Albino mice with the point mutation at the tyrosinase locus show high cholesterol diet-induced NASH susceptibility

Abstract Non-alcoholic fatty liver disease (NAFLD) constitutes a metabolic disorder with high worldwide prevalence and increasing incidence. The inflammatory progressive state, non-alcoholic steatohepatitis (NASH), leads to liver fibrosis and carcinogenesis. Here, we evaluated whether tyrosinase mut...

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Autores principales:	Kaushalya Kulathunga, Arata Wakimoto, Yukiko Hiraishi, Manoj Kumar Yadav, Kyle Gentleman, Eiji Warabi, Tomoki Sakasai, Yoshihiro Miwa, Seiya Mizuno, Satoru Takahashi, Michito Hamada
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/1e3d06d303874791b7d8c5107ec033d1
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spelling	oai:doaj.org-article:1e3d06d303874791b7d8c5107ec033d12021-11-14T12:22:10ZAlbino mice with the point mutation at the tyrosinase locus show high cholesterol diet-induced NASH susceptibility10.1038/s41598-021-00501-52045-2322https://doaj.org/article/1e3d06d303874791b7d8c5107ec033d12021-11-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-00501-5https://doaj.org/toc/2045-2322Abstract Non-alcoholic fatty liver disease (NAFLD) constitutes a metabolic disorder with high worldwide prevalence and increasing incidence. The inflammatory progressive state, non-alcoholic steatohepatitis (NASH), leads to liver fibrosis and carcinogenesis. Here, we evaluated whether tyrosinase mutation underlies NASH pathophysiology. Tyrosinase point-mutated B6 (Cg)-Tyr c-2J /J mice (B6 albino) and C57BL/6J black mice (B6 black) were fed with high cholesterol diet (HCD) for 10 weeks. Normal diet-fed mice served as controls. HCD-fed B6 albino exhibited high NASH susceptibility compared to B6 black, a phenotype not previously reported. Liver injury occurred in approximately 50% of B6 albino from one post HCD feeding, with elevated serum alanine aminotransferase and aspartate aminotransferase levels. NASH was induced following 2 weeks in severe-phenotypic B6 albino (sB6), but B6 black exhibited no symptoms, even after 10 weeks. HCD-fed sB6 albino showed significantly higher mortality rate. Histological analysis of the liver revealed significant inflammatory cell and lipid infiltration and severe fibrosis. Serum lipoprotein analysis revealed significantly higher chylomicron and very low-density lipoprotein levels in sB6 albino. Moreover, significantly higher small intestinal lipid absorption and lower fecal lipid excretion occurred together with elevated intestinal NPC1L1 expression. As the tyrosinase point mutation represents the only genetic difference between B6 albino and B6 black, our work will facilitate the identification of susceptible genetic factors for NASH development and expand the understanding of NASH pathophysiology.Kaushalya KulathungaArata WakimotoYukiko HiraishiManoj Kumar YadavKyle GentlemanEiji WarabiTomoki SakasaiYoshihiro MiwaSeiya MizunoSatoru TakahashiMichito HamadaNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-11 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Kaushalya Kulathunga Arata Wakimoto Yukiko Hiraishi Manoj Kumar Yadav Kyle Gentleman Eiji Warabi Tomoki Sakasai Yoshihiro Miwa Seiya Mizuno Satoru Takahashi Michito Hamada Albino mice with the point mutation at the tyrosinase locus show high cholesterol diet-induced NASH susceptibility
description	Abstract Non-alcoholic fatty liver disease (NAFLD) constitutes a metabolic disorder with high worldwide prevalence and increasing incidence. The inflammatory progressive state, non-alcoholic steatohepatitis (NASH), leads to liver fibrosis and carcinogenesis. Here, we evaluated whether tyrosinase mutation underlies NASH pathophysiology. Tyrosinase point-mutated B6 (Cg)-Tyr c-2J /J mice (B6 albino) and C57BL/6J black mice (B6 black) were fed with high cholesterol diet (HCD) for 10 weeks. Normal diet-fed mice served as controls. HCD-fed B6 albino exhibited high NASH susceptibility compared to B6 black, a phenotype not previously reported. Liver injury occurred in approximately 50% of B6 albino from one post HCD feeding, with elevated serum alanine aminotransferase and aspartate aminotransferase levels. NASH was induced following 2 weeks in severe-phenotypic B6 albino (sB6), but B6 black exhibited no symptoms, even after 10 weeks. HCD-fed sB6 albino showed significantly higher mortality rate. Histological analysis of the liver revealed significant inflammatory cell and lipid infiltration and severe fibrosis. Serum lipoprotein analysis revealed significantly higher chylomicron and very low-density lipoprotein levels in sB6 albino. Moreover, significantly higher small intestinal lipid absorption and lower fecal lipid excretion occurred together with elevated intestinal NPC1L1 expression. As the tyrosinase point mutation represents the only genetic difference between B6 albino and B6 black, our work will facilitate the identification of susceptible genetic factors for NASH development and expand the understanding of NASH pathophysiology.
format	article
author	Kaushalya Kulathunga Arata Wakimoto Yukiko Hiraishi Manoj Kumar Yadav Kyle Gentleman Eiji Warabi Tomoki Sakasai Yoshihiro Miwa Seiya Mizuno Satoru Takahashi Michito Hamada
author_facet	Kaushalya Kulathunga Arata Wakimoto Yukiko Hiraishi Manoj Kumar Yadav Kyle Gentleman Eiji Warabi Tomoki Sakasai Yoshihiro Miwa Seiya Mizuno Satoru Takahashi Michito Hamada
author_sort	Kaushalya Kulathunga
title	Albino mice with the point mutation at the tyrosinase locus show high cholesterol diet-induced NASH susceptibility
title_short	Albino mice with the point mutation at the tyrosinase locus show high cholesterol diet-induced NASH susceptibility
title_full	Albino mice with the point mutation at the tyrosinase locus show high cholesterol diet-induced NASH susceptibility
title_fullStr	Albino mice with the point mutation at the tyrosinase locus show high cholesterol diet-induced NASH susceptibility
title_full_unstemmed	Albino mice with the point mutation at the tyrosinase locus show high cholesterol diet-induced NASH susceptibility
title_sort	albino mice with the point mutation at the tyrosinase locus show high cholesterol diet-induced nash susceptibility
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/1e3d06d303874791b7d8c5107ec033d1
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Albino mice with the point mutation at the tyrosinase locus show high cholesterol diet-induced NASH susceptibility

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