Cathepsin D regulates lipid metabolism in murine steatohepatitis

Abstract Due to the obesity epidemic, non-alcoholic steatohepatitis (NASH) is a prevalent liver disease, characterized by fat accumulation and inflammation of the liver. However, due to a lack of mechanistic insight, diagnostic and therapeutic options for NASH are poor. Recent evidence has indicated...

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Autores principales:	Tom Houben, Yvonne Oligschlaeger, Tim Hendrikx, Albert V. Bitorina, Sofie M. A. Walenbergh, Patrick J. van Gorp, Marion J. J. Gijbels, Silvia Friedrichs, Jogchum Plat, Frank G. Schaap, Dieter Lütjohann, Marten H. Hofker, Ronit Shiri-Sverdlov
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/cfb2f1134c3242eca9f6af53a9707ebd
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spelling	oai:doaj.org-article:cfb2f1134c3242eca9f6af53a9707ebd2021-12-02T16:06:31ZCathepsin D regulates lipid metabolism in murine steatohepatitis10.1038/s41598-017-03796-52045-2322https://doaj.org/article/cfb2f1134c3242eca9f6af53a9707ebd2017-06-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-03796-5https://doaj.org/toc/2045-2322Abstract Due to the obesity epidemic, non-alcoholic steatohepatitis (NASH) is a prevalent liver disease, characterized by fat accumulation and inflammation of the liver. However, due to a lack of mechanistic insight, diagnostic and therapeutic options for NASH are poor. Recent evidence has indicated cathepsin D (CTSD), a lysosomal enzyme, as a marker for NASH. Here, we investigated the function of CTSD in NASH by using an in vivo and in vitro model. In addition to diminished hepatic inflammation, inhibition of CTSD activity dramatically improved lipid metabolism, as demonstrated by decreased plasma and liver levels of both cholesterol and triglycerides. Mechanistically, CTSD inhibition resulted in an increased conversion of cholesterol into bile acids and an elevated excretion of bile acids via the feces, indicating that CTSD influences lipid metabolism. Consistent with these findings, treating Wt BMDMs with PepA in vitro showed a similar decrease in inflammation and an analogous effect on cholesterol metabolism. Conclusion: CTSD is a key player in the development of hepatic inflammation and dyslipidemia. Therefore, aiming at the inhibition of the activity of CTSD may lead to novel treatments to combat NASH.Tom HoubenYvonne OligschlaegerTim HendrikxAlbert V. BitorinaSofie M. A. WalenberghPatrick J. van GorpMarion J. J. GijbelsSilvia FriedrichsJogchum PlatFrank G. SchaapDieter LütjohannMarten H. HofkerRonit Shiri-SverdlovNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-10 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Tom Houben Yvonne Oligschlaeger Tim Hendrikx Albert V. Bitorina Sofie M. A. Walenbergh Patrick J. van Gorp Marion J. J. Gijbels Silvia Friedrichs Jogchum Plat Frank G. Schaap Dieter Lütjohann Marten H. Hofker Ronit Shiri-Sverdlov Cathepsin D regulates lipid metabolism in murine steatohepatitis
description	Abstract Due to the obesity epidemic, non-alcoholic steatohepatitis (NASH) is a prevalent liver disease, characterized by fat accumulation and inflammation of the liver. However, due to a lack of mechanistic insight, diagnostic and therapeutic options for NASH are poor. Recent evidence has indicated cathepsin D (CTSD), a lysosomal enzyme, as a marker for NASH. Here, we investigated the function of CTSD in NASH by using an in vivo and in vitro model. In addition to diminished hepatic inflammation, inhibition of CTSD activity dramatically improved lipid metabolism, as demonstrated by decreased plasma and liver levels of both cholesterol and triglycerides. Mechanistically, CTSD inhibition resulted in an increased conversion of cholesterol into bile acids and an elevated excretion of bile acids via the feces, indicating that CTSD influences lipid metabolism. Consistent with these findings, treating Wt BMDMs with PepA in vitro showed a similar decrease in inflammation and an analogous effect on cholesterol metabolism. Conclusion: CTSD is a key player in the development of hepatic inflammation and dyslipidemia. Therefore, aiming at the inhibition of the activity of CTSD may lead to novel treatments to combat NASH.
format	article
author	Tom Houben Yvonne Oligschlaeger Tim Hendrikx Albert V. Bitorina Sofie M. A. Walenbergh Patrick J. van Gorp Marion J. J. Gijbels Silvia Friedrichs Jogchum Plat Frank G. Schaap Dieter Lütjohann Marten H. Hofker Ronit Shiri-Sverdlov
author_facet	Tom Houben Yvonne Oligschlaeger Tim Hendrikx Albert V. Bitorina Sofie M. A. Walenbergh Patrick J. van Gorp Marion J. J. Gijbels Silvia Friedrichs Jogchum Plat Frank G. Schaap Dieter Lütjohann Marten H. Hofker Ronit Shiri-Sverdlov
author_sort	Tom Houben
title	Cathepsin D regulates lipid metabolism in murine steatohepatitis
title_short	Cathepsin D regulates lipid metabolism in murine steatohepatitis
title_full	Cathepsin D regulates lipid metabolism in murine steatohepatitis
title_fullStr	Cathepsin D regulates lipid metabolism in murine steatohepatitis
title_full_unstemmed	Cathepsin D regulates lipid metabolism in murine steatohepatitis
title_sort	cathepsin d regulates lipid metabolism in murine steatohepatitis
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/cfb2f1134c3242eca9f6af53a9707ebd
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Cathepsin D regulates lipid metabolism in murine steatohepatitis

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