Macrophage-derived thrombospondin 1 promotes obesity-associated non-alcoholic fatty liver disease
| العنوان: | Macrophage-derived thrombospondin 1 promotes obesity-associated non-alcoholic fatty liver disease |
|---|---|
| المؤلفون: | Taesik Gwag, Shuxia Wang, Eun Y. Lee, Dong Li, Raja Gopal Reddy Mooli, Sangderk Lee |
| المصدر: | JHEP Reports JHEP Reports, Vol 3, Iss 1, Pp 100193-(2021) |
| بيانات النشر: | Elsevier BV, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | HFD, high-fat diet, Cirrhosis, Th, T helper type, Macrophage, AST, aspartate aminotransferase, Chronic liver disease, α-SMA, smooth muscle actin, TNF, tumour necrosis factor, TSP1, TSP1, thrombospondin 1, DEG, differentially expressed gene, IL-, interleukin, Immunology and Allergy, Medicine, TGF, transforming growth factor, scRNA-seq, single-cell RNA sequencing, Liver injury, NAS, NAFLD activity score, Fatty liver, NASH, SMPDL3B, Gastroenterology, AMLN, amylin liver NASH, ASMase, acid sphingomyelinase, BMDM, bone marrow-derived macrophage, HSC, hepatic stellate cell, ECM, extracellular matrix, SMPDL3B, sphingomyelin phosphodiesterase acid-like 3B, LPS, lipopolysaccharide, Research Article, TLR, Toll-like receptor, GPI, glycosylphosphatidylinositol, NAFLD, non-alcoholic fatty liver disease, NASH, non-alcoholic steatohepatitis, NF-κB, nuclear factor-κB, KEGG, Kyoto Encyclopedia of Genes and Genomes, MP, mononuclear phagocyte, digestive system, Tsp1Δmɸ, macrophage-specific TSP1-knockout mice, Insulin resistance, NAFLD, ALT, alanine aminotransferase, Internal Medicine, KC, Kupffer cell, Tsp1Δadipo, adipocyte-specific TSP1-knockout mice, Obesity, lcsh:RC799-869, Hepatology, EC, endothelial cell, business.industry, nutritional and metabolic diseases, medicine.disease, digestive system diseases, LFD, low-fat diet, SREBP1c, sterol regulatory element-binding protein-1 c, Cancer research, Hepatic stellate cell, Tsp1fl/fl, TSP1 floxed mice, lcsh:Diseases of the digestive system. Gastroenterology, MDM, monocyte-derived macrophage, qPCR, quantitative PCR, Steatosis, Steatohepatitis, business |
| الوصف: | 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-derived TSP1 is a significant contributor to obesity-associated NAFLD/NASH development and progression and could serve as a therapeutic target for this disease. Lay summary Obesity-associated non-alcoholic fatty liver disease is a most common chronic liver disease in the Western world and can progress to liver cirrhosis and cancer. No treatment is currently available for this disease. The present study reveals an important factor (macrophage-derived TSP1) that drives macrophage activation and non-alcoholic fatty liver disease development and progression and that could serve as a therapeutic target for non-alcoholic fatty liver disease/steatohepatitis. Graphical abstract Highlights • Obesity induces TSP1 expression in several tissues, such as adipose tissue and liver. • Macrophages are an important cellular source of increased TSP1 in mouse NASH livers. • Deletion of TSP1 in macrophages protects mice from diet-induced NASH. • SMPDL3B negatively regulates TSP1-mediated macrophage activation. |
| تدمد: | 2589-5559 |
| DOI: | 10.1016/j.jhepr.2020.100193 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::063dac1179b4deacdbae7ecdef605114 https://doi.org/10.1016/j.jhepr.2020.100193 |
| Rights: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....063dac1179b4deacdbae7ecdef605114 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 25895559 |
|---|---|
| DOI: | 10.1016/j.jhepr.2020.100193 |