Hepatocyte specific TIMP3 expression prevents diet dependent fatty liver disease and hepatocellular carcinoma

Abstract Non-alcoholic fatty liver disease (NAFLD) encompasses a broad spectrum of conditions, ranging from non-progressive bland steatosis to hepatocarcinoma. Tissue inhibitor of metalloproteinase 3 (Timp3) has a role in the pathogenesis of fatty liver disease associated with obesity and is silence...

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Autores principales:	Viviana Casagrande, Alessandro Mauriello, Simone Bischetti, Maria Mavilio, Massimo Federici, Rossella Menghini
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/2f139bd734ac4b6788a18df4d09b30e0
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spelling	oai:doaj.org-article:2f139bd734ac4b6788a18df4d09b30e02021-12-02T15:05:15ZHepatocyte specific TIMP3 expression prevents diet dependent fatty liver disease and hepatocellular carcinoma10.1038/s41598-017-06439-x2045-2322https://doaj.org/article/2f139bd734ac4b6788a18df4d09b30e02017-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-06439-xhttps://doaj.org/toc/2045-2322Abstract Non-alcoholic fatty liver disease (NAFLD) encompasses a broad spectrum of conditions, ranging from non-progressive bland steatosis to hepatocarcinoma. Tissue inhibitor of metalloproteinase 3 (Timp3) has a role in the pathogenesis of fatty liver disease associated with obesity and is silenced during metabolic disorders and liver cancer. We generated an hepatocyte-specific TIMP3 ‘gain-of-function’ mouse model under the control of the Albumin promoter (AlbT3) and investigated its effects during high-fat diet (HFD). After 16 weeks of HFD, TIMP3 overexpression significantly improved glucose metabolism, hepatic fatty acid oxidation and cholesterol homeostasis. In AlbT3 mice CYP7A1, MDR3 and MRP2 gene expressions were observed, consistent with higher bile acid synthesis and export. Next, to evaluate the role of A Disintegrin and Metalloproteinase 17 (ADAM17), a crucial target of TIMP3, in these processes, we created mice deficient in Adam17 specifically in hepatocyte (A17LKO) or in myeloid lineage (A17MKO), founding that only A17LKO showed improvement in liver steatosis induced by HFD. Moreover, both, AlbT3 and A17LKO significantly reduced diethylnitrosamine-initiated, HFD-promoted hepatic tumorigenesis assessed by tumor multiplicity and total tumor area. Taken together, these data indicate that hepatic TIMP3 can slow progression of NAFLD, and tumorigenesis, at least in part, through the regulation of ADAM17 activity.Viviana CasagrandeAlessandro MaurielloSimone BischettiMaria MavilioMassimo FedericiRossella MenghiniNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-12 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Viviana Casagrande Alessandro Mauriello Simone Bischetti Maria Mavilio Massimo Federici Rossella Menghini Hepatocyte specific TIMP3 expression prevents diet dependent fatty liver disease and hepatocellular carcinoma
description	Abstract Non-alcoholic fatty liver disease (NAFLD) encompasses a broad spectrum of conditions, ranging from non-progressive bland steatosis to hepatocarcinoma. Tissue inhibitor of metalloproteinase 3 (Timp3) has a role in the pathogenesis of fatty liver disease associated with obesity and is silenced during metabolic disorders and liver cancer. We generated an hepatocyte-specific TIMP3 ‘gain-of-function’ mouse model under the control of the Albumin promoter (AlbT3) and investigated its effects during high-fat diet (HFD). After 16 weeks of HFD, TIMP3 overexpression significantly improved glucose metabolism, hepatic fatty acid oxidation and cholesterol homeostasis. In AlbT3 mice CYP7A1, MDR3 and MRP2 gene expressions were observed, consistent with higher bile acid synthesis and export. Next, to evaluate the role of A Disintegrin and Metalloproteinase 17 (ADAM17), a crucial target of TIMP3, in these processes, we created mice deficient in Adam17 specifically in hepatocyte (A17LKO) or in myeloid lineage (A17MKO), founding that only A17LKO showed improvement in liver steatosis induced by HFD. Moreover, both, AlbT3 and A17LKO significantly reduced diethylnitrosamine-initiated, HFD-promoted hepatic tumorigenesis assessed by tumor multiplicity and total tumor area. Taken together, these data indicate that hepatic TIMP3 can slow progression of NAFLD, and tumorigenesis, at least in part, through the regulation of ADAM17 activity.
format	article
author	Viviana Casagrande Alessandro Mauriello Simone Bischetti Maria Mavilio Massimo Federici Rossella Menghini
author_facet	Viviana Casagrande Alessandro Mauriello Simone Bischetti Maria Mavilio Massimo Federici Rossella Menghini
author_sort	Viviana Casagrande
title	Hepatocyte specific TIMP3 expression prevents diet dependent fatty liver disease and hepatocellular carcinoma
title_short	Hepatocyte specific TIMP3 expression prevents diet dependent fatty liver disease and hepatocellular carcinoma
title_full	Hepatocyte specific TIMP3 expression prevents diet dependent fatty liver disease and hepatocellular carcinoma
title_fullStr	Hepatocyte specific TIMP3 expression prevents diet dependent fatty liver disease and hepatocellular carcinoma
title_full_unstemmed	Hepatocyte specific TIMP3 expression prevents diet dependent fatty liver disease and hepatocellular carcinoma
title_sort	hepatocyte specific timp3 expression prevents diet dependent fatty liver disease and hepatocellular carcinoma
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/2f139bd734ac4b6788a18df4d09b30e0
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Hepatocyte specific TIMP3 expression prevents diet dependent fatty liver disease and hepatocellular carcinoma

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