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...

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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/8844bd7497d64e73ab87e18292a072e0
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spelling	oai:doaj.org-article:8844bd7497d64e73ab87e18292a072e02021-11-18T06:20:43ZDeficiency of ASGR1 in pigs recapitulates reduced risk factor for cardiovascular disease in humans1553-73901553-7404https://doaj.org/article/8844bd7497d64e73ab87e18292a072e02021-11-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8584755/?tool=EBIhttps://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. Author summary Previous studies have reported an association between ASGR1 variants and CVD in humans. However, the underlying mechanism is unknown. We used ASGR1-deficient pig to recapitulate the reduced risk features of CVD in humans with ASGR1 variants, indicating that ASGR1 inhibition could be an effective strategy to treat atherosclerotic CVD. Our results highlight the demand for taking advantage of genetically modified large animal models to investigate the pathogenesis and therapeutic development of CVD in humans. Unexpectedly, we demonstrate the first link between ASGR1 deficiency and liver injury, a feature that has not been documented in humans with ASGR1 variants. These results suggest that ASGR1 might be an effective target for reducing CVD, whereas revealing a genetic predisposition to liver disease in humans with ASGR1 variants.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 (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. Author summary Previous studies have reported an association between ASGR1 variants and CVD in humans. However, the underlying mechanism is unknown. We used ASGR1-deficient pig to recapitulate the reduced risk features of CVD in humans with ASGR1 variants, indicating that ASGR1 inhibition could be an effective strategy to treat atherosclerotic CVD. Our results highlight the demand for taking advantage of genetically modified large animal models to investigate the pathogenesis and therapeutic development of CVD in humans. Unexpectedly, we demonstrate the first link between ASGR1 deficiency and liver injury, a feature that has not been documented in humans with ASGR1 variants. These results suggest that ASGR1 might be an effective target for reducing CVD, whereas revealing a genetic predisposition to liver disease in humans with ASGR1 variants.
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/8844bd7497d64e73ab87e18292a072e0
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_version_	1718424492022169600

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

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