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Dysregulated hepatic lipid metabolism and gut microbiota associated with early-stage NAFLD in ASPP2-deficiency mice

BACKGROUND: Growing evidence indicates that lipid metabolism disorders and gut microbiota dysbiosis were related to the progression of non-alcoholic fatty liver disease (NAFLD). Apoptosis-stimulating p53 protein 2 (ASPP2) has been reported to protect against hepatocyte injury by regulating the lipid...

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Autores principales: Xie, Fang, Xu, Hang-fei, Zhang, Jing, Liu, Xiao-ni, Kou, Bu-xin, Cai, Meng-yin, Wu, Jing, Dong, Jin-ling, Meng, Qing-hua, Wang, Yi, Chen, Dexi, Zhang, Yang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9716097/
https://www.ncbi.nlm.nih.gov/pubmed/36466835
http://dx.doi.org/10.3389/fimmu.2022.974872
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author Xie, Fang
Xu, Hang-fei
Zhang, Jing
Liu, Xiao-ni
Kou, Bu-xin
Cai, Meng-yin
Wu, Jing
Dong, Jin-ling
Meng, Qing-hua
Wang, Yi
Chen, Dexi
Zhang, Yang
author_facet Xie, Fang
Xu, Hang-fei
Zhang, Jing
Liu, Xiao-ni
Kou, Bu-xin
Cai, Meng-yin
Wu, Jing
Dong, Jin-ling
Meng, Qing-hua
Wang, Yi
Chen, Dexi
Zhang, Yang
author_sort Xie, Fang
collection PubMed
description BACKGROUND: Growing evidence indicates that lipid metabolism disorders and gut microbiota dysbiosis were related to the progression of non-alcoholic fatty liver disease (NAFLD). Apoptosis-stimulating p53 protein 2 (ASPP2) has been reported to protect against hepatocyte injury by regulating the lipid metabolism, but the mechanisms remain largely unknown. In this study, we investigate the effect of ASPP2 deficiency on NAFLD, lipid metabolism and gut microbiota using ASPP2 globally heterozygous knockout (ASPP2(+/-)) mice. METHODS: ASPP2(+/-) Balb/c mice were fed with methionine and choline deficient diet for 3, 10 and 40 day to induce an early and later-stage of NAFLD, respectively. Fresh fecal samples were collected and followed by 16S rRNA sequencing. HPLC-MRM relative quantification analysis was used to identify changes in hepatic lipid profiles. The expression level of innate immunity-, lipid metabolism- and intestinal permeability-related genes were determined. A spearman’s rank correlation analysis was performed to identify possible correlation between hepatic medium and long-chain fatty acid and gut microbiota in ASPP2-deficiency mice. RESULTS: Compared with the WT control, ASPP2-deficiency mice developed moderate steatosis at day 10 and severe steatosis at day 40. The levels of hepatic long chain omega-3 fatty acid, eicosapentaenoic (EPA, 20:5 n-3) and docosahexaenoic (DHA, 22:6 n-3), were decreased at day 10 and increased at day 40 in ASPP(+/-) mice. Fecal microbiota analysis showed significantly increased alpha and beta diversity, as well as the composition of gut microbiota at the phylum, class, order, family, genus, species levels in ASPP2(+/-) mice. Moreover, ASPP-deficiency mice exhibited impaired intestinal barrier function, reduced expression of genes associated with chemical barrier (REG3B, REG3G, Lysozyme and IAP), and increased expression of innate immune components (TLR4 and TLR2). Furthermore, correlation analysis between gut microbiota and fatty acids revealed that EPA was significantly negatively correlated with Bifidobacterium family. CONCLUSION: Our findings suggested that ASPP2-deficiency promotes the progression of NAFLD, alterations in fatty acid metabolism and gut microbiota dysbiosis. The long chain fatty acid EPA was significantly negatively correlated with Bifidobacterial abundance, which is a specific feature of NAFLD in ASPP2-deficiency mice. Totally, the results provide evidence for a mechanism of ASPP2 on dysregulation of fatty acid metabolism and gut microbiota dysbiosis.
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spelling pubmed-97160972022-12-03 Dysregulated hepatic lipid metabolism and gut microbiota associated with early-stage NAFLD in ASPP2-deficiency mice Xie, Fang Xu, Hang-fei Zhang, Jing Liu, Xiao-ni Kou, Bu-xin Cai, Meng-yin Wu, Jing Dong, Jin-ling Meng, Qing-hua Wang, Yi Chen, Dexi Zhang, Yang Front Immunol Immunology BACKGROUND: Growing evidence indicates that lipid metabolism disorders and gut microbiota dysbiosis were related to the progression of non-alcoholic fatty liver disease (NAFLD). Apoptosis-stimulating p53 protein 2 (ASPP2) has been reported to protect against hepatocyte injury by regulating the lipid metabolism, but the mechanisms remain largely unknown. In this study, we investigate the effect of ASPP2 deficiency on NAFLD, lipid metabolism and gut microbiota using ASPP2 globally heterozygous knockout (ASPP2(+/-)) mice. METHODS: ASPP2(+/-) Balb/c mice were fed with methionine and choline deficient diet for 3, 10 and 40 day to induce an early and later-stage of NAFLD, respectively. Fresh fecal samples were collected and followed by 16S rRNA sequencing. HPLC-MRM relative quantification analysis was used to identify changes in hepatic lipid profiles. The expression level of innate immunity-, lipid metabolism- and intestinal permeability-related genes were determined. A spearman’s rank correlation analysis was performed to identify possible correlation between hepatic medium and long-chain fatty acid and gut microbiota in ASPP2-deficiency mice. RESULTS: Compared with the WT control, ASPP2-deficiency mice developed moderate steatosis at day 10 and severe steatosis at day 40. The levels of hepatic long chain omega-3 fatty acid, eicosapentaenoic (EPA, 20:5 n-3) and docosahexaenoic (DHA, 22:6 n-3), were decreased at day 10 and increased at day 40 in ASPP(+/-) mice. Fecal microbiota analysis showed significantly increased alpha and beta diversity, as well as the composition of gut microbiota at the phylum, class, order, family, genus, species levels in ASPP2(+/-) mice. Moreover, ASPP-deficiency mice exhibited impaired intestinal barrier function, reduced expression of genes associated with chemical barrier (REG3B, REG3G, Lysozyme and IAP), and increased expression of innate immune components (TLR4 and TLR2). Furthermore, correlation analysis between gut microbiota and fatty acids revealed that EPA was significantly negatively correlated with Bifidobacterium family. CONCLUSION: Our findings suggested that ASPP2-deficiency promotes the progression of NAFLD, alterations in fatty acid metabolism and gut microbiota dysbiosis. The long chain fatty acid EPA was significantly negatively correlated with Bifidobacterial abundance, which is a specific feature of NAFLD in ASPP2-deficiency mice. Totally, the results provide evidence for a mechanism of ASPP2 on dysregulation of fatty acid metabolism and gut microbiota dysbiosis. Frontiers Media S.A. 2022-11-18 /pmc/articles/PMC9716097/ /pubmed/36466835 http://dx.doi.org/10.3389/fimmu.2022.974872 Text en Copyright © 2022 Xie, Xu, Zhang, Liu, Kou, Cai, Wu, Dong, Meng, Wang, Chen and Zhang https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Xie, Fang
Xu, Hang-fei
Zhang, Jing
Liu, Xiao-ni
Kou, Bu-xin
Cai, Meng-yin
Wu, Jing
Dong, Jin-ling
Meng, Qing-hua
Wang, Yi
Chen, Dexi
Zhang, Yang
Dysregulated hepatic lipid metabolism and gut microbiota associated with early-stage NAFLD in ASPP2-deficiency mice
title Dysregulated hepatic lipid metabolism and gut microbiota associated with early-stage NAFLD in ASPP2-deficiency mice
title_full Dysregulated hepatic lipid metabolism and gut microbiota associated with early-stage NAFLD in ASPP2-deficiency mice
title_fullStr Dysregulated hepatic lipid metabolism and gut microbiota associated with early-stage NAFLD in ASPP2-deficiency mice
title_full_unstemmed Dysregulated hepatic lipid metabolism and gut microbiota associated with early-stage NAFLD in ASPP2-deficiency mice
title_short Dysregulated hepatic lipid metabolism and gut microbiota associated with early-stage NAFLD in ASPP2-deficiency mice
title_sort dysregulated hepatic lipid metabolism and gut microbiota associated with early-stage nafld in aspp2-deficiency mice
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9716097/
https://www.ncbi.nlm.nih.gov/pubmed/36466835
http://dx.doi.org/10.3389/fimmu.2022.974872
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