Estimating Drug Efficacy with a Diet-Induced NASH Model in Chimeric Mice with Humanized Livers

Nonalcoholic fatty liver disease/steatohepatitis (NAFLD/NASH) is the most common liver disorder in developed countries. Although many new therapeutics for NASH are present in the drug development pipeline, there are still no approved drugs. One of the reasons that makes NASH drug development challen...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Keishi Kisoh, Go Sugahara, Yuko Ogawa, Suzue Furukawa, Yuji Ishida, Takeshi Okanoue, Michinori Kohara, Chise Tateno
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	human liver chimeric mice NAFLD/NASH ballooning hepatocytes Mallory–Denk body human disease animal model Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/65006a448cac4620b052520da4f8a0a4
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:65006a448cac4620b052520da4f8a0a4
record_format	dspace
spelling	oai:doaj.org-article:65006a448cac4620b052520da4f8a0a42021-11-25T16:50:07ZEstimating Drug Efficacy with a Diet-Induced NASH Model in Chimeric Mice with Humanized Livers10.3390/biomedicines91116472227-9059https://doaj.org/article/65006a448cac4620b052520da4f8a0a42021-11-01T00:00:00Zhttps://www.mdpi.com/2227-9059/9/11/1647https://doaj.org/toc/2227-9059Nonalcoholic fatty liver disease/steatohepatitis (NAFLD/NASH) is the most common liver disorder in developed countries. Although many new therapeutics for NASH are present in the drug development pipeline, there are still no approved drugs. One of the reasons that makes NASH drug development challenging is the lack of appropriate animal NASH models that resolve issues arising from inter-species differences between humans and rodents. In the present study, we developed a choline-deficient, L-amino-acid-defined, high-fat-diet (CDAHFD)-induced human NASH model using human liver chimeric mice. We demonstrated human hepatocyte injury by an elevation of plasma human alanine aminotransferase 1 in mice fed CDAHFD. Histological analysis showed that CDAHFD feeding induced similar histological changes to human NASH patients, including ballooning, inflammation, apoptosis, regeneration of human hepatocytes, and pericellular and perisinusoidal fibrosis. The chimeric mice fed CDAHFD were treated with a peroxisome-proliferator-activated receptor α/δ agonist, Elafibranor. Elafibranor ameliorated steatosis, ballooning of hepatocytes, and preserved fibrosis progression. We developed a novel humanized NASH model that can elucidate pathophysiological mechanisms and predict therapeutic efficacy in human NASH. This model will be useful in exploring new drugs and biomarkers in the early stages of human NASH.Keishi KisohGo SugaharaYuko OgawaSuzue FurukawaYuji IshidaTakeshi OkanoueMichinori KoharaChise TatenoMDPI AGarticlehuman liver chimeric miceNAFLD/NASHballooning hepatocytesMallory–Denk bodyhuman disease animal modelBiology (General)QH301-705.5ENBiomedicines, Vol 9, Iss 1647, p 1647 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	human liver chimeric mice NAFLD/NASH ballooning hepatocytes Mallory–Denk body human disease animal model Biology (General) QH301-705.5
spellingShingle	human liver chimeric mice NAFLD/NASH ballooning hepatocytes Mallory–Denk body human disease animal model Biology (General) QH301-705.5 Keishi Kisoh Go Sugahara Yuko Ogawa Suzue Furukawa Yuji Ishida Takeshi Okanoue Michinori Kohara Chise Tateno Estimating Drug Efficacy with a Diet-Induced NASH Model in Chimeric Mice with Humanized Livers
description	Nonalcoholic fatty liver disease/steatohepatitis (NAFLD/NASH) is the most common liver disorder in developed countries. Although many new therapeutics for NASH are present in the drug development pipeline, there are still no approved drugs. One of the reasons that makes NASH drug development challenging is the lack of appropriate animal NASH models that resolve issues arising from inter-species differences between humans and rodents. In the present study, we developed a choline-deficient, L-amino-acid-defined, high-fat-diet (CDAHFD)-induced human NASH model using human liver chimeric mice. We demonstrated human hepatocyte injury by an elevation of plasma human alanine aminotransferase 1 in mice fed CDAHFD. Histological analysis showed that CDAHFD feeding induced similar histological changes to human NASH patients, including ballooning, inflammation, apoptosis, regeneration of human hepatocytes, and pericellular and perisinusoidal fibrosis. The chimeric mice fed CDAHFD were treated with a peroxisome-proliferator-activated receptor α/δ agonist, Elafibranor. Elafibranor ameliorated steatosis, ballooning of hepatocytes, and preserved fibrosis progression. We developed a novel humanized NASH model that can elucidate pathophysiological mechanisms and predict therapeutic efficacy in human NASH. This model will be useful in exploring new drugs and biomarkers in the early stages of human NASH.
format	article
author	Keishi Kisoh Go Sugahara Yuko Ogawa Suzue Furukawa Yuji Ishida Takeshi Okanoue Michinori Kohara Chise Tateno
author_facet	Keishi Kisoh Go Sugahara Yuko Ogawa Suzue Furukawa Yuji Ishida Takeshi Okanoue Michinori Kohara Chise Tateno
author_sort	Keishi Kisoh
title	Estimating Drug Efficacy with a Diet-Induced NASH Model in Chimeric Mice with Humanized Livers
title_short	Estimating Drug Efficacy with a Diet-Induced NASH Model in Chimeric Mice with Humanized Livers
title_full	Estimating Drug Efficacy with a Diet-Induced NASH Model in Chimeric Mice with Humanized Livers
title_fullStr	Estimating Drug Efficacy with a Diet-Induced NASH Model in Chimeric Mice with Humanized Livers
title_full_unstemmed	Estimating Drug Efficacy with a Diet-Induced NASH Model in Chimeric Mice with Humanized Livers
title_sort	estimating drug efficacy with a diet-induced nash model in chimeric mice with humanized livers
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/65006a448cac4620b052520da4f8a0a4
work_keys_str_mv	AT keishikisoh estimatingdrugefficacywithadietinducednashmodelinchimericmicewithhumanizedlivers AT gosugahara estimatingdrugefficacywithadietinducednashmodelinchimericmicewithhumanizedlivers AT yukoogawa estimatingdrugefficacywithadietinducednashmodelinchimericmicewithhumanizedlivers AT suzuefurukawa estimatingdrugefficacywithadietinducednashmodelinchimericmicewithhumanizedlivers AT yujiishida estimatingdrugefficacywithadietinducednashmodelinchimericmicewithhumanizedlivers AT takeshiokanoue estimatingdrugefficacywithadietinducednashmodelinchimericmicewithhumanizedlivers AT michinorikohara estimatingdrugefficacywithadietinducednashmodelinchimericmicewithhumanizedlivers AT chisetateno estimatingdrugefficacywithadietinducednashmodelinchimericmicewithhumanizedlivers
_version_	1718412900136124416

Estimating Drug Efficacy with a Diet-Induced NASH Model in Chimeric Mice with Humanized Livers

Ejemplares similares