Macrophage-derived thrombospondin 1 promotes obesity-associated non-alcoholic fatty liver disease

作者：Taesik Gwag, Raja Gopal Reddy Mooli, Dong Li, Sangderk Lee, Eun Y. Lee, Shuxia Wang · 发表于：JHEP Reports · 年份：2020 · DOI：10.1016/j.jhepr.2020.100193 · 被引用次数：55 · 研究领域：Liver Disease Diagnosis and Treatment、Angiogenesis and VEGF in Cancer、Liver physiology and pathology

Background & Aims Thrombospondin 1 (TSP1) is a multifunctional matricellular protein. We previously showed that TSP1 has an important role in obesity-associated metabolic complications, including inflammation, insulin resistance, cardiovascular, and renal disease. However, its contribution to obesity-associated non-alcoholic fatty liver disease/non-alcoholic steatohepatitis (NAFLD or NASH) remains largely unknown; thus, we aimed to determine its role. Methods High-fat diet or AMLN (amylin liver NASH) diet-induced obese and insulin-resistant NAFLD/NASH mouse models were utilised, in addition to tissue-specific Tsp1 -knockout mice, to determine the contribution of different cellular sources of obesity-induced TSP1 to NAFLD/NASH development. Results Liver TSP1 levels were increased in experimental obese and insulin-resistant NAFLD/NASH mouse models as well as in obese patients with NASH. Moreover, TSP1 deletion in adipocytes did not protect mice from diet-induced NAFLD/NASH. However, myeloid/macrophage-specific TSP1 deletion protected mice against obesity-associated liver injury, accompanied by reduced liver inflammation and fibrosis. Importantly, this protection was independent of the levels of obesity and hepatic steatosis. Mechanistically, through an autocrine effect, macrophage-derived TSP1 suppressed Smpdl3b expression in liver, which amplified liver proinflammatory signalling (Toll-like receptor 4 signal pathway) and promoted NAFLD progression. Conclusions Macrophage-deriv...