COL6A3-derived endotrophin links reciprocal interactions among hepatic cells in the pathology of chronic liver disease

Changhu Lee; Min Kim; Jun Ho Lee; Jiyoung Oh; Hyun Hee Shin; Sang Min Lee; Philipp E Scherer; Hyug Moo Kwon; Jang Hyun Choi; Jiyoung Park

doi:10.1002/path.5172

COL6A3-derived endotrophin links reciprocal interactions among hepatic cells in the pathology of chronic liver disease

Changhu Lee, Min Kim, Jun Ho Lee, Jiyoung Oh, Hyun Hee Shin, Sang Min Lee, Philipp E Scherer, Hyug Moo Kwon, Jang Hyun Choi, Jiyoung Park

Research output: Contribution to journal › Article › peer-review

28 Scopus citations

Abstract

Extracellular matrix dysregulation is associated with chronic liver disease. CollagenVI-alpha3 chain (COL6A3) is a biomarker for hepatic fibrosis and poor prognosis of hepatocellular carcinoma (HCC), but its function in liver pathology remains unknown. High levels of COL6A3 and its cleaved product, endotrophin (ETP) in tumor-neighboring regions are strongly associated with poor prognosis in HCC patients. Here, we report that the high levels of ETP in injured hepatocytes induce JNK-dependent hepatocyte apoptosis and activate nonparenchymal cells to lead further activation of hepatic inflammation, fibrosis, and apoptosis. Nevertheless ETP per se showed limited phenotypic changes in normal liver tissues. Furthermore, inhibition of ETP activity by utilizing neutralizing antibodies efficiently suppressed the pathological consequences in chronic liver diseases. Our results implicate ETP mechanistically as a crucial mediator in reciprocal interactions among various hepatic cell populations in the pathogenesis of chronic liver disease, and it could be a promising therapeutic target particularly in individuals with high local levels of COL6A3.

Original language	English (US)
Pages (from-to)	99-109
Number of pages	11
Journal	Journal of Pathology
Volume	247
Issue number	1
DOIs	https://doi.org/10.1002/path.5172
State	Published - Jan 2019

Keywords

JNK pathway
apoptosis
chronic liver disease
collagen VI A3
endotrophin
fibrosis
inflammation
pathology

ASJC Scopus subject areas

Pathology and Forensic Medicine

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10.1002/path.5172

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@article{103602b46c3341a78bfeb6e2ebb2753e,

title = "COL6A3-derived endotrophin links reciprocal interactions among hepatic cells in the pathology of chronic liver disease",

abstract = "Extracellular matrix dysregulation is associated with chronic liver disease. CollagenVI-alpha3 chain (COL6A3) is a biomarker for hepatic fibrosis and poor prognosis of hepatocellular carcinoma (HCC), but its function in liver pathology remains unknown. High levels of COL6A3 and its cleaved product, endotrophin (ETP) in tumor-neighboring regions are strongly associated with poor prognosis in HCC patients. Here, we report that the high levels of ETP in injured hepatocytes induce JNK-dependent hepatocyte apoptosis and activate nonparenchymal cells to lead further activation of hepatic inflammation, fibrosis, and apoptosis. Nevertheless ETP per se showed limited phenotypic changes in normal liver tissues. Furthermore, inhibition of ETP activity by utilizing neutralizing antibodies efficiently suppressed the pathological consequences in chronic liver diseases. Our results implicate ETP mechanistically as a crucial mediator in reciprocal interactions among various hepatic cell populations in the pathogenesis of chronic liver disease, and it could be a promising therapeutic target particularly in individuals with high local levels of COL6A3.",

keywords = "JNK pathway, apoptosis, chronic liver disease, collagen VI A3, endotrophin, fibrosis, inflammation, pathology",

author = "Changhu Lee and Min Kim and Lee, {Jun Ho} and Jiyoung Oh and Shin, {Hyun Hee} and Lee, {Sang Min} and Scherer, {Philipp E} and Kwon, {Hyug Moo} and Choi, {Jang Hyun} and Jiyoung Park",

note = "Funding Information: We thank Dr. Kyungbun Lee and Dr. Sun Wook Cho for IRB approval and for providing human HCC patient specimens from the Tissue Bank of SNUH. This work was supported by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI, HI14C1277), a grant of Comprehensive and Integrative Medicine R&D project through Comprehensive and Integrative Medicine Institute (CIMI, 090-091-3000-3038-301-320-01) funded by the Ministry of Health & Welfare, the Bio-Synergy Research Project (NRF-2017M3A9C4065956) of the Ministry of Science, ICT and Future Planning and Basic Science Research Program (NRF-2018R1A2B6003878) through the National Research Foundation, and the 2017 (1.170078.01) and 2018 research fund (1.180018.01) of UNIST to J.P. This work was also supported by the Ministry of Education, Science and Technology (NRF-2017R1C1B1008424 and NRF-2018R1A5A1024340). Publisher Copyright: Copyright {\textcopyright} 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.",

year = "2019",

month = jan,

doi = "10.1002/path.5172",

language = "English (US)",

volume = "247",

pages = "99--109",

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issn = "0022-3417",

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T1 - COL6A3-derived endotrophin links reciprocal interactions among hepatic cells in the pathology of chronic liver disease

AU - Lee, Changhu

AU - Kim, Min

AU - Lee, Jun Ho

AU - Oh, Jiyoung

AU - Shin, Hyun Hee

AU - Lee, Sang Min

AU - Scherer, Philipp E

AU - Kwon, Hyug Moo

AU - Choi, Jang Hyun

AU - Park, Jiyoung

N1 - Funding Information: We thank Dr. Kyungbun Lee and Dr. Sun Wook Cho for IRB approval and for providing human HCC patient specimens from the Tissue Bank of SNUH. This work was supported by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI, HI14C1277), a grant of Comprehensive and Integrative Medicine R&D project through Comprehensive and Integrative Medicine Institute (CIMI, 090-091-3000-3038-301-320-01) funded by the Ministry of Health & Welfare, the Bio-Synergy Research Project (NRF-2017M3A9C4065956) of the Ministry of Science, ICT and Future Planning and Basic Science Research Program (NRF-2018R1A2B6003878) through the National Research Foundation, and the 2017 (1.170078.01) and 2018 research fund (1.180018.01) of UNIST to J.P. This work was also supported by the Ministry of Education, Science and Technology (NRF-2017R1C1B1008424 and NRF-2018R1A5A1024340). Publisher Copyright: Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

PY - 2019/1

Y1 - 2019/1

N2 - Extracellular matrix dysregulation is associated with chronic liver disease. CollagenVI-alpha3 chain (COL6A3) is a biomarker for hepatic fibrosis and poor prognosis of hepatocellular carcinoma (HCC), but its function in liver pathology remains unknown. High levels of COL6A3 and its cleaved product, endotrophin (ETP) in tumor-neighboring regions are strongly associated with poor prognosis in HCC patients. Here, we report that the high levels of ETP in injured hepatocytes induce JNK-dependent hepatocyte apoptosis and activate nonparenchymal cells to lead further activation of hepatic inflammation, fibrosis, and apoptosis. Nevertheless ETP per se showed limited phenotypic changes in normal liver tissues. Furthermore, inhibition of ETP activity by utilizing neutralizing antibodies efficiently suppressed the pathological consequences in chronic liver diseases. Our results implicate ETP mechanistically as a crucial mediator in reciprocal interactions among various hepatic cell populations in the pathogenesis of chronic liver disease, and it could be a promising therapeutic target particularly in individuals with high local levels of COL6A3.

AB - Extracellular matrix dysregulation is associated with chronic liver disease. CollagenVI-alpha3 chain (COL6A3) is a biomarker for hepatic fibrosis and poor prognosis of hepatocellular carcinoma (HCC), but its function in liver pathology remains unknown. High levels of COL6A3 and its cleaved product, endotrophin (ETP) in tumor-neighboring regions are strongly associated with poor prognosis in HCC patients. Here, we report that the high levels of ETP in injured hepatocytes induce JNK-dependent hepatocyte apoptosis and activate nonparenchymal cells to lead further activation of hepatic inflammation, fibrosis, and apoptosis. Nevertheless ETP per se showed limited phenotypic changes in normal liver tissues. Furthermore, inhibition of ETP activity by utilizing neutralizing antibodies efficiently suppressed the pathological consequences in chronic liver diseases. Our results implicate ETP mechanistically as a crucial mediator in reciprocal interactions among various hepatic cell populations in the pathogenesis of chronic liver disease, and it could be a promising therapeutic target particularly in individuals with high local levels of COL6A3.

KW - JNK pathway

KW - apoptosis

KW - chronic liver disease

KW - collagen VI A3

KW - endotrophin

KW - fibrosis

KW - inflammation

KW - pathology

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DO - 10.1002/path.5172

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VL - 247

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JO - Journal of Pathology

JF - Journal of Pathology

IS - 1

ER -

COL6A3-derived endotrophin links reciprocal interactions among hepatic cells in the pathology of chronic liver disease

Abstract

Keywords

ASJC Scopus subject areas

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