Cargando…

SIRT5 deacylates metabolism-related proteins and attenuates hepatic steatosis in ob/ob mice

BACKGROUND: Sirtuin 5 (SIRT5) is a NAD(+)-dependent lysine deacylase. The SIRT5 deficiency mouse model shows that it is dispensable for metabolic homeostasis under normal conditions. However, the biological role of SIRT5 and acylation in pathological states such as obesity and type 2 diabetes (T2D)...

Descripción completa

Detalles Bibliográficos
Autores principales: Du, Yipeng, Hu, Hao, Qu, Saisi, Wang, Jifeng, Hua, Chaoju, Zhang, Jialing, Wei, Peng, He, Xiaolong, Hao, Junfeng, Liu, Pingsheng, Yang, Fuquan, Li, Tingting, Wei, Taotao
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6197389/
https://www.ncbi.nlm.nih.gov/pubmed/30279144
http://dx.doi.org/10.1016/j.ebiom.2018.09.037
_version_ 1783364756613103616
author Du, Yipeng
Hu, Hao
Qu, Saisi
Wang, Jifeng
Hua, Chaoju
Zhang, Jialing
Wei, Peng
He, Xiaolong
Hao, Junfeng
Liu, Pingsheng
Yang, Fuquan
Li, Tingting
Wei, Taotao
author_facet Du, Yipeng
Hu, Hao
Qu, Saisi
Wang, Jifeng
Hua, Chaoju
Zhang, Jialing
Wei, Peng
He, Xiaolong
Hao, Junfeng
Liu, Pingsheng
Yang, Fuquan
Li, Tingting
Wei, Taotao
author_sort Du, Yipeng
collection PubMed
description BACKGROUND: Sirtuin 5 (SIRT5) is a NAD(+)-dependent lysine deacylase. The SIRT5 deficiency mouse model shows that it is dispensable for metabolic homeostasis under normal conditions. However, the biological role of SIRT5 and acylation in pathological states such as obesity and type 2 diabetes (T2D) remains elusive. METHODS: The hepatic SIRT5-overexpressing ob/ob mouse model (ob/ob-SIRT5 OE) was established by CRISPR/Cas9 gene editing tool Protein malonylation and succinylation lysine sites were identified by immunoprecipitation coupled lipid chromatography - tandem mass spectrometry (LC-MS/MS) methods. FINDINGS: The ob/ob-SIRT5 OE mice showed decreased malonylation and succinylation, improved cellular glycolysis, suppressed gluconeogenesis, enhanced fatty acid oxidation, and attenuated hepatic steatosis. A total of 955 malonylation sites on 434 proteins and 1377 succinylation sites on 429 proteins were identified and quantitated. Bioinformatics analysis revealed that malonylation was the major SIRT5 target in the glycolysis/gluconeogenesis pathway, whereas succinylation was the preferred SIRT5 target in the oxidative phosphorylation pathway. INTERPRETATION: Hepatic overexpression of SIRT5 ameliorated the metabolic abnormalities of ob/ob mice, probably through demalonylating and desuccinylating proteins in the main metabolic pathways. SIRT5 and related acylation might be potential targets for metabolic disorders. FUND: National Key R&D Program of China, the National Natural Science Foundation of China, the Strategic Priority Research Programs (Category A) of the Chinese Academy of Sciences, the Interdisciplinary Medicine Seed Fund of Peking University and the National Laboratory of Biomacromolecules.
format Online
Article
Text
id pubmed-6197389
institution National Center for Biotechnology Information
language English
publishDate 2018
publisher Elsevier
record_format MEDLINE/PubMed
spelling pubmed-61973892018-10-24 SIRT5 deacylates metabolism-related proteins and attenuates hepatic steatosis in ob/ob mice Du, Yipeng Hu, Hao Qu, Saisi Wang, Jifeng Hua, Chaoju Zhang, Jialing Wei, Peng He, Xiaolong Hao, Junfeng Liu, Pingsheng Yang, Fuquan Li, Tingting Wei, Taotao EBioMedicine Research paper BACKGROUND: Sirtuin 5 (SIRT5) is a NAD(+)-dependent lysine deacylase. The SIRT5 deficiency mouse model shows that it is dispensable for metabolic homeostasis under normal conditions. However, the biological role of SIRT5 and acylation in pathological states such as obesity and type 2 diabetes (T2D) remains elusive. METHODS: The hepatic SIRT5-overexpressing ob/ob mouse model (ob/ob-SIRT5 OE) was established by CRISPR/Cas9 gene editing tool Protein malonylation and succinylation lysine sites were identified by immunoprecipitation coupled lipid chromatography - tandem mass spectrometry (LC-MS/MS) methods. FINDINGS: The ob/ob-SIRT5 OE mice showed decreased malonylation and succinylation, improved cellular glycolysis, suppressed gluconeogenesis, enhanced fatty acid oxidation, and attenuated hepatic steatosis. A total of 955 malonylation sites on 434 proteins and 1377 succinylation sites on 429 proteins were identified and quantitated. Bioinformatics analysis revealed that malonylation was the major SIRT5 target in the glycolysis/gluconeogenesis pathway, whereas succinylation was the preferred SIRT5 target in the oxidative phosphorylation pathway. INTERPRETATION: Hepatic overexpression of SIRT5 ameliorated the metabolic abnormalities of ob/ob mice, probably through demalonylating and desuccinylating proteins in the main metabolic pathways. SIRT5 and related acylation might be potential targets for metabolic disorders. FUND: National Key R&D Program of China, the National Natural Science Foundation of China, the Strategic Priority Research Programs (Category A) of the Chinese Academy of Sciences, the Interdisciplinary Medicine Seed Fund of Peking University and the National Laboratory of Biomacromolecules. Elsevier 2018-09-29 /pmc/articles/PMC6197389/ /pubmed/30279144 http://dx.doi.org/10.1016/j.ebiom.2018.09.037 Text en © 2018 The Authors http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Research paper
Du, Yipeng
Hu, Hao
Qu, Saisi
Wang, Jifeng
Hua, Chaoju
Zhang, Jialing
Wei, Peng
He, Xiaolong
Hao, Junfeng
Liu, Pingsheng
Yang, Fuquan
Li, Tingting
Wei, Taotao
SIRT5 deacylates metabolism-related proteins and attenuates hepatic steatosis in ob/ob mice
title SIRT5 deacylates metabolism-related proteins and attenuates hepatic steatosis in ob/ob mice
title_full SIRT5 deacylates metabolism-related proteins and attenuates hepatic steatosis in ob/ob mice
title_fullStr SIRT5 deacylates metabolism-related proteins and attenuates hepatic steatosis in ob/ob mice
title_full_unstemmed SIRT5 deacylates metabolism-related proteins and attenuates hepatic steatosis in ob/ob mice
title_short SIRT5 deacylates metabolism-related proteins and attenuates hepatic steatosis in ob/ob mice
title_sort sirt5 deacylates metabolism-related proteins and attenuates hepatic steatosis in ob/ob mice
topic Research paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6197389/
https://www.ncbi.nlm.nih.gov/pubmed/30279144
http://dx.doi.org/10.1016/j.ebiom.2018.09.037
work_keys_str_mv AT duyipeng sirt5deacylatesmetabolismrelatedproteinsandattenuateshepaticsteatosisinobobmice
AT huhao sirt5deacylatesmetabolismrelatedproteinsandattenuateshepaticsteatosisinobobmice
AT qusaisi sirt5deacylatesmetabolismrelatedproteinsandattenuateshepaticsteatosisinobobmice
AT wangjifeng sirt5deacylatesmetabolismrelatedproteinsandattenuateshepaticsteatosisinobobmice
AT huachaoju sirt5deacylatesmetabolismrelatedproteinsandattenuateshepaticsteatosisinobobmice
AT zhangjialing sirt5deacylatesmetabolismrelatedproteinsandattenuateshepaticsteatosisinobobmice
AT weipeng sirt5deacylatesmetabolismrelatedproteinsandattenuateshepaticsteatosisinobobmice
AT hexiaolong sirt5deacylatesmetabolismrelatedproteinsandattenuateshepaticsteatosisinobobmice
AT haojunfeng sirt5deacylatesmetabolismrelatedproteinsandattenuateshepaticsteatosisinobobmice
AT liupingsheng sirt5deacylatesmetabolismrelatedproteinsandattenuateshepaticsteatosisinobobmice
AT yangfuquan sirt5deacylatesmetabolismrelatedproteinsandattenuateshepaticsteatosisinobobmice
AT litingting sirt5deacylatesmetabolismrelatedproteinsandattenuateshepaticsteatosisinobobmice
AT weitaotao sirt5deacylatesmetabolismrelatedproteinsandattenuateshepaticsteatosisinobobmice