Platelet-derived thrombospondin 1 promotes immune cell liver infiltration and exacerbates diet-induced steatohepatitis
Taesik Gwag, Sangderk Lee, Zhenyu Li, Alana Newcomb, Josephine Otuagomah, Steven A. Weinman, Ying Liang, Changcheng Zhou, Shuxia Wang
Abstract
Background and AimsRecent studies have implicated platelets, particularly α-granules, in the development of steatohepatitis (NASH). However, the specific mechanisms involved have yet to be determined. Notably, thrombospondin 1 (TSP1) is a major component of the platelet α-granules released during platelet activation. The role of platelet derived TSP1 in NASH remains unknown and was investigated in this study.MethodsPlatelet-specific TSP1 knockout mice (TSP1Δpf4) and their wild type littermates (TSP1F/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.ResultsAlthough TSP1 deletion in platelets did not affect diet-induced steatosis, TSP1Δpf4 mice exhibited attenuated NASH and liver fibrosis, accompanied by improvements in plasma glucose and lipid homeostasis. Furthermore, TSP1Δpf4 mice showed reduced intrahepatic platelet accumulation, activation, and chemokine production, correlating with decreased immune cell infiltration into the liver. Consequently, this diminished pro-inflammatory signaling in the liver, thereby mitigating 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.ConclusionsThese data suggest that platelet α-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.Lay SummaryNon-alcoholic fatty liver disease is becoming the most common chronic disease worldwide. TSP1, which is abundant in platelet α-granules, plays an important role in obesity-associated metabolic disease. In this study, we show that depletion of TSP1 in platelets attenuates diet-induced hepatic inflammation and fibrosis partially through regulating immune cells infiltration into the liver.Impact and implicationsRecent studies implicate platelets, specifically α-granules, in the development of steatohepatitis (NASH), 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 α-granule-derived TSP1 significantly contributes to diet-induced NASH and fibrosis. This contribution is, in part, attributed to the regulation of intrahepatic immune cell infiltration and potential crosstalk between fat and liver. These findings suggest that platelet-derived TSP1 may represent a novel therapeutic target for non-alcoholic fatty liver disease.