Deficiency of ASGR1 in pigs recapitulates reduced risk factor for cardiovascular disease in humans.

Genetic variants in the asialoglycoprotein receptor 1 (ASGR1) are associated with a reduced risk of cardiovascular disease (CVD) in humans. However, the underlying molecular mechanism remains elusive. Given the cardiovascular similarities between pigs and humans, we generated ASGR1-deficient pigs us...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Baocai Xie, Xiaochen Shi, Yan Li, Bo Xia, Jia Zhou, Minjie Du, Xiangyang Xing, Liang Bai, Enqi Liu, Fernando Alvarez, Long Jin, Shaoping Deng, Grant A Mitchell, Dengke Pan, Mingzhou Li, Jiangwei Wu
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Genetics QH426-470
Acceso en línea:	https://doaj.org/article/5f59ff9059cb42af911248984f470136
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:5f59ff9059cb42af911248984f470136
record_format	dspace
spelling	oai:doaj.org-article:5f59ff9059cb42af911248984f4701362021-12-02T20:03:15ZDeficiency of ASGR1 in pigs recapitulates reduced risk factor for cardiovascular disease in humans.1553-73901553-740410.1371/journal.pgen.1009891https://doaj.org/article/5f59ff9059cb42af911248984f4701362021-11-01T00:00:00Zhttps://doi.org/10.1371/journal.pgen.1009891https://doaj.org/toc/1553-7390https://doaj.org/toc/1553-7404Genetic variants in the asialoglycoprotein receptor 1 (ASGR1) are associated with a reduced risk of cardiovascular disease (CVD) in humans. However, the underlying molecular mechanism remains elusive. Given the cardiovascular similarities between pigs and humans, we generated ASGR1-deficient pigs using the CRISPR/Cas9 system. These pigs show age-dependent low levels of non-HDL-C under standard diet. When received an atherogenic diet for 6 months, ASGR1-deficient pigs show lower levels of non-HDL-C and less atherosclerotic lesions than that of controls. Furthermore, by analysis of hepatic transcriptome and in vivo cholesterol metabolism, we show that ASGR1 deficiency reduces hepatic de novo cholesterol synthesis by downregulating 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), and increases cholesterol clearance by upregulating the hepatic low-density lipoprotein receptor (LDLR), which together contribute to the low levels of non-HDL-C. Despite the cardioprotective effect, we unexpectedly observed mild to moderate hepatic injury in ASGR1-deficient pigs, which has not been documented in humans with ASGR1 variants. Thus, targeting ASGR1 might be an effective strategy to reduce hypercholesterolemia and atherosclerosis, whereas further clinical evidence is required to assess its hepatic impact.Baocai XieXiaochen ShiYan LiBo XiaJia ZhouMinjie DuXiangyang XingLiang BaiEnqi LiuFernando AlvarezLong JinShaoping DengGrant A MitchellDengke PanMingzhou LiJiangwei WuPublic Library of Science (PLoS)articleGeneticsQH426-470ENPLoS Genetics, Vol 17, Iss 11, p e1009891 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Genetics QH426-470
spellingShingle	Genetics QH426-470 Baocai Xie Xiaochen Shi Yan Li Bo Xia Jia Zhou Minjie Du Xiangyang Xing Liang Bai Enqi Liu Fernando Alvarez Long Jin Shaoping Deng Grant A Mitchell Dengke Pan Mingzhou Li Jiangwei Wu Deficiency of ASGR1 in pigs recapitulates reduced risk factor for cardiovascular disease in humans.
description	Genetic variants in the asialoglycoprotein receptor 1 (ASGR1) are associated with a reduced risk of cardiovascular disease (CVD) in humans. However, the underlying molecular mechanism remains elusive. Given the cardiovascular similarities between pigs and humans, we generated ASGR1-deficient pigs using the CRISPR/Cas9 system. These pigs show age-dependent low levels of non-HDL-C under standard diet. When received an atherogenic diet for 6 months, ASGR1-deficient pigs show lower levels of non-HDL-C and less atherosclerotic lesions than that of controls. Furthermore, by analysis of hepatic transcriptome and in vivo cholesterol metabolism, we show that ASGR1 deficiency reduces hepatic de novo cholesterol synthesis by downregulating 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), and increases cholesterol clearance by upregulating the hepatic low-density lipoprotein receptor (LDLR), which together contribute to the low levels of non-HDL-C. Despite the cardioprotective effect, we unexpectedly observed mild to moderate hepatic injury in ASGR1-deficient pigs, which has not been documented in humans with ASGR1 variants. Thus, targeting ASGR1 might be an effective strategy to reduce hypercholesterolemia and atherosclerosis, whereas further clinical evidence is required to assess its hepatic impact.
format	article
author	Baocai Xie Xiaochen Shi Yan Li Bo Xia Jia Zhou Minjie Du Xiangyang Xing Liang Bai Enqi Liu Fernando Alvarez Long Jin Shaoping Deng Grant A Mitchell Dengke Pan Mingzhou Li Jiangwei Wu
author_facet	Baocai Xie Xiaochen Shi Yan Li Bo Xia Jia Zhou Minjie Du Xiangyang Xing Liang Bai Enqi Liu Fernando Alvarez Long Jin Shaoping Deng Grant A Mitchell Dengke Pan Mingzhou Li Jiangwei Wu
author_sort	Baocai Xie
title	Deficiency of ASGR1 in pigs recapitulates reduced risk factor for cardiovascular disease in humans.
title_short	Deficiency of ASGR1 in pigs recapitulates reduced risk factor for cardiovascular disease in humans.
title_full	Deficiency of ASGR1 in pigs recapitulates reduced risk factor for cardiovascular disease in humans.
title_fullStr	Deficiency of ASGR1 in pigs recapitulates reduced risk factor for cardiovascular disease in humans.
title_full_unstemmed	Deficiency of ASGR1 in pigs recapitulates reduced risk factor for cardiovascular disease in humans.
title_sort	deficiency of asgr1 in pigs recapitulates reduced risk factor for cardiovascular disease in humans.
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/5f59ff9059cb42af911248984f470136
work_keys_str_mv	AT baocaixie deficiencyofasgr1inpigsrecapitulatesreducedriskfactorforcardiovasculardiseaseinhumans AT xiaochenshi deficiencyofasgr1inpigsrecapitulatesreducedriskfactorforcardiovasculardiseaseinhumans AT yanli deficiencyofasgr1inpigsrecapitulatesreducedriskfactorforcardiovasculardiseaseinhumans AT boxia deficiencyofasgr1inpigsrecapitulatesreducedriskfactorforcardiovasculardiseaseinhumans AT jiazhou deficiencyofasgr1inpigsrecapitulatesreducedriskfactorforcardiovasculardiseaseinhumans AT minjiedu deficiencyofasgr1inpigsrecapitulatesreducedriskfactorforcardiovasculardiseaseinhumans AT xiangyangxing deficiencyofasgr1inpigsrecapitulatesreducedriskfactorforcardiovasculardiseaseinhumans AT liangbai deficiencyofasgr1inpigsrecapitulatesreducedriskfactorforcardiovasculardiseaseinhumans AT enqiliu deficiencyofasgr1inpigsrecapitulatesreducedriskfactorforcardiovasculardiseaseinhumans AT fernandoalvarez deficiencyofasgr1inpigsrecapitulatesreducedriskfactorforcardiovasculardiseaseinhumans AT longjin deficiencyofasgr1inpigsrecapitulatesreducedriskfactorforcardiovasculardiseaseinhumans AT shaopingdeng deficiencyofasgr1inpigsrecapitulatesreducedriskfactorforcardiovasculardiseaseinhumans AT grantamitchell deficiencyofasgr1inpigsrecapitulatesreducedriskfactorforcardiovasculardiseaseinhumans AT dengkepan deficiencyofasgr1inpigsrecapitulatesreducedriskfactorforcardiovasculardiseaseinhumans AT mingzhouli deficiencyofasgr1inpigsrecapitulatesreducedriskfactorforcardiovasculardiseaseinhumans AT jiangweiwu deficiencyofasgr1inpigsrecapitulatesreducedriskfactorforcardiovasculardiseaseinhumans
_version_	1718375662417346560

Deficiency of ASGR1 in pigs recapitulates reduced risk factor for cardiovascular disease in humans.

Ejemplares similares