美国加州大学圣迭戈分校Wei Ying等研究人员合作发现，肝细胞-星状细胞信号轴介导的铁分布异常驱动肝脏脂肪生成和纤维化。这一研究成果发表在2022年8月2日出版的国际学术期刊《细胞—代谢》上。

研究人员发现，非酒精性脂肪肝（NAFLD）和脂肪性肝炎（NASH）的特点是肝细胞缺铁和肝星状细胞（HSC）铁过载。缺铁通过HIF2α-ATF4信号传导增强了肝细胞的脂肪生成和胰岛素抵抗。含铁的肝细胞外囊泡（EV）的分泌量增加，这些囊泡通常由枯否细胞清除，是NAFLD/NASH肝脏中肝细胞缺铁和HSC铁过载的原因。铁的积累导致了活性氧的过度产生，从而促进了HSC的纤维化激活。相反，阻断肝细胞EV的分泌或耗尽EV的铁货物可以恢复肝脏的铁平衡，同时减轻NAFLD/NASH相关的肝脏脂肪变性和纤维化。因此，这些研究表明，铁分布紊乱导致了肝脏代谢疾病的发展。

据了解，肝细胞在肝脏铁平衡中具有重要作用，其异常与肝脏脂肪变性和纤维化密切相关。

附：英文原文

Title: Aberrant iron distribution via hepatocyte-stellate cell axis drives liver lipogenesis and fibrosis

Author: Hong Gao, Zhongmou Jin, Gautam Bandyopadhyay, Gaowei Wang, Dinghong Zhang, Karina Cunha e Rocha, Xiao Liu, Huayi Zhao, Tatiana Kisseleva, David A. Brenner, Michael Karin, Wei Ying

Issue&Volume: 2022/08/02

Abstract: Hepatocytes have important roles in liver iron homeostasis, abnormalities in whichare tightly associated with liver steatosis and fibrosis. Here, we show that non-alcoholicfatty liver disease (NAFLD) and steatohepatitis (NASH) are characterized by iron-deficienthepatocytes and iron overload in hepatic stellate cells (HSCs). Iron deficiency enhanceshepatocyte lipogenesis and insulin resistance through HIF2α-ATF4 signaling. Elevatedsecretion of iron-containing hepatocyte extracellular vesicles (EVs), which are normallycleared by Kupffer cells, accounts for hepatocyte iron deficiency and HSC iron overloadin NAFLD/NASH livers. Iron accumulation results in overproduction of reactive oxygenspecies that promote HSC fibrogenic activation. Conversely, blocking hepatocyte EVsecretion or depleting EV iron cargo restores liver iron homeostasis, concomitantwith mitigation of NAFLD/NASH-associated liver steatosis and fibrosis. Taken together,these studies show that iron distribution disorders contribute to the developmentof liver metabolic diseases.

DOI: 10.1016/j.cmet.2022.07.006

Source: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(22)00305-9