Heliyon (Jul 2024)

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

Journal volume & issue
Vol. 10, no. 13
p. e33741

Abstract

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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.

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