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

Abstract

Background

A crucial component of non‐alcoholic 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

Methods

This hypothesis was tested by using RNA‐seq methods to characterize and analyze sort‐purified hepatic macrophage populations that were isolated from mice fed diets with varying amounts of fat and cholesterol

Results

The addition of cholesterol to a high fat diet triggered hepatic pathology reminiscent of advanced non‐alcoholic steatohepatitis (NASH) in humans characterized by signs of cholesterol dysregulation, generation of oxidized LDL, increased recruitment of hepatic macrophages, and significant fibrosis. RNA‐seq analyses of hepatic macrophages in this model revealed that dietary cholesterol induced a tissue repair and regeneration phenotype in Kupffer cells and recruited infiltrating macrophages to a greater degree than fat. Furthermore, comparison of diseased Kupffer cells and infiltrating macrophages revealed that these two macrophage subsets are transcriptionally diverse. Finally, direct stimulation of murine and human macrophages with oxidized LDL recapitulated some of the transcriptional changes observed in the RNA‐seq study. These findings indicate that fat and cholesterol synergize to alter macrophage phenotype, and they also challenge the dogma that Kupffer cells are purely pro‐inflammatory in NASH

Conclusion

This comprehensive view of macrophage populations in NASH indicates novel mechanisms by which cholesterol contribute to NASH progression and identifies potential therapeutic targets for this common disease.

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