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Inducible Systemic Gcn1 Deletion in Mice Leads to Transient Body Weight Loss upon Tamoxifen Treatment Associated with Decrease of Fat and Liver Glycogen Storage

GCN1 is an evolutionarily-conserved ribosome-binding protein that mediates the amino acid starvation response as well as the ribotoxic stress response. We previously demonstrated that Gcn1 mutant mice lacking the GCN2-binding domain suffer from growth retardation and postnatal lethality via GCN2-ind...

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Autores principales: Liu, Jun, Kasai, Shuya, Tatara, Yota, Yamazaki, Hiromi, Mimura, Junsei, Mizuno, Seiya, Sugiyama, Fumihiro, Takahashi, Satoru, Sato, Tsubasa, Ozaki, Taku, Tanji, Kunikazu, Wakabayashi, Koichi, Maeda, Hayato, Mizukami, Hiroki, Shinkai, Yasuhiro, Kumagai, Yoshito, Tomita, Hirofumi, Itoh, Ken
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8949040/
https://www.ncbi.nlm.nih.gov/pubmed/35328622
http://dx.doi.org/10.3390/ijms23063201
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author Liu, Jun
Kasai, Shuya
Tatara, Yota
Yamazaki, Hiromi
Mimura, Junsei
Mizuno, Seiya
Sugiyama, Fumihiro
Takahashi, Satoru
Sato, Tsubasa
Ozaki, Taku
Tanji, Kunikazu
Wakabayashi, Koichi
Maeda, Hayato
Mizukami, Hiroki
Shinkai, Yasuhiro
Kumagai, Yoshito
Tomita, Hirofumi
Itoh, Ken
author_facet Liu, Jun
Kasai, Shuya
Tatara, Yota
Yamazaki, Hiromi
Mimura, Junsei
Mizuno, Seiya
Sugiyama, Fumihiro
Takahashi, Satoru
Sato, Tsubasa
Ozaki, Taku
Tanji, Kunikazu
Wakabayashi, Koichi
Maeda, Hayato
Mizukami, Hiroki
Shinkai, Yasuhiro
Kumagai, Yoshito
Tomita, Hirofumi
Itoh, Ken
author_sort Liu, Jun
collection PubMed
description GCN1 is an evolutionarily-conserved ribosome-binding protein that mediates the amino acid starvation response as well as the ribotoxic stress response. We previously demonstrated that Gcn1 mutant mice lacking the GCN2-binding domain suffer from growth retardation and postnatal lethality via GCN2-independent mechanisms, while Gcn1-null mice die early in embryonic development. In this study, we explored the role of GCN1 in adult mice by generating tamoxifen-inducible conditional knockout (CKO) mice. Unexpectedly, the Gcn1 CKO mice showed body weight loss during tamoxifen treatment, which gradually recovered following its cessation. They also showed decreases in liver weight, hepatic glycogen and lipid contents, blood glucose and non-esterified fatty acids, and visceral white adipose tissue weight with no changes in food intake and viability. A decrease of serum VLDL suggested that hepatic lipid supply to the peripheral tissues was primarily impaired. Liver proteomic analysis revealed the downregulation of mitochondrial β-oxidation that accompanied increases of peroxisomal β-oxidation and aerobic glucose catabolism that maintain ATP levels. These findings show the involvement of GCN1 in hepatic lipid metabolism during tamoxifen treatment in adult mice.
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spelling pubmed-89490402022-03-26 Inducible Systemic Gcn1 Deletion in Mice Leads to Transient Body Weight Loss upon Tamoxifen Treatment Associated with Decrease of Fat and Liver Glycogen Storage Liu, Jun Kasai, Shuya Tatara, Yota Yamazaki, Hiromi Mimura, Junsei Mizuno, Seiya Sugiyama, Fumihiro Takahashi, Satoru Sato, Tsubasa Ozaki, Taku Tanji, Kunikazu Wakabayashi, Koichi Maeda, Hayato Mizukami, Hiroki Shinkai, Yasuhiro Kumagai, Yoshito Tomita, Hirofumi Itoh, Ken Int J Mol Sci Article GCN1 is an evolutionarily-conserved ribosome-binding protein that mediates the amino acid starvation response as well as the ribotoxic stress response. We previously demonstrated that Gcn1 mutant mice lacking the GCN2-binding domain suffer from growth retardation and postnatal lethality via GCN2-independent mechanisms, while Gcn1-null mice die early in embryonic development. In this study, we explored the role of GCN1 in adult mice by generating tamoxifen-inducible conditional knockout (CKO) mice. Unexpectedly, the Gcn1 CKO mice showed body weight loss during tamoxifen treatment, which gradually recovered following its cessation. They also showed decreases in liver weight, hepatic glycogen and lipid contents, blood glucose and non-esterified fatty acids, and visceral white adipose tissue weight with no changes in food intake and viability. A decrease of serum VLDL suggested that hepatic lipid supply to the peripheral tissues was primarily impaired. Liver proteomic analysis revealed the downregulation of mitochondrial β-oxidation that accompanied increases of peroxisomal β-oxidation and aerobic glucose catabolism that maintain ATP levels. These findings show the involvement of GCN1 in hepatic lipid metabolism during tamoxifen treatment in adult mice. MDPI 2022-03-16 /pmc/articles/PMC8949040/ /pubmed/35328622 http://dx.doi.org/10.3390/ijms23063201 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Liu, Jun
Kasai, Shuya
Tatara, Yota
Yamazaki, Hiromi
Mimura, Junsei
Mizuno, Seiya
Sugiyama, Fumihiro
Takahashi, Satoru
Sato, Tsubasa
Ozaki, Taku
Tanji, Kunikazu
Wakabayashi, Koichi
Maeda, Hayato
Mizukami, Hiroki
Shinkai, Yasuhiro
Kumagai, Yoshito
Tomita, Hirofumi
Itoh, Ken
Inducible Systemic Gcn1 Deletion in Mice Leads to Transient Body Weight Loss upon Tamoxifen Treatment Associated with Decrease of Fat and Liver Glycogen Storage
title Inducible Systemic Gcn1 Deletion in Mice Leads to Transient Body Weight Loss upon Tamoxifen Treatment Associated with Decrease of Fat and Liver Glycogen Storage
title_full Inducible Systemic Gcn1 Deletion in Mice Leads to Transient Body Weight Loss upon Tamoxifen Treatment Associated with Decrease of Fat and Liver Glycogen Storage
title_fullStr Inducible Systemic Gcn1 Deletion in Mice Leads to Transient Body Weight Loss upon Tamoxifen Treatment Associated with Decrease of Fat and Liver Glycogen Storage
title_full_unstemmed Inducible Systemic Gcn1 Deletion in Mice Leads to Transient Body Weight Loss upon Tamoxifen Treatment Associated with Decrease of Fat and Liver Glycogen Storage
title_short Inducible Systemic Gcn1 Deletion in Mice Leads to Transient Body Weight Loss upon Tamoxifen Treatment Associated with Decrease of Fat and Liver Glycogen Storage
title_sort inducible systemic gcn1 deletion in mice leads to transient body weight loss upon tamoxifen treatment associated with decrease of fat and liver glycogen storage
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8949040/
https://www.ncbi.nlm.nih.gov/pubmed/35328622
http://dx.doi.org/10.3390/ijms23063201
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