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      Dietary Lipids Differentially Shape NASH Progression and the Transcriptome of Kupffer Cells and Infiltrating Macrophages

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          Abstract

          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.

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          Author and article information

          Journal
          Hepatology
          Hepatology
          Wiley
          02709139
          December 05 2018
          Affiliations
          [1 ]Department of Medicine; University of Colorado; Denver Division of Gastroenterology & Hepatology
          [2 ]Departments of Immunology; University of Colorado; Denver Division of Gastroenterology & Hepatology
          [3 ]Departments of Pathology; University of Colorado; Denver Division of Gastroenterology & Hepatology
          [4 ]Division of Biostatistics and Bioinformatics; National Jewish Health; Denver CO
          [5 ]Department of Medicine; University of Southern California
          [6 ]USC Research Center for Liver Diseases
          Article
          10.1002/hep.30401
          6923128
          30516830
          fdf9e154-43a1-4e92-af97-6d455914508e
          © 2018

          http://doi.wiley.com/10.1002/tdm_license_1.1

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