{"title":"Chronic Peroxisome Proliferator-Activated Receptor α/γ and Cannabinoid Receptor 2 Agonist Treatments Attenuated Visceral Adipose Tissue (VAT)-Derived Extracellular Vesicle-Related VAT and Intestinal Abnormalities in Nonalcoholic Steatohepatitis Mice.","authors":"Chia-Chang Huang, Ching-Hsiang Wang, Hsiao-Yun Yeh, Hung-Cheng Tsai, Ching-Wen Yang, Tzu-Hao Li, Chien-Wei Su, Ying-Ying Yang, Han-Chieh Lin, Ming-Chih Hou","doi":"10.1016/j.ajpath.2024.10.006","DOIUrl":null,"url":null,"abstract":"<p><p>This study explores the mechanisms and combined effects of chronic peroxisome proliferator-activated receptor (PPAR)α/γ and cannabinoid receptor 2 (CB<sub>2</sub>R) agonists on visceral adipose tissue (VAT)-derived extracellular vesicle (EV) release and associated systemic/VAT inflammation, decreased VAT capillary density/fibrosis, and intestinal inflammation/hyperpermeability in nonalcoholic steatohepatitis (NASH) mice. NASH mice received 1 month of PPARα/γ agonist aleglitazar (10 mg/kg per day) or CB<sub>2</sub>R agonist JWH015 (3 mg/kg per day) alone or combined. High EV release from VAT of NASH mice was associated with severe systemic/VAT/intestinal inflammation, reduced capillary network of VAT, and intestinal hyperpermeability. Combined JWH015 with aleglitazar treatment significantly suppressed high-fat diet-induced obesity/adiposity, inhibited VAT expansion, reduced VAT inflammation/fibrosis, normalized VAT capillary network, and attenuated intestinal mucosal injury, inflammation, and hyperpermeability in NASH + aleglitazar + JWH015 mice. The inhibition of AT-derived EV release and hypoxia-inducible factor (HIF)1α levels in AT-derived EV, normalization of CB<sub>2</sub>R, PPARα, PPARγ, PPARγ1, PPARγ2, tight junction proteins, vascular endothelial growth factor/CD31 expression, and down-regulation of HIF1α, monocyte chemoattractant protein-1, and transforming growth factor-β1 were observed in the VAT and intestine of the NASH + aleglitazar + jwh015 group. In vitro experiments revealed that PPARα/γ and CB<sub>2</sub>R activation attenuated NASH AT-derived EV-induced pathogenic changes in the J774/SVEC4-10/Caco2/3T3-L1 cell system. This study suggested that VAT-derived EVs contribute to the pathogenesis of nonalcoholic fatty liver disease and that combined PPARα/γ and CB<sub>2</sub>R agonist treatment reduces VAT-released EV release and HIF1/monocyte chemoattractant protein-1 signals to ameliorate hepatic steatosis and VAT/intestine abnormalities of NASH mice.</p>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":null,"pages":null},"PeriodicalIF":4.7000,"publicationDate":"2024-10-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"American Journal of Pathology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.ajpath.2024.10.006","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"PATHOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
This study explores the mechanisms and combined effects of chronic peroxisome proliferator-activated receptor (PPAR)α/γ and cannabinoid receptor 2 (CB2R) agonists on visceral adipose tissue (VAT)-derived extracellular vesicle (EV) release and associated systemic/VAT inflammation, decreased VAT capillary density/fibrosis, and intestinal inflammation/hyperpermeability in nonalcoholic steatohepatitis (NASH) mice. NASH mice received 1 month of PPARα/γ agonist aleglitazar (10 mg/kg per day) or CB2R agonist JWH015 (3 mg/kg per day) alone or combined. High EV release from VAT of NASH mice was associated with severe systemic/VAT/intestinal inflammation, reduced capillary network of VAT, and intestinal hyperpermeability. Combined JWH015 with aleglitazar treatment significantly suppressed high-fat diet-induced obesity/adiposity, inhibited VAT expansion, reduced VAT inflammation/fibrosis, normalized VAT capillary network, and attenuated intestinal mucosal injury, inflammation, and hyperpermeability in NASH + aleglitazar + JWH015 mice. The inhibition of AT-derived EV release and hypoxia-inducible factor (HIF)1α levels in AT-derived EV, normalization of CB2R, PPARα, PPARγ, PPARγ1, PPARγ2, tight junction proteins, vascular endothelial growth factor/CD31 expression, and down-regulation of HIF1α, monocyte chemoattractant protein-1, and transforming growth factor-β1 were observed in the VAT and intestine of the NASH + aleglitazar + jwh015 group. In vitro experiments revealed that PPARα/γ and CB2R activation attenuated NASH AT-derived EV-induced pathogenic changes in the J774/SVEC4-10/Caco2/3T3-L1 cell system. This study suggested that VAT-derived EVs contribute to the pathogenesis of nonalcoholic fatty liver disease and that combined PPARα/γ and CB2R agonist treatment reduces VAT-released EV release and HIF1/monocyte chemoattractant protein-1 signals to ameliorate hepatic steatosis and VAT/intestine abnormalities of NASH mice.
期刊介绍:
The American Journal of Pathology, official journal of the American Society for Investigative Pathology, published by Elsevier, Inc., seeks high-quality original research reports, reviews, and commentaries related to the molecular and cellular basis of disease. The editors will consider basic, translational, and clinical investigations that directly address mechanisms of pathogenesis or provide a foundation for future mechanistic inquiries. Examples of such foundational investigations include data mining, identification of biomarkers, molecular pathology, and discovery research. Foundational studies that incorporate deep learning and artificial intelligence are also welcome. High priority is given to studies of human disease and relevant experimental models using molecular, cellular, and organismal approaches.