Extracellular vesicles-derived ferritin from lipid-induced hepatocytes regulates activation of hepatic stellate cells
Mengxue Sun,
Min Tang,
Yiting Qian,
Guannan Zong,
Gaowang Zhu,
Yan Jiang,
Yingjie Mu,
Minjun Zhou,
Qin Ding,
Hao Wang,
Fengshang Zhu,
Changqing Yang
Affiliations
Mengxue Sun
Department of Gastroenterology and Hepatology, Digestive Disease Institute, Tongji Hospital, Tongji University School of Medicine, Shanghai, China
Min Tang
Department of Gastroenterology and Hepatology, Digestive Disease Institute, Tongji Hospital, Tongji University School of Medicine, Shanghai, China
Yiting Qian
Department of Gastroenterology and Hepatology, Digestive Disease Institute, Tongji Hospital, Tongji University School of Medicine, Shanghai, China
Guannan Zong
Department of Endocrinology and Metabolism, Tongji Hospital, School of Medicine, Tongji University, Shanghai, China
Gaowang Zhu
Department of Gastroenterology, Luodian Hospital, Baoshan District, Shanghai, China
Yan Jiang
Department of Infectious Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
Yingjie Mu
Department of Cadre Ward, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
Minjun Zhou
Kunshan Maternal and Child Health Care Hospital, Suzhou, China
Qin Ding
Nutrition Department, Shanghai Pulmonary Hospital Affiliated to Tongji University, Shanghai, China
Hao Wang
Department of Oncology, The Air Force Hospital of Northern Theater PLA, Shenyang, China; Corresponding author.
Fengshang Zhu
Department of Gastroenterology and Hepatology, Digestive Disease Institute, Tongji Hospital, Tongji University School of Medicine, Shanghai, China; State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia & Xinjiang Key Laboratory of Neurological Disorder Research, Xinjiang Medical University, Xinjiang Uygur Autonomous Region, Urumqi, China; Department of Gastroenterology, Second Affiliated Hospital of Xinjiang Medical University, Urumqi, China; Corresponding author. Department of Gastroenterology and Hepatology, Digestive Disease Institute, Tongji Hospital, Tongji University School of Medicine, Shanghai, China.
Changqing Yang
Department of Gastroenterology and Hepatology, Digestive Disease Institute, Tongji Hospital, Tongji University School of Medicine, Shanghai, China; Corresponding author.
Introduction: and objectives: Extracellular vesicles (EVs) have emerged as key players in intercellular communication within the context of non-alcoholic fatty liver disease (NAFLD). This study aims to explore the intricate crosstalk between hepatocytes and hepatic stellate cells (HSCs) mediated by EVs in NAFLD. Materials and methods: EVs ferritin was detected in hepatocytes stimulated with free fatty acids (FFA) as well as in NAFLD mice. Deferoxamine (DFO) was employed to reduce ferritin levels, while GW4869 was utilized to inhibit EVs. The impact of EVs ferritin on the HSCs activation was evaluated both in vitro and in vivo. Additionally, serum EVs ferritin levels were compared between NAFLD patients and controls. Results: FFA treatment induces the formation and secretion of EVs and facilitates the release of ferritin from hepatocytes via EVs. Subsequently, EVs ferritin is hijacked by HSCs, prompting accelerated HSCs activation. Silencing ferritin with DFO and inhibiting EVs formation and secretion with GW4869 can reverse the effects of FFA treatment and disrupt the communication between hepatocytes and HSCs. Accumulation of ferritin leads to excessive reactive oxygen species (ROS) production, promoting HSCs fibrogenesis. Conversely, depleting EVs ferritin cargo restores liver function, concurrently mitigating NAFLD-associated fibrosis. Notably, NAFLD patients exhibit significantly elevated levels of serum EVs ferritin. Conclusions: This study unveils a previously underestimated role of ferritin in HSCs upon its release from hepatocytes, emphasizing DFO as a promising compound to impede NAFLD advancement.
