Abstract

Background & Aims: Recent studies have implicated platelets, particularly a-granules, in the development of non-alcoholic steatohepatitis (NASH). However, the specific mechanisms involved have yet to be determined. Notably, thrombospondin 1 (TSP1) is a major component of the platelet a-granules released during platelet activation. Hence, we aimed to determine the role of platelet-derived TSP1 in NASH.

Methods: Platelet-specific Tsp1 knockout mice (TSP1Dpf4 ) and their wild-type littermates (TSP1 F/F) were used. NASH was induced by feeding the mice with a diet enriched in fat, sucrose, fructose, and cholesterol (AMLN diet). A human liver NASH organoid model was also employed.

Results: Although TSP1 deletion in platelets did not affect diet-induced steatosis, TSP1Dpf4 mice exhibited attenuated NASH and liver fibrosis, accompanied by improvements in plasma glucose and lipid homeostasis. Furthermore, TSP1Dpf4 mice showed reduced intrahepatic platelet accumulation, activation, and chemokine production, correlating with decreased immune cell infiltration into the liver. Consequently, this diminished proinflammatory signaling in the liver, thereby miti- gating the progression of NAFLD. Moreover, in vitro data revealed that co-culturing TSP1-deficient platelets in a human liver NASH organoid model attenuated hepatic stellate cell activation and NASH progression. Additionally, TSP1-deficient platelets play a role in regulating brown fat endocrine function, specifically affecting Nrg4 (neuregulin 4) production. Crosstalk between brown fat and the liver may also influence the progression of NAFLD.

Conclusions: These data suggest that platelet a-granule-derived TSP1 is a significant contributor to diet-induced NASH and fibrosis, potentially serving as a new therapeutic target for this severe liver disease.

Impact and implications: Recent studies have implicated platelets, specifically a-granules, in the development of non-alcoholic steatohepatitis, yet the precise mechanisms remain unknown. In this study, through the utilization of a tissue- specific knockout mouse model and human 3D liver organoid, we demonstrated that platelet a-granule-derived TSP1 significantly contributes to diet-induced non-alcoholic steatohepatitis and fibrosis. This contribution is, in part, attributed to the regulation of intrahepatic immune cell infiltration and potential crosstalk between fat and the liver. These findings suggest that platelet-derived TSP1 may represent a novel therapeutic target in non-alcoholic fatty liver disease.

Document Type

Article

Publication Date

4-2024

Notes/Citation Information

© 2024 The Author(s). Published by Elsevier B.V. on behalf of European Association for the Study of the Liver (EASL). This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Digital Object Identifier (DOI)

https://doi.org/10.1016/j.jhepr.2024.101019

Funding Information

This work was supported by the Department of Veterans Affairs Merit Review Award (BX004252 to SW), the National Institutes of Health (NIH) Grant (DK131786, to SW), and an Institutional Development Award (IDeA) from the National Institute of General Medical Sciences under grant number P30 GM127211.

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