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Dietary Lipids Differentially Shape Nonalcoholic Steatohepatitis Progression and the Transcriptome of Kupffer Cells and Infiltrating Macrophages.
McGettigan, Brett; McMahan, Rachel; Orlicky, David; Burchill, Matthew; Danhorn, Thomas; Francis, Prashanth; Cheng, Lin Ling; Golden-Mason, Lucy; Jakubzick, Claudia V; Rosen, Hugo R.
Afiliação
  • McGettigan B; Division of Gastroenterology & Hepatology, Department of Medicine, University of Colorado Denver, Denver, CO.
  • McMahan R; Department of Immunology, University of Colorado Denver, Denver, CO.
  • Orlicky D; Division of Gastroenterology & Hepatology, Department of Medicine, University of Colorado Denver, Denver, CO.
  • Burchill M; Department of Pathology, University of Colorado Denver, Denver, CO.
  • Danhorn T; Division of Gastroenterology & Hepatology, Department of Medicine, University of Colorado Denver, Denver, CO.
  • Francis P; Division of Biostatistics and Bioinformatics, National Jewish Health, Denver, CO.
  • Cheng LL; Division of Gastroenterology & Hepatology, Department of Medicine, University of Colorado Denver, Denver, CO.
  • Golden-Mason L; Division of Gastroenterology & Hepatology, Department of Medicine, University of Colorado Denver, Denver, CO.
  • Jakubzick CV; Division of Gastroenterology & Hepatology, Department of Medicine, University of Colorado Denver, Denver, CO.
  • Rosen HR; Department of Immunology, University of Colorado Denver, Denver, CO.
Hepatology ; 70(1): 67-83, 2019 07.
Article em En | MEDLINE | ID: mdl-30516830
A crucial component of nonalcoholic fatty liver disease (NAFLD) pathogenesis is lipid stress, which may contribute to hepatic inflammation and activation of innate immunity in the liver. However, little is known regarding how dietary lipids, including fat and cholesterol, may facilitate innate immune activation in vivo. We hypothesized that dietary fat and cholesterol drive NAFLD progression to steatohepatitis and hepatic fibrosis by altering the transcription and phenotype of hepatic macrophages. This hypothesis was tested by using RNA-sequencing methods to characterize and analyze sort-purified hepatic macrophage populations that were isolated from mice fed diets with varying amounts of fat and cholesterol. The addition of cholesterol to a high-fat diet triggered hepatic pathology reminiscent of advanced nonalcoholic steatohepatitis (NASH) in humans characterized by signs of cholesterol dysregulation, generation of oxidized low-density lipoprotein, increased recruitment of hepatic macrophages, and significant fibrosis. RNA-sequencing analyses of hepatic macrophages in this model revealed that dietary cholesterol induced a tissue repair and regeneration phenotype in Kupffer cells (KCs) and recruited infiltrating macrophages to a greater degree than fat. Furthermore, comparison of diseased KCs and infiltrating macrophages revealed that these two macrophage subsets are transcriptionally diverse. Finally, direct stimulation of murine and human macrophages with oxidized low-density lipoprotein recapitulated some of the transcriptional changes observed in the RNA-sequencing study. These findings indicate that fat and cholesterol synergize to alter macrophage phenotype, and they also challenge the dogma that KCs are purely proinflammatory in NASH. Conclusion: This comprehensive view of macrophage populations in NASH indicates mechanisms by which cholesterol contributes to NASH progression and identifies potential therapeutic targets for this common disease.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Colesterol na Dieta / Hepatopatia Gordurosa não Alcoólica / Células de Kupffer / Fígado Tipo de estudo: Etiology_studies / Prognostic_studies Limite: Animals Idioma: En Revista: Hepatology Ano de publicação: 2019 Tipo de documento: Article País de publicação: Estados Unidos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Colesterol na Dieta / Hepatopatia Gordurosa não Alcoólica / Células de Kupffer / Fígado Tipo de estudo: Etiology_studies / Prognostic_studies Limite: Animals Idioma: En Revista: Hepatology Ano de publicação: 2019 Tipo de documento: Article País de publicação: Estados Unidos