Abstract 13042: Circulating Obesity Associated Pro-Fibrotic Protein as a Brown Adipokine Promotes Liver and Heart Fibrosis in Obese Nash Mice

Abstract

Introduction: Non-alcoholic steatohepatitis (NASH), driven by the obesity epidemic, has become the most common form of liver disease. Excessive calorie intake inflames visceral adipose tissue, and let this organ produce pro-inflammatory adipokines. Brown adipose tissue (BAT) is another type of fat pad equipped with the thermogenic capacity, and the role of BAT-derived adipokines (BATokines) in pathogenesis of NASH remains to be explored. Hypothesis: Various kinds of white adipokines are known in obesity. However, BATokines in pathogenesis of NASH still remain to be explored. Methods: To identify the function of obesity associated pro-fibrotic protein (OAFP), we generated a murine obese NASH model by imposing a high fat diet in C57BL6/NCr mice, and murine OAFP knockout (KO) model. We also conducted functional in vitro studies with differentiated brown adipocytes. Results: Here we identified a secreted type pro-fibrotic protein OAFP, as one of the BATokines contributing for the promotion of liver fibrosis in a murine NASH model. We also found that OAFP increased in circulation of human NASH patients. Genetic models with OAFP suppression ameliorated liver fibrosis, in contrast, OAFP gain of function model enhanced this in our NASH model. In addition, we found that cardiac fibrosis also developed in the NASH model, and this was ameliorated in OAFP-KO model, indicating the pathogenic role of OAFP in heart failure with preserved ejection fraction (HFpEF). Our biobank studies also showed OAFP increased in HFpEF patients. We also found ER stress-mediated signaling enhanced the production of this BATokine. Conclusions: Our results testing mice models, and human studies indicate suppression of OAFP becomes therapies for HFpEF and NASH.