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

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 he...

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Published in:Cell metabolism 2022-08, Vol.34 (8), p.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: Article
Language:English
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
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Summary: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.
ISSN:1550-4131
1932-7420
DOI:10.1016/j.cmet.2022.07.006