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

• Published in: Cell metabolism Vol. 34; no. 8; pp. 1201 - 1213.e5
• Main Authors: Gao, Hong, Jin, Zhongmou, Bandyopadhyay, Gautam, Wang, Gaowei, Zhang, Dinghong, Rocha, Karina Cunha e, Liu, Xiao, Zhao, Huayi, Kisseleva, Tatiana, Brenner, David A., Karin, Michael, Ying, Wei
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 02.08.2022
• Subjects: Animals; Disease Models, Animal; extracellular vesicle; Fibrosis; hepatic stellate cell; Hepatic Stellate Cells - metabolism; hepatocyte; Hepatocytes - metabolism; iron; Iron - metabolism; Iron Overload - complications; Iron Overload - metabolism; Iron Overload - pathology; Kupffer Cells - metabolism; Lipogenesis; Liver - metabolism; Liver Cirrhosis - metabolism; liver fibrosis; liver steatosis; NAFLD; NASH; Non-alcoholic Fatty Liver Disease - metabolism; NAFLD; liver fibrosis; hepatocyte; iron; liver steatosis; hepatic stellate cell; NASH; extracellular vesicle
• ISSN: 1550-4131; 1932-7420; 1932-7420
• DOI: 10.1016/j.cmet.2022.07.006

Hepatocytes have important roles in liver iron homeostasis, abnormalities in which are tightly associated with liver steatosis and fibrosis. Here, we show that non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH) are characterized by iron-deficient hepatocytes and iron overload in hepatic stellate cells (HSCs). Iron deficiency enhances hepatocyte lipogenesis and insulin resistance through HIF2α-ATF4 signaling. Elevated secretion of iron-containing hepatocyte extracellular vesicles (EVs), which are normally cleared by Kupffer cells, accounts for hepatocyte iron deficiency and HSC iron overload in NAFLD/NASH livers. Iron accumulation results in overproduction of reactive oxygen species that promote HSC fibrogenic activation. Conversely, blocking hepatocyte EV secretion or depleting EV iron cargo restores liver iron homeostasis, concomitant with mitigation of NAFLD/NASH-associated liver steatosis and fibrosis. Taken together, these studies show that iron distribution disorders contribute to the development of liver metabolic diseases. [Display omitted] •NAFLD/NASH livers present iron-deficient hepatocytes and iron overloaded HSCs•Hepatocyte iron deficiency enhances lipogenesis and insulin resistance via HIF2α-ATF4•Hepatocyte EVs shuttle iron into HSCs in NAFLD/NASH•Iron overload stimulates HSC ROS production and fibrogenic activation Hepatocytes have important roles in liver iron homeostasis. Gao et al. report that hepatocyte-derived, iron-containing extracellular vesicles lead to hepatocyte iron deficiency and hepatic stellate cell iron overload, which contributes to the development of liver steatosis and fibrosis in Western diet-fed mice.