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 Vol. 34; no. 8; pp. 1201 - 1213.e5 |
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| Main Authors | , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
United States
Elsevier Inc
02.08.2022
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| Subjects | |
| Online Access | Get full text |
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| Abstract | 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.
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•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. |
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| AbstractList | 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. 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 restore 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. 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 cells iron overload, which contributes to the development of liver steatosis and fibrosis in Western diet fed mice. 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.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. 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. |
| Author | Wang, Gaowei Gao, Hong Karin, Michael Zhao, Huayi Jin, Zhongmou Zhang, Dinghong Kisseleva, Tatiana Liu, Xiao Brenner, David A. Ying, Wei Rocha, Karina Cunha e Bandyopadhyay, Gautam |
| AuthorAffiliation | 1 Division of Endocrinology & Metabolism, Department of Medicine, University of California, San Diego, La Jolla, California, USA 6 Department of Pharmacology, University of California, San Diego, La Jolla, California, USA 4 Department of Medicine, University of California, San Diego, California, USA 2 Division of Biological Sciences, University of California, San Diego, California, USA 7 Lead Contact 3 Department of Pediatrics, Pediatric Diabetes Research Center, University of California, San Diego, La Jolla, California, USA 5 Department of Surgery, University of California, La Jolla, San Diego, California, USA |
| AuthorAffiliation_xml | – name: 7 Lead Contact – name: 3 Department of Pediatrics, Pediatric Diabetes Research Center, University of California, San Diego, La Jolla, California, USA – name: 4 Department of Medicine, University of California, San Diego, California, USA – name: 6 Department of Pharmacology, University of California, San Diego, La Jolla, California, USA – name: 2 Division of Biological Sciences, University of California, San Diego, California, USA – name: 5 Department of Surgery, University of California, La Jolla, San Diego, California, USA – name: 1 Division of Endocrinology & Metabolism, Department of Medicine, University of California, San Diego, La Jolla, California, USA |
| Author_xml | – sequence: 1 givenname: Hong surname: Gao fullname: Gao, Hong email: hog007@health.ucsd.edu organization: Division of Endocrinology & Metabolism, Department of Medicine, University of California, San Diego, La Jolla, CA, USA – sequence: 2 givenname: Zhongmou surname: Jin fullname: Jin, Zhongmou organization: Division of Biological Sciences, University of California, San Diego, La Jolla, CA, USA – sequence: 3 givenname: Gautam surname: Bandyopadhyay fullname: Bandyopadhyay, Gautam organization: Division of Endocrinology & Metabolism, Department of Medicine, University of California, San Diego, La Jolla, CA, USA – sequence: 4 givenname: Gaowei surname: Wang fullname: Wang, Gaowei organization: Department of Pediatrics, Pediatric Diabetes Research Center, University of California, San Diego, La Jolla, CA, USA – sequence: 5 givenname: Dinghong surname: Zhang fullname: Zhang, Dinghong organization: Division of Endocrinology & Metabolism, Department of Medicine, University of California, San Diego, La Jolla, CA, USA – sequence: 6 givenname: Karina Cunha e surname: Rocha fullname: Rocha, Karina Cunha e organization: Division of Endocrinology & Metabolism, Department of Medicine, University of California, San Diego, La Jolla, CA, USA – sequence: 7 givenname: Xiao surname: Liu fullname: Liu, Xiao organization: Department of Medicine, University of California, San Diego, La Jolla, CA, USA – sequence: 8 givenname: Huayi surname: Zhao fullname: Zhao, Huayi organization: Department of Medicine, University of California, San Diego, La Jolla, CA, USA – sequence: 9 givenname: Tatiana surname: Kisseleva fullname: Kisseleva, Tatiana organization: Department of Surgery, University of California, San Diego, La Jolla, CA, USA – sequence: 10 givenname: David A. surname: Brenner fullname: Brenner, David A. organization: Department of Medicine, University of California, San Diego, La Jolla, CA, USA – sequence: 11 givenname: Michael surname: Karin fullname: Karin, Michael email: karinoffice@health.ucsd.edu organization: Department of Pharmacology, University of California, San Diego, La Jolla, CA, USA – sequence: 12 givenname: Wei surname: Ying fullname: Ying, Wei email: weying@health.ucsd.edu organization: Division of Endocrinology & Metabolism, Department of Medicine, University of California, San Diego, La Jolla, CA, USA |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/35921818$$D View this record in MEDLINE/PubMed |
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| Keywords | NAFLD liver fibrosis hepatocyte iron liver steatosis hepatic stellate cell NASH extracellular vesicle |
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| Notes | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 H.G., M.K., and W.Y. designed the studies, and H.G. performed most of the experiments. G.B. performed lipogenesis assays. Z.J., D.Z., and K.R. assisted with tissue collection, cell culture, qPCR analysis, and western blot analysis. G.W. performed RNAseq analysis. X.L., H.Z., T.K., and D.A.B. contributed the human liver samples. M.K. and W.Y. supervised the project. T.K. and D.A.B. edited manuscript. H.G., M.K., and W.Y. analyzed and interpreted the data and co-wrote the manuscript. Author contributions |
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| SubjectTerms | 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 |
| Title | Aberrant iron distribution via hepatocyte-stellate cell axis drives liver lipogenesis and fibrosis |
| URI | https://dx.doi.org/10.1016/j.cmet.2022.07.006 https://www.ncbi.nlm.nih.gov/pubmed/35921818 https://www.proquest.com/docview/2698630980 https://pubmed.ncbi.nlm.nih.gov/PMC9365100 |
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