The role of adipose tissue macrophages-derived exosomes on steatohepatitis progression in diet-induced obese mice

Abstract

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease and the third leading indication for liver transplantation in the US. Its prevalence is increasing worldwide, generally parallel to the prevalence of obesity. NAFLD is primary characterized by a fatty liver (NAFL) which can progress to steatohepatitis (NASH), characterized by liver cell injury/death and inflammation, possibly advancing through stages of fibrosis to cirrhosis and hepatocellular cancer. The progression from NALF to NASH is not fully understood. Recently, the exosome, a type of extracellular vesicle that plays a central role in cell-to-cell communication, has shown to participate in the pathophysiology of NASH. It has been proposed that hepatocytes-derived exosomes may contribute to NASH progression, once those can act in neighboring hepatocytes or liver nonparenchymal cells. However, no study has so far investigated if exosomes derived from another tissue participate in NASH pathophysiology. Here, we hypothesize that adipose tissue macrophages (ATM)-derived exosomes could play a role in NASH progression. To test our hypothesis, we will use two diet-induced mouse models of NAFLD: standard high-fat diet (HFD) and western diet (WD). Both diets can induce NAFL, however only long-term WD feeding can induce a NASH phenotype. Thus, we will treat HFD fed mice with ATM-derived exosomes from mice fed a WD to investigate if exosomes derived from ATM of NASH mice can induce NASH progression in mice that, normally, are not expected to develop a NASH phenotype. (AU)