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

ABSTRACT: 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.

SUBMITTER: Xie B

PROVIDER: S-EPMC8584755 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundProteomics of atypical phenotypes may help unravel cardiovascular disease mechanisms.AimWe aimed to prospectively screen the proteome of four types of individuals: with or without coronary artery disease (CAD), each with or without multiple risk factors. Associations with individual risk factors and circulating biomarkers were also tested to provide a functional context to the protein hits.Materials and methodsThe CAPIRE study (ClinicalTrials.gov Identifier: NCT02157662) is a cross-sectional study aimed at identifying possible new mechanisms promoting or protecting against atherothrombosis. Quantification (by aptamer technology), ranking (using partial least squares), and correlations (by multivariate regression) of ~5000 plasma proteins were performed in consecutive individuals aged 45-75 years, without previous cardiovascular disease, undergoing computed tomography angiography for suspected CAD, showing either >5/16 atherosclerotic segments (CAD+) or completely clean arteries (CAD-) and either ≤ 1 risk factor (RF+) or ≥3 risk factors (RF-) (based on history, blood pressure, glycemia, lipids, and smoking).ResultsOf 544 individuals, 39% were atypical (93 CAD+/RF-; 120 CAD-/RF+) and 61% typical (102 CAD+/RF+; 229 CAD-/RF-). In the comparison with CAD+/RF- adjusted for sex and age, CAD-/RF+ was associated with increased atrial myosin regulatory light chain 2 (MYO) and C-C motif chemokine-22 (C-C-22), and reduced protein shisa-3 homolog (PS-3) and platelet-activating factor acetylhydrolase (PAF-AH). Extending the analysis to the entire cohort, an additional 8 proteins were independently associated with CAD or RF; by logistic regression, the 12-protein panel alone discriminated the four groups with AUCROC's of 0.72-0.81 (overall p = 1.0e-38). Among them, insulin-like growth factor binding protein-3 is positively associated with RF, lower BMI, and HDL-cholesterol, renin with CAD higher glycated hemoglobin HbA1c, and smoking.ConclusionsIn a CCTA-based cohort, four proteins, involved in opposing vascular processes (healing vs. adverse remodeling), are specifically associated with low CAD burden in high CV-risk individuals (high MYO and C-C-22) and high CAD burden in low-risk subjects (high PS-3 and PAF-AH), in interaction with BMI, smoking, diabetes, HDL-cholesterol, and HbA1c. These findings could contribute to a deeper understanding of the atherosclerotic process beyond traditional risk profile assessment and potentially constitute new treatment targets.

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

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