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.
http://aasldpubs.onlinelibrary.wiley.com/hub/journal/10.1002/(ISSN)2046-2484/video/15-1-reading-prashanth a video presentation of this article
https://aasldpubs.onlinelibrary.wiley.com/hub/journal/20462484/video/15-1-interview-francis an interview with the author
Careful patient selection forms the foundation for improving patient outcomes after liver transplantation (LT). This also provides inherent selection bias in studies suggesting comparable post-LT outcomes in patients with advanced age compared with younger cohorts. • Despite this, studies from the United States, Europe, and Asia have demonstrated higher mortality in transplant recipients of advanced age. • Older transplant recipients in the United States are more likely to receive grafts from older donors. The use of organs from older donors (>60 years old) is associated with worse 5-year graft outcomes and increased 5-year mortality, further compounding the increased mortality in transplant recipients of advanced age. • Studies supporting the "pro" argument have significant limitations that preclude generalizability for most transplant centers.In the United States, the number of individuals older than 75 years is projected to double to more than 10% of the population by the year 2050, 1 and the question of whether to transplant patients of advanced age has thus become increasingly relevant. In practice, however, this is not a question of whether these patients deserve transplantation any more or less than younger patients. Nor is it a question of whether the transplant community is capable of successfully transplanting and caring for such a patient.After all, in the modern era of LT, overall 5-year graft and patient survival are each greater than 70% and continue to improve. 2 Although this is a testament to high-quality medical and surgical care of transplant registrants and recipients, the foundation for these outcomes is responsible allocation of donor organs via careful patient selection for transplantation. In that context, patients of advanced age (>70 years) should not routinely be considered appropriate candidates for LT.
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