Abstract 10784: Circulating Obesity Associated Pro-Fibrotic Protein Promotes Fibrosis in Liver and Heart

脂肪因子 脂肪性肝炎 医学 脂肪组织 纤维化 脂肪肝 内科学 内分泌学 基因剔除小鼠 白色脂肪组织 肥胖 炎症 疾病 瘦素 受体
作者
Yung-ting Hsiao,Ippei Shimizu,Yohko Yoshida,Goro Katsuumi,Tohru Minamino
出处
期刊:Circulation [Ovid Technologies (Wolters Kluwer)]
卷期号:144 (Suppl_1)
标识
DOI:10.1161/circ.144.suppl_1.10784
摘要

Introduction: Non-alcoholic steatohepatitis (NASH), driven by the obesity epidemic, has become the most common form of liver disease. Obesity contributes inflamed visceral adipose tissue secretes pro-inflammatory adipokines that is causal for systemic metabolic disorders. Despite its importance, the mechanism of NASH in the presence of morbid obesity related adipokines from BAT remains unclear. Hypothesis: Various kinds of white adipokines are known in obesity. However, brown adipokines 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 systemic OAFP knockout (KO) model. We also conducted functional in vitro studies with differentiated brown adipocytes. Results: Analyzing two sets of DNA microarray data with bioinformatics, we identified a secreted form OAFP expressed in dysfunctional brown adipose tissue (BAT) in mice. Testing our biobank samples, we found this protein increased in plasma of NASH patients or aged individuals. We generated a murine obese NASH model by imposing a high fat diet in C57BL6/NCr mice, and found that OAFP is produced predominantly by BAT. In this model, we also found that OAFP increased in plasma. For this reason, we generated a murine systemic OAFP knockout (KO) model and found that liver fibrosis ameliorated in OAFP-KO model. In addition, vaccination therapy also inhibited liver fibrosis. In contrast, liver fibrosis augmented in OAFP gain of function (GOF) model, and these results suggested that OAFP has causal role for the progression of fibrotic response in liver. In the obese NASH model, we found that cardiac fibrosis also developed and this ameliorated in OAFP-KO model, indicating that OAFP may have pathological roles for heart failure with preserved ejection fraction (HFpEF) related with age-related disorders. In vitro studies with differentiated brown adipocytes showed that OAFP was upregulated through by PERK/JNK/c-fos/AP1 pathways. Conclusions: Our results suggest that OAFP contributes for the progression of fibrotic responses in obese or aged models. Inhibition of OAFP may become a therapy for NASH or HFpEF.

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