Department of Cellular and Molecular Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
Section of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Yale School of Medicine, New Haven, CT 06514, USA.
Sci Transl Med. 2023 Sep 27;15(715):eade3157. doi: 10.1126/scitranslmed.ade3157.
Obesity is increasing worldwide and leads to a multitude of metabolic diseases, including cardiovascular disease, type 2 diabetes, nonalcoholic fatty liver disease, and nonalcoholic steatohepatitis (NASH). Cysteine-rich angiogenic inducer 61 (CYR61) is associated with the progression of NASH, but it has been described to have anti- and proinflammatory properties. We sought to examine the role of liver CYR61 in NASH progression. CYR61 liver-specific knockout mice on a NASH diet showed improved glucose tolerance, decreased liver inflammation, and reduced fibrosis. CYR61 polarized infiltrating monocytes promoting a proinflammatory/profibrotic phenotype through an IRAK4/SYK/NF-κB signaling cascade. In vitro, CYR61 activated a profibrotic program, including PDGFa/PDGFb expression in macrophages, in an IRAK4/SYK/NF-κB-dependent manner. Furthermore, targeted-antibody blockade reduced CYR61-driven signaling in macrophages in vitro and in vivo, reducing fibrotic development. This study demonstrates that CYR61 is a key driver of liver inflammation and fibrosis in NASH.
肥胖症在全球范围内不断增加，并导致多种代谢性疾病，包括心血管疾病、2 型糖尿病、非酒精性脂肪肝和非酒精性脂肪性肝炎（NASH）。富含半胱氨酸的血管生成诱导因子 61（CYR61）与 NASH 的进展有关，但它具有抗炎和促炎特性。我们试图研究肝脏 CYR61 在 NASH 进展中的作用。NASH 饮食下的肝脏特异性 CYR61 敲除小鼠表现出改善的葡萄糖耐量、降低的肝脏炎症和减少的纤维化。CYR61 极化浸润单核细胞，通过 IRAK4/SYK/NF-κB 信号级联促进促炎/促纤维化表型。在体外，CYR61 通过 IRAK4/SYK/NF-κB 依赖性方式激活促纤维化程序，包括巨噬细胞中 PDGFa/PDGFb 的表达。此外，靶向抗体阻断减少了体外和体内巨噬细胞中 CYR61 驱动的信号，从而减少了纤维化的发展。这项研究表明，CYR61 是 NASH 中肝脏炎症和纤维化的关键驱动因素。
