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| Status |
Public on Dec 07, 2020 |
| Title |
Macrophage-derived thrombospondin1 promotes obesity-associated non-alcoholic fatty liver disease |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Thrombospondin 1 (TSP1) is a multifunctional matricellular protein. Previously we have shown that TSP1 plays 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 (NAFLD) or non-alcoholic steatohepatitis (NASH) remains largely unknown and is determined in this study. High fat diet or AMLN diet-induced obese and insulin resistant NAFLD/NASH mouse models were utilized. In addition, tissue specific TSP1 knockout mice were utilized to determine the contribution of different cellular sources of obesity-induced TSP1 to NAFLD/NASH development. The data demonstrated that liver TSP1 levels were increased in experimental obese and insulin resistant NAFLD/NASH mouse models as well as in human obese NASH patients. Moreover, TSP1 deletion in hepatocyte or 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 is 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 pro-inflammatory signaling (TLR4 signal pathway) and promoted NAFLD progression. Together, out data suggest that macrophage-derived TSP1 is a significant contributor to obesity-associated NAFLD/NASH development and progression and may serve as a therapeutic target for this disease.
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| Overall design |
TSP1 floxed mice and macrophage specific TSP1 knockout mice were fed with LF or HF diet for 8 months. Then mie were sacrficed and livers were harvested for further analysis.
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| Contributor(s) |
Gawg T, Mooli RG, Li D, Lee EY, Wang S |
| Citation(s) |
33294831 |
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https://doi.org/10.1016/j.jhepr.2020.100193
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| Submission date |
Aug 10, 2020 |
| Last update date |
Dec 15, 2020 |
| Contact name |
Shuxia Wang |
| E-mail(s) |
swang7@uky.edu
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| Phone |
8592181367
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| Organization name |
University of Kentucky
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| Department |
Pharmacology and Nutritional Sciences
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| Street address |
900 S. Limestone street, Wethington Bldg. Room 583
|
| City |
lexington |
| State/province |
KY |
| ZIP/Postal code |
40536 |
| Country |
USA |
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| Platforms (1) |
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| Samples (12)
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| Relations |
| BioProject |
PRJNA656249 |
| SRA |
SRP276889 |
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