Molecular and histological traits of reduced lysosomal acid lipase activity in the fatty liver

Abstract Recent studies demonstrated reduced blood lysosomal acid lipase (LAL) activity in patients with nonalcoholic fatty liver disease (NAFLD). We aimed to verify hepatic LAL protein content and activity in in vitro and in vivo models of fat overload and in NAFLD patients. LAL protein content and...

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Autores principales:	Simone Carotti, Daniele Lettieri-Barbato, Fiorella Piemonte, Sergio Ruggiero, Marco Rosina, Francesca Zalfa, Maria Zingariello, Francesca Arciprete, Francesco Valentini, Maria Francesconi, Jessica D’Amico, Antonio De Vincentis, Andrea Baiocchini, Giuseppe Perrone, Raffaele Antonelli-Incalzi, Sergio Morini, Antonio Picardi, Katia Aquilano, Umberto Vespasiani-Gentilucci
Formato:	article
Lenguaje:	EN
Publicado:	Nature Publishing Group 2021
Materias:	Cytology QH573-671
Acceso en línea:	https://doaj.org/article/d2687a261333480896347537214e9a61
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spelling	oai:doaj.org-article:d2687a261333480896347537214e9a612021-11-21T12:03:29ZMolecular and histological traits of reduced lysosomal acid lipase activity in the fatty liver10.1038/s41419-021-04382-42041-4889https://doaj.org/article/d2687a261333480896347537214e9a612021-11-01T00:00:00Zhttps://doi.org/10.1038/s41419-021-04382-4https://doaj.org/toc/2041-4889Abstract Recent studies demonstrated reduced blood lysosomal acid lipase (LAL) activity in patients with nonalcoholic fatty liver disease (NAFLD). We aimed to verify hepatic LAL protein content and activity in in vitro and in vivo models of fat overload and in NAFLD patients. LAL protein content and activity were firstly evaluated in Huh7 cells exposed to high-glucose/high-lipid (HGHL) medium and in the liver of C57BL/6 mice fed with high-fat diet (HFD) for 4 and 8 months. LAL protein was also evaluated by immunohistochemistry in liver biopsies from 87 NAFLD patients and 10 controls, and correlated with hepatic histology. Huh7 cells treated with HGHL medium showed a significant reduction of LAL activity, which was consistent with reduced LAL protein levels by western blotting using an antibody towards the N-term of the enzyme. Conversely, antibodies towards the C-term of the enzyme evidenced LAL accumulation, suggesting a post-translational modification that masks the LAL N-term epitope and affects enzymatic activity. Indeed, we found a high rate of ubiquitination and extra-lysosomal localization of LAL protein in cells treated with HGHL medium. Consistent with these findings, inhibition of proteasome triggered dysfunctional LAL accumulation and affected LAL activity. Accumulation of ubiquitinated/dysfunctional LAL was also found in the liver of HFD fed mice. In NAFLD patients, hepatic levels of non-ubiquitinated/functional LAL were lower than in controls and inversely correlated with disease activity and some of the hallmarks of reduced LAL. Fat overload leads to LAL ubiquitination and impairs its function, possibly reducing hepatic fat disposal and promoting NAFLD activity.Simone CarottiDaniele Lettieri-BarbatoFiorella PiemonteSergio RuggieroMarco RosinaFrancesca ZalfaMaria ZingarielloFrancesca ArcipreteFrancesco ValentiniMaria FrancesconiJessica D’AmicoAntonio De VincentisAndrea BaiocchiniGiuseppe PerroneRaffaele Antonelli-IncalziSergio MoriniAntonio PicardiKatia AquilanoUmberto Vespasiani-GentilucciNature Publishing GrouparticleCytologyQH573-671ENCell Death and Disease, Vol 12, Iss 12, Pp 1-10 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Cytology QH573-671
spellingShingle	Cytology QH573-671 Simone Carotti Daniele Lettieri-Barbato Fiorella Piemonte Sergio Ruggiero Marco Rosina Francesca Zalfa Maria Zingariello Francesca Arciprete Francesco Valentini Maria Francesconi Jessica D’Amico Antonio De Vincentis Andrea Baiocchini Giuseppe Perrone Raffaele Antonelli-Incalzi Sergio Morini Antonio Picardi Katia Aquilano Umberto Vespasiani-Gentilucci Molecular and histological traits of reduced lysosomal acid lipase activity in the fatty liver
description	Abstract Recent studies demonstrated reduced blood lysosomal acid lipase (LAL) activity in patients with nonalcoholic fatty liver disease (NAFLD). We aimed to verify hepatic LAL protein content and activity in in vitro and in vivo models of fat overload and in NAFLD patients. LAL protein content and activity were firstly evaluated in Huh7 cells exposed to high-glucose/high-lipid (HGHL) medium and in the liver of C57BL/6 mice fed with high-fat diet (HFD) for 4 and 8 months. LAL protein was also evaluated by immunohistochemistry in liver biopsies from 87 NAFLD patients and 10 controls, and correlated with hepatic histology. Huh7 cells treated with HGHL medium showed a significant reduction of LAL activity, which was consistent with reduced LAL protein levels by western blotting using an antibody towards the N-term of the enzyme. Conversely, antibodies towards the C-term of the enzyme evidenced LAL accumulation, suggesting a post-translational modification that masks the LAL N-term epitope and affects enzymatic activity. Indeed, we found a high rate of ubiquitination and extra-lysosomal localization of LAL protein in cells treated with HGHL medium. Consistent with these findings, inhibition of proteasome triggered dysfunctional LAL accumulation and affected LAL activity. Accumulation of ubiquitinated/dysfunctional LAL was also found in the liver of HFD fed mice. In NAFLD patients, hepatic levels of non-ubiquitinated/functional LAL were lower than in controls and inversely correlated with disease activity and some of the hallmarks of reduced LAL. Fat overload leads to LAL ubiquitination and impairs its function, possibly reducing hepatic fat disposal and promoting NAFLD activity.
format	article
author	Simone Carotti Daniele Lettieri-Barbato Fiorella Piemonte Sergio Ruggiero Marco Rosina Francesca Zalfa Maria Zingariello Francesca Arciprete Francesco Valentini Maria Francesconi Jessica D’Amico Antonio De Vincentis Andrea Baiocchini Giuseppe Perrone Raffaele Antonelli-Incalzi Sergio Morini Antonio Picardi Katia Aquilano Umberto Vespasiani-Gentilucci
author_facet	Simone Carotti Daniele Lettieri-Barbato Fiorella Piemonte Sergio Ruggiero Marco Rosina Francesca Zalfa Maria Zingariello Francesca Arciprete Francesco Valentini Maria Francesconi Jessica D’Amico Antonio De Vincentis Andrea Baiocchini Giuseppe Perrone Raffaele Antonelli-Incalzi Sergio Morini Antonio Picardi Katia Aquilano Umberto Vespasiani-Gentilucci
author_sort	Simone Carotti
title	Molecular and histological traits of reduced lysosomal acid lipase activity in the fatty liver
title_short	Molecular and histological traits of reduced lysosomal acid lipase activity in the fatty liver
title_full	Molecular and histological traits of reduced lysosomal acid lipase activity in the fatty liver
title_fullStr	Molecular and histological traits of reduced lysosomal acid lipase activity in the fatty liver
title_full_unstemmed	Molecular and histological traits of reduced lysosomal acid lipase activity in the fatty liver
title_sort	molecular and histological traits of reduced lysosomal acid lipase activity in the fatty liver
publisher	Nature Publishing Group
publishDate	2021
url	https://doaj.org/article/d2687a261333480896347537214e9a61
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Molecular and histological traits of reduced lysosomal acid lipase activity in the fatty liver

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