Platelet-derived thrombospondin 1 promotes immune cell liver infiltration and exacerbates diet-induced steatohepatitis
Background & Aims: Recent studies have implicated platelets, particularly α-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 α-granu...
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2024-04-01
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| Series: | JHEP Reports |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S258955592400020X |
| _version_ | 1797220542129897472 |
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| author | Taesik Gwag Sangderk Lee Zhenyu Li Alana Newcomb Josephine Otuagomah Steven A. Weinman Ying Liang Changcheng Zhou Shuxia Wang |
| author_facet | Taesik Gwag Sangderk Lee Zhenyu Li Alana Newcomb Josephine Otuagomah Steven A. Weinman Ying Liang Changcheng Zhou Shuxia Wang |
| author_sort | Taesik Gwag |
| collection | DOAJ |
| description | Background & Aims: Recent studies have implicated platelets, particularly α-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 α-granules released during platelet activation. Hence, we aimed to determine the role of platelet-derived TSP1 in NASH. Methods: Platelet-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. Results: Although 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 proinflammatory 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. Conclusions: These 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. Impact and implications: Recent studies have implicated platelets, specifically α-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 α-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. |
| first_indexed | 2024-03-07T14:28:06Z |
| format | Article |
| id | doaj.art-8012d90658f944b4a8331c2acf09a7f0 |
| institution | Directory Open Access Journal |
| issn | 2589-5559 |
| language | English |
| last_indexed | 2024-04-24T12:51:11Z |
| publishDate | 2024-04-01 |
| publisher | Elsevier |
| record_format | Article |
| series | JHEP Reports |
| spelling | doaj.art-8012d90658f944b4a8331c2acf09a7f02024-04-06T04:40:25ZengElsevierJHEP Reports2589-55592024-04-0164101019Platelet-derived thrombospondin 1 promotes immune cell liver infiltration and exacerbates diet-induced steatohepatitisTaesik Gwag0Sangderk Lee1Zhenyu Li2Alana Newcomb3Josephine Otuagomah4Steven A. Weinman5Ying Liang6Changcheng Zhou7Shuxia Wang8Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY 40536, United States; Lexington Veterans Affairs Medical Center, Lexington, KY 40502, United StatesSanders-Brown Center on Aging, University of Kentucky, Lexington, KY 40536, United StatesIrma Lerma Rangel School of Pharmacy, Texas A&M University, College Station, TX, 77843, United StatesDepartment of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY 40536, United StatesDepartment of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY 40536, United StatesDepartment of Internal Medicine, University of Kansas Medical Center, Kansas City, KS 66160, United States; Research Service, Kansas City VA Medical Center, Kansas City, MO 64128, United StatesNew York Blood Center, 310 East 72nd Street, New York, NY 10065, United StatesDivision of Biomedical Sciences, School of Medicine, University of California, Riverside, CA92521, United StatesDepartment of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY 40536, United States; Lexington Veterans Affairs Medical Center, Lexington, KY 40502, United States; Corresponding author. Address: Department of Pharmacology and Nutritional Sciences, University of Kentucky, Wethington Bldg. Room 583, 900 S. Limestone Street, Lexington, KY 40536, United States; Tel.: +1 859 218 1367, fax: +1 859 257 3646.Background & Aims: Recent studies have implicated platelets, particularly α-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 α-granules released during platelet activation. Hence, we aimed to determine the role of platelet-derived TSP1 in NASH. Methods: Platelet-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. Results: Although 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 proinflammatory 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. Conclusions: These 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. Impact and implications: Recent studies have implicated platelets, specifically α-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 α-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.http://www.sciencedirect.com/science/article/pii/S258955592400020XPlatelet α granuleTSP1NASHbrown adipocytesorgan crosstalk |
| spellingShingle | Taesik Gwag Sangderk Lee Zhenyu Li Alana Newcomb Josephine Otuagomah Steven A. Weinman Ying Liang Changcheng Zhou Shuxia Wang Platelet-derived thrombospondin 1 promotes immune cell liver infiltration and exacerbates diet-induced steatohepatitis JHEP Reports Platelet α granule TSP1 NASH brown adipocytes organ crosstalk |
| title | Platelet-derived thrombospondin 1 promotes immune cell liver infiltration and exacerbates diet-induced steatohepatitis |
| title_full | Platelet-derived thrombospondin 1 promotes immune cell liver infiltration and exacerbates diet-induced steatohepatitis |
| title_fullStr | Platelet-derived thrombospondin 1 promotes immune cell liver infiltration and exacerbates diet-induced steatohepatitis |
| title_full_unstemmed | Platelet-derived thrombospondin 1 promotes immune cell liver infiltration and exacerbates diet-induced steatohepatitis |
| title_short | Platelet-derived thrombospondin 1 promotes immune cell liver infiltration and exacerbates diet-induced steatohepatitis |
| title_sort | platelet derived thrombospondin 1 promotes immune cell liver infiltration and exacerbates diet induced steatohepatitis |
| topic | Platelet α granule TSP1 NASH brown adipocytes organ crosstalk |
| url | http://www.sciencedirect.com/science/article/pii/S258955592400020X |
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