Targeting CCN2 protects against progressive non-alcoholic steatohepatitis in a preclinical model induced by high-fat feeding and type 2 diabetes.

Ren, J; Wang, X; Parry, SN; Yee, C; Gorrell, MD; McLennan, SV; Twigg, SM

Targeting CCN2 protects against progressive non-alcoholic steatohepatitis in a preclinical model induced by high-fat feeding and type 2 diabetes.

Ren, J Wang, X Parry, SN Yee, C

Gorrell, MD McLennan, SV Twigg, SM

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Publisher:: SPRINGER
Publication Type:: Journal Article
Citation:: J Cell Commun Signal, 2022, 16, (3), pp. 447-460
Issue Date:: 2022-09

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Field	Value	Language
dc.contributor.author	Ren, J
dc.contributor.author	Wang, X
dc.contributor.author	Parry, SN
dc.contributor.author	Yee, C https://orcid.org/0000-0001-7243-5634
dc.contributor.author	Gorrell, MD
dc.contributor.author	McLennan, SV
dc.contributor.author	Twigg, SM
dc.date.accessioned	2023-02-28T03:44:22Z
dc.date.available	2022-01-06
dc.date.available	2023-02-28T03:44:22Z
dc.date.issued	2022-09
dc.identifier.citation	J Cell Commun Signal, 2022, 16, (3), pp. 447-460
dc.identifier.issn	1873-9601
dc.identifier.issn	1873-961X
dc.identifier.uri	http://hdl.handle.net/10453/166533
dc.description.abstract	Type 2 diabetes is an independent risk factor for non-alcoholic steatohepatitis (NASH) progression and its mediators have not been resolved. In this study, a pathogenic role of cellular communication network factor 2 (CCN2) protein in NASH pathology, was investigated in an established preclinical NASH model. Male wild type C57BL/6 mice received either Chow or high fat diet (HFD) for 26 weeks, with some mice in each group randomly selected to receive low dose streptozotocin (STZ: 3 i.p. injections, 65 mg/kg) at 15 weeks to induce type 2 diabetes. In the final 10 of the 26 weeks mice from each group were administered i.p. either rabbit anti-CCN2 neutralizing antibody (CCN2Ab) or as control normal rabbit IgG, at a dose of 150 µg per mouse twice/week. NASH developed in the HFD plus diabetes (HFD+DM) group. Administration of CCN2Ab significantly downregulated collagen I and collagen III mRNA induction and prevented pro-inflammatory MCP-1 mRNA induction in HFD+DM mice. At the protein level, CCN2Ab significantly attenuated collagen accumulation by PSR stain and collagen I protein induction in HFD+DM. Phosphorylation of the pro-fibrotic ERK signalling pathway in liver in HFD+DM was attenuated by CCN2Ab treatment. Intrahepatic CCN1 mRNA was induced, whereas CCN3 was downregulated at both the mRNA and protein levels in HFD+DM. CCN3 down-regulation was prevented by CCN2Ab treatment. This in vivo study indicates that CCN2 is a molecular target in NASH with high fat diet and diabetes, and that regulation of ERK signalling is implicated in this process.
dc.format	Print-Electronic
dc.language	eng
dc.publisher	SPRINGER
dc.relation.ispartof	J Cell Commun Signal
dc.relation.isbasedon	10.1007/s12079-022-00667-1
dc.rights	info:eu-repo/semantics/openAccess
dc.subject	0601 Biochemistry and Cell Biology, 1103 Clinical Sciences, 1112 Oncology and Carcinogenesis
dc.title	Targeting CCN2 protects against progressive non-alcoholic steatohepatitis in a preclinical model induced by high-fat feeding and type 2 diabetes.
dc.type	Journal Article
utslib.citation.volume	16
utslib.location.activity	Netherlands
utslib.for	0601 Biochemistry and Cell Biology
utslib.for	1103 Clinical Sciences
utslib.for	1112 Oncology and Carcinogenesis
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Science
pubs.organisational-group	/University of Technology Sydney/Faculty of Science/School of Life Sciences
utslib.copyright.status	open_access	*
dc.date.updated	2023-02-28T03:43:42Z
pubs.issue	3
pubs.publication-status	Published
pubs.volume	16
utslib.citation.issue	3

Abstract:

Type 2 diabetes is an independent risk factor for non-alcoholic steatohepatitis (NASH) progression and its mediators have not been resolved. In this study, a pathogenic role of cellular communication network factor 2 (CCN2) protein in NASH pathology, was investigated in an established preclinical NASH model. Male wild type C57BL/6 mice received either Chow or high fat diet (HFD) for 26 weeks, with some mice in each group randomly selected to receive low dose streptozotocin (STZ: 3 i.p. injections, 65 mg/kg) at 15 weeks to induce type 2 diabetes. In the final 10 of the 26 weeks mice from each group were administered i.p. either rabbit anti-CCN2 neutralizing antibody (CCN2Ab) or as control normal rabbit IgG, at a dose of 150 µg per mouse twice/week. NASH developed in the HFD plus diabetes (HFD+DM) group. Administration of CCN2Ab significantly downregulated collagen I and collagen III mRNA induction and prevented pro-inflammatory MCP-1 mRNA induction in HFD+DM mice. At the protein level, CCN2Ab significantly attenuated collagen accumulation by PSR stain and collagen I protein induction in HFD+DM. Phosphorylation of the pro-fibrotic ERK signalling pathway in liver in HFD+DM was attenuated by CCN2Ab treatment. Intrahepatic CCN1 mRNA was induced, whereas CCN3 was downregulated at both the mRNA and protein levels in HFD+DM. CCN3 down-regulation was prevented by CCN2Ab treatment. This in vivo study indicates that CCN2 is a molecular target in NASH with high fat diet and diabetes, and that regulation of ERK signalling is implicated in this process.

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