Hepatic lipid-associated macrophages mediate the beneficial effects of bariatric surgery against MASH

Abstract

Immune mechanisms are considered a major contributing factor to the inflammatory process and progression of non-alcoholic steatohepatitis (NASH). Bariatric procedures such as vertical sleeve gastrectomy (VSG) have been shown successful in ameliorating the progression of the disease. Several mechanisms of weight-loss-independent improvements due to bariatric surgery have been proposed including bile acid signaling, gut hormones, intestinal tissue reprogramming, and changes in the gut microbiome. However, whether bariatric surgery ameliorates the progression of NASH through anti-inflammatory mechanisms has not been investigated. To determine the effects of VSG on hepatic inflammation, we fed mice a high-fat high-carbohydrate (HFHC) diet for 12 weeks and assigned them to either VSG or Sham surgeries. Independent from weight loss, VSG resulted in reduced hepatic lipid accumulation and ameliorated NASH as early as 5 weeks after VSG. To profile the gene expression of macrophages in the NASH liver following VSG, we performed single-cell RNA sequencing and identified 18 clusters of monocytes and macrophages with a unique gene expression signature. We found substantial alterations in macrophage subsets in association with VSG-induced reversal of NASH. In particular, hepatic lipid-associated macrophages (LAMs), which are enriched in genes associated with lipid metabolism and collagen degradation, were highly responsive to VSG. Differential gene expression analysis revealed that VSG increased the expression of genes involved in lysosomal activity, antigen presentation, and repression of inflammation in LAMs, suggesting that VSG sustains their protective function. Spatial transcriptomic analysis of human liver sections confirmed the enrichment of LAM genes within periportal regions during NASH and a marked reduction following VSG. To determine a causal role for hepatic LAMs in the restorative process induced by VSG against NASH, we performed VSG in mice deficient for the triggering receptor expressed on myeloid cells 2 (Trem2). TREM2-deficiency ablated the protective effects of VSG against NASH, suggesting that LAMs mediate this reparative process. Mechanistically, Trem2 prevents the inflammatory activation of bone marrow-derived macrophages, in agreement with the anti-inflammatory effects of VSG in LAMs. Overall, our findings suggest that bariatric surgery improves NASH through a reparative process driven by hepatic lipid-associated macrophages.