Imaging and immunometabolic phenotyping uncover changes in the hepatic immune response in the early phases of NAFLD

Abstract Background & Aims NAFLD is the most frequent chronic disease in the world, and limitations in our understanding of its pathogenesis, especially in initial stages, are precluding the development of diagnosis tools and new treatments. In fact, the precise determination of NAFLD onset in patients is challenging; therefore, the initial events of hepatic response to fat accumulation are largely elusive and may be fundamental in our understanding of NAFLD evolution and different outcomes in the clinic. Here we chronologically mapped the immunologic and metabolic changes in liver during the early stages of fatty liver disease in mouse and compared with human samples with NAFLD. Methods Liver biopsies from patients with NAFLD (NAS 2-3) were collected for gene expression profiling. Mice received high fat diet for short periods to mimic initial steatosis and liver immune response was investigated using a combination of confocal intravital imaging, gene expression, cell isolation, flow cytometry and bone marrow transplantation assays. Results We observed major immunologic changes in NAS 2-3 patients and mice in the initial stages of NAFLD. In mice, these changes significantly enhanced mortality rate upon drug-induced liver injury and also predisposed mice to bacterial infections. Moreover, deletion of TLR4 in liver cells dampened tolerogenesis, particularly in Kupffer cells, in the initial time points of dietary insult. Conclusion Liver immune system acts as a sentinel for early and minor changes in hepatic lipid content, mounting a biphasic response upon high fat diet insult. Priming of liver immune cells by gut-derived TLR4 ligands play an important role in liver tolerance in initial phases, but continuous exposure to insults may lead to damage and reduced ability to control infections.