Z Gastroenterol 2019; 57(01): e11
DOI: 10.1055/s-0038-1677068
1. Basic Hepatology (Fibrogenesis, NPC, Transport)
Georg Thieme Verlag KG Stuttgart · New York

ECM1 is a gatekeeper that restrains TGF-β activation to maintain liver homeostasis and prevent fibrogenesis

S Dooley
1   Sektion Molekulare Hepatologie, II. Medizinische Klinik, Medizinische Fakultät Mannheim, Universität Heidelberg, Germany
,
W Fan
2   State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences; University of Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China
,
S Hammad
1   Sektion Molekulare Hepatologie, II. Medizinische Klinik, Medizinische Fakultät Mannheim, Universität Heidelberg, Germany
,
K Gould
1   Sektion Molekulare Hepatologie, II. Medizinische Klinik, Medizinische Fakultät Mannheim, Universität Heidelberg, Germany
,
T Longerich
5   Sektion Translational Gastrointestinal Pathology, Inst of Pathology, Heidelberg University, Germany
,
T Liu
3   Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China
,
W Chen
2   State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences; University of Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China
,
C Liu
2   State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences; University of Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China
,
J Hou
4   Department of Infectious Diseases, Institute of Hepatology, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, Guangzhou, China
,
J Jia
3   Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China
,
B Sun
2   State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences; University of Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China
› Author Affiliations
Further Information

Publication History

Publication Date:
04 January 2019 (online)

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Background & aims:

Excessive amounts of active TGF-β drive activation of hepatic stellate cells (HSCs) and promote extracellular matrix production, which results in fibrosis and cirrhosis. The mechanism on how the liver controls active TGF-β supply has not fully been understood. We investigated the role of extracellular matrix protein 1 (ECM1), a new extracellular matrix component in the liver, in TGF-β activation and fibrogenesis of mice and humans.

Methods:

Mice with total hepatocyte specific ECM1 knockout were examined as such or upon treatment with carbon tetrachloride (CCl4). ECM1 and soluble TGF-β receptor II were expressed in liver by AAV8 infection. HSC and hepatocytes from mice were purified in vitro to measure effects of ECM1 on TGF-β driven activation. Levels of ECM1 were compared with the degree of fibrosis in liver samples from chronically injured mice and patients.

Results:

ECM1 deficiency in mice results in a severe disturbance of liver architecture, liver cirrhosis and death, without a significant initial hepatocyte damage or inflammation. Mechanistically, ECM1 depletion leads to spontaneous activation of extracellular matrix deposited latent TGF-β, HSC activation and matrix production in healthy liver. Upon liver damage, ECM1 expression is consistently down-regulated during hepatic fibrogenesis in mouse models, and clinically, a reverse correlation between ECM1 expression levels and liver fibrosis severity was found in patients with liver diseases. Interestingly, hepatocytes and not HSCs is the major ECM1 producing cell type. Ectopic expression of ECM1 or soluble TGF-β receptor II in liver rescued ECM1 knockout mice from spontaneous hepatic fibrogenesis and death. Further, ECM1 reexpression in liver attenuated fibrosis progression in chronically CCl4 treated mice.

Conclusions:

ECM1 maintains hepatic homeostasis by inhibiting TGF-β activation and TGF-β mediated fibrogenesis. Up-regulating ECM1 levels in liver seems to be a promising therapeutic approach for liver fibrosis.