Clodronate, an inhibitor of the vesicular nucleotide transporter, ameliorates steatohepatitis and acute liver injury

Abstract The vesicular nucleotide transporter (VNUT) is responsible for the vesicular storage and release of ATP from various ATP-secreting cells, and it plays an essential role in purinergic signaling. Although extracellular ATP and its degradation products are known to mediate various inflammatory...

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Autores principales:	Nao Hasuzawa, Keita Tatsushima, Lixiang Wang, Masaharu Kabashima, Rie Tokubuchi, Ayako Nagayama, Kenji Ashida, Yoshihiro Ogawa, Yoshinori Moriyama, Masatoshi Nomura
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/d3f14301c3c44d5685aab6724d28a090
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spelling	oai:doaj.org-article:d3f14301c3c44d5685aab6724d28a0902021-12-02T13:35:03ZClodronate, an inhibitor of the vesicular nucleotide transporter, ameliorates steatohepatitis and acute liver injury10.1038/s41598-021-83144-w2045-2322https://doaj.org/article/d3f14301c3c44d5685aab6724d28a0902021-03-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-83144-whttps://doaj.org/toc/2045-2322Abstract The vesicular nucleotide transporter (VNUT) is responsible for the vesicular storage and release of ATP from various ATP-secreting cells, and it plays an essential role in purinergic signaling. Although extracellular ATP and its degradation products are known to mediate various inflammatory responses via purinoceptors, whether vesicular ATP release affects steatohepatitis and acute liver injury is far less understood. In the present study, we investigated the effects of clodronate, a potent and selective VNUT inhibitor, on acute and chronic liver inflammation in mice. In a model of methionine/choline-deficient diet-induced non-alcoholic steatohepatitis (NASH), the administration of clodronate reduced hepatic inflammation, fibrosis, and triglyceride accumulation. Clodronate also protected mice against high-fat/high-cholesterol diet-induced steatohepatitis. Moreover, prophylactic administration of clodronate prevented d-galactosamine and lipopolysaccharide-induced acute liver injury by reducing inflammatory cytokines and hepatocellular apoptosis. In vitro, clodronate inhibited glucose-induced vesicular ATP release mediated by VNUT and reduced the intracellular level and secretion of triglycerides in isolated hepatocytes. These results suggest that VNUT-dependent vesicular ATP release plays a crucial role in the recruitment of immune cells, cytokine production, and the aggravation of steatosis in the liver. Pharmacological inhibition of VNUT may provide therapeutic benefits in liver inflammatory disorders, including NASH and acute toxin-induced injury.Nao HasuzawaKeita TatsushimaLixiang WangMasaharu KabashimaRie TokubuchiAyako NagayamaKenji AshidaYoshihiro OgawaYoshinori MoriyamaMasatoshi NomuraNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-13 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Nao Hasuzawa Keita Tatsushima Lixiang Wang Masaharu Kabashima Rie Tokubuchi Ayako Nagayama Kenji Ashida Yoshihiro Ogawa Yoshinori Moriyama Masatoshi Nomura Clodronate, an inhibitor of the vesicular nucleotide transporter, ameliorates steatohepatitis and acute liver injury
description	Abstract The vesicular nucleotide transporter (VNUT) is responsible for the vesicular storage and release of ATP from various ATP-secreting cells, and it plays an essential role in purinergic signaling. Although extracellular ATP and its degradation products are known to mediate various inflammatory responses via purinoceptors, whether vesicular ATP release affects steatohepatitis and acute liver injury is far less understood. In the present study, we investigated the effects of clodronate, a potent and selective VNUT inhibitor, on acute and chronic liver inflammation in mice. In a model of methionine/choline-deficient diet-induced non-alcoholic steatohepatitis (NASH), the administration of clodronate reduced hepatic inflammation, fibrosis, and triglyceride accumulation. Clodronate also protected mice against high-fat/high-cholesterol diet-induced steatohepatitis. Moreover, prophylactic administration of clodronate prevented d-galactosamine and lipopolysaccharide-induced acute liver injury by reducing inflammatory cytokines and hepatocellular apoptosis. In vitro, clodronate inhibited glucose-induced vesicular ATP release mediated by VNUT and reduced the intracellular level and secretion of triglycerides in isolated hepatocytes. These results suggest that VNUT-dependent vesicular ATP release plays a crucial role in the recruitment of immune cells, cytokine production, and the aggravation of steatosis in the liver. Pharmacological inhibition of VNUT may provide therapeutic benefits in liver inflammatory disorders, including NASH and acute toxin-induced injury.
format	article
author	Nao Hasuzawa Keita Tatsushima Lixiang Wang Masaharu Kabashima Rie Tokubuchi Ayako Nagayama Kenji Ashida Yoshihiro Ogawa Yoshinori Moriyama Masatoshi Nomura
author_facet	Nao Hasuzawa Keita Tatsushima Lixiang Wang Masaharu Kabashima Rie Tokubuchi Ayako Nagayama Kenji Ashida Yoshihiro Ogawa Yoshinori Moriyama Masatoshi Nomura
author_sort	Nao Hasuzawa
title	Clodronate, an inhibitor of the vesicular nucleotide transporter, ameliorates steatohepatitis and acute liver injury
title_short	Clodronate, an inhibitor of the vesicular nucleotide transporter, ameliorates steatohepatitis and acute liver injury
title_full	Clodronate, an inhibitor of the vesicular nucleotide transporter, ameliorates steatohepatitis and acute liver injury
title_fullStr	Clodronate, an inhibitor of the vesicular nucleotide transporter, ameliorates steatohepatitis and acute liver injury
title_full_unstemmed	Clodronate, an inhibitor of the vesicular nucleotide transporter, ameliorates steatohepatitis and acute liver injury
title_sort	clodronate, an inhibitor of the vesicular nucleotide transporter, ameliorates steatohepatitis and acute liver injury
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/d3f14301c3c44d5685aab6724d28a090
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Clodronate, an inhibitor of the vesicular nucleotide transporter, ameliorates steatohepatitis and acute liver injury

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