology Research Center, Xiangya Hospital of Central South University, Changsha, Hunan, 410008, China.
Department of Endocrinology, The Second Affiliated Hospital of University of South China, Hengyang, Hunan, 421000, China.
Adv Sci (Weinh). 2024 Nov;11(42):e2406500. doi: 10.1002/advs.202406500. Epub 2024 Sep 16.
The dynamic interplay between parenchymal hepatocytes and non-parenchymal cells (NPCs), such as macrophages, is an important mechanism for liver metabolic homeostasis. Although numerous endeavors have been made to identify the mediators of metabolic dysfunction associated steatohepatitis (MASH), the molecular underpinnings of MASH progression remain poorly understood, and therapies to arrest MASH progression remain elusive. Herein, it is revealed that the expression of grancalcin (GCA) is upregulated in the macrophages of patients and rodents with MASH and correlates with MASH progression. Notably, the administration of recombinant GCA aggravates the development of MASH, whereas, Gca deletion in myeloid cells blunts liver steatosis and inflammation in multiple MASH murine models. Mechanistically, GCA activates macrophages via TLR9-NF-κB signaling, and the activated macrophages promote hepatocyte lipid accumulation and apoptosis via secretion of Interleukin-6(IL-6), Tumor Necrosis Factor α (TNFα), and Interleukin-1β(IL-1β), thereby leading to hepatic steatosis and inflammation. Finally, the therapeutic administration of antibody blocking GCA effectively halts the progression of MASH. Collectively, these findings implicate GCA as a crucial mediator of MASH and clarify a new metabolic signaling axis between the hepatocytes and macrophages, implying that GCA can emerge as a particularly interesting putative therapeutic target for reversing MASH progression.
实质肝细胞与非实质细胞（NPCs）之间的动态相互作用，如巨噬细胞，是肝脏代谢稳态的重要机制。尽管已经进行了许多努力来确定与脂肪性肝炎（MASH）相关的代谢功能障碍的介质，但 MASH 进展的分子基础仍知之甚少，并且阻止 MASH 进展的疗法仍然难以捉摸。在此，研究表明，在 MASH 患者和啮齿动物的巨噬细胞中，颗粒钙结合蛋白（GCA）的表达上调，并与 MASH 的进展相关。值得注意的是，重组 GCA 的给药会加重 MASH 的发展，而髓样细胞中 Gca 的缺失则会减弱多种 MASH 小鼠模型中的肝脂肪变性和炎症。从机制上讲，GCA 通过 TLR9-NF-κB 信号激活巨噬细胞，激活的巨噬细胞通过分泌白细胞介素-6（IL-6）、肿瘤坏死因子α（TNFα）和白细胞介素-1β（IL-1β）促进肝细胞脂质积累和凋亡，从而导致肝脂肪变性和炎症。最后，抗体阻断 GCA 的治疗给药可有效阻止 MASH 的进展。总的来说，这些发现表明 GCA 是 MASH 的关键介质，并阐明了肝细胞和巨噬细胞之间新的代谢信号轴，这意味着 GCA 可能成为逆转 MASH 进展的一个特别有趣的潜在治疗靶点。
