Inhibition of ASGR1 decreases lipid levels by promoting cholesterol excretion

Wang, Ju-Qiong; Li, Liang-Liang; Hu, Ao; Deng, Gang; Wei, Jian; Li, Yunfeng; Liu, Yuanbin; Lu, Xiao-Yi; Qiu, Zhiping; Shi, Xiongjie; Zhao, Xiaolu; Luo, Jie; Song, Bao-Liang

doi:10.1038/s41586-022-05006-3

Cited by 77 publications

(86 citation statements)

References 38 publications

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“…To determine the mechanism of action, Xie et al analyzed the hepatic transcriptomic profile and in vivo cholesterol metabolism and found that ASGR1 deficiency downregulated HMGCR but upregulated hepatic LDLR. However, the study by Wang et al 1 found no difference in hepatic LDLR expression among Asgr1 +/+ , Asgr1 +/− , and Asgr1 −/− mice. This result may be due to the different animal models, having different metabolic characteristics which were used in these studies.…”

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confidence: 88%

“…In a recent study published in Nature , Wang et al 1 discovered that inhibition of asialoglycoprotein receptor 1 (ASGR1) increased cholesterol efflux and thus lowered blood cholesterol and reduced atherosclerosis. This study offers an emerging new therapeutic target in hypercholesterolemia and its comorbidities and complications (such as fatty liver and atherosclerosis), which are major threats to public health.…”

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confidence: 99%

“…However, only upregulating the function of LXR to increase cholesterol excretion and reverse cholesterol transport is not clinically useful, because sterol regulatory element binding protein 1 (SREBP1) upregulation resulting from LXR activation increases lipid synthesis. In a recent study, Wang et al 1 discovered that inhibition of asialoglycoprotein receptor 1 (ASGR1) (a GWAS identified gene associated coronary artery disease) could upregulate ABCG5, ABCG8, and ABCA1 by increasing LXRα, but inhibiting SREBP1, which is distinguished from canonical LXRα activation by pharmacological activators.…”

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confidence: 99%

“…There is a relevant example that the LXR-IDOL-LDLR (IDOL, inducible degrader of low-density lipoprotein receptor) axis is both tissue- and species-specific and is not present in mouse liver. Wang et al 1 found that ASGR1 regulates LXR, and the effect of LXR on LDLR may differ between pig and mouse livers depending on the presence or absence of the LXR-IDOL-LDLR axis.…”

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confidence: 99%

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ASGR1: an emerging therapeutic target in hypercholesterolemia

Zhao

2023

Sig Transduct Target Ther

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confidence: 88%

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confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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ASGR1: an emerging therapeutic target in hypercholesterolemia

Zhao

2023

Sig Transduct Target Ther

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“…The main role of ASGR1 is to bind galactosyl residues, facilitating glycoproteins turnover ( Muramatsu, 2007 ). In fact, it was recently studied in the context of cardiovascular diseases ( Xie et al, 2021 ; Wang et al, 2022a ) demonstrating that its inhibition reduces hypercholesterolemia and atherosclerosis ( Xie et al, 2021 ) by increasing cholesterol excretion ( Wang et al, 2022a ). In the context of liver cancer, the role of ASGR1 as tumor suppressor was first suggested via its interaction with LASS2 (longevity assurance homolog 2 of yeast LAG1) ( Gu et al, 2016 ) and more recently by its association with DNA methylation ( Zhu et al, 2022 ), confirming the prior findings of loss of ASGR1 expression in HCC tissue ( Shi et al, 2013 ; Witzigmann et al, 2016 ).…”

Section: Introductionmentioning

confidence: 99%

Hepatocellular carcinoma risk-stratification based on ASGR1 in circulating epithelial cells for cancer interception

Roa-Colomo

Garrido

Molina-Vallejo

et al. 2022

Front. Mol. Biosci.

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Purpose: Lack of diagnostic and prognostic biomarkers in hepatocellular carcinoma impedes stratifying patients based on their risk of developing cancer. The aim of this study was to evaluate phenotypic and genetic heterogeneity of circulating epithelial cells (CECs) based on asialoglycoprotein receptor 1 (ASGR1) and miR-122-5p expression as potential diagnostic and prognostic tools in patients with hepatocellular carcinoma (HCC) and liver cirrhosis (LC).Methods: Peripheral blood samples were extracted from LC and HCC patients at different disease stages. CECs were isolated using positive immunomagnetic selection. Genetic and phenotypic characterization was validated by double immunocytochemistry for cytokeratin (CK) and ASGR1 or by in situ hybridization with miR-122-5p and CECs were visualized by confocal microscopy.Results: The presence of CECs increased HCC risk by 2.58-fold, however, this was only significant for patients with previous LC (p = 0.028) and not for those without prior LC (p = 0.23). Furthermore, the number of CECs lacking ASGR1 expression correlated significantly with HCC incidence and absence of miR-122-5p expression (p = 0.014; r = 0.23). Finally, overall survival was significantly greater for patients at earlier cancer stages (p = 0.018), but this difference was only maintained in the group with the presence of CECs (p = 0.021) whereas progression-free survival was influenced by the absence of ASGR1 expression.Conclusion: Identification and characterization of CECs by ASGR1 and/or miR-122-5p expression may be used as a risk-stratification tool in LC patients, as it was shown to be an independent prognostic and risk-stratification marker in LC and early disease stage HCC patients.

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Prospective therapeutics for intestinal and hepatic fibrosis

Zhao

et al. 2023

Bioengineering & Transla Med

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Currently, there are no effective therapies for intestinal and hepatic fibrosis representing a considerable unmet need. Breakthroughs in pathogenesis have accelerated the development of anti‐fibrotic therapeutics in recent years. Particularly, with the development of nanotechnology, the harsh environment of the gastrointestinal tract and inaccessible microenvironment of fibrotic lesions seem to be no longer considered a great barrier to the use of anti‐fibrotic drugs. In this review, we comprehensively summarize recent preclinical and clinical studies on intestinal and hepatic fibrosis. It is found that the targets for preclinical studies on intestinal fibrosis is varied, which could be divided into molecular, cellular, and tissues level, although little clinical trials are ongoing. Liver fibrosis clinical trials have focused on improving metabolic disorders, preventing the activation and proliferation of hepatic stellate cells, promoting the degradation of collagen, and reducing inflammation and cell death. At the preclinical stage, the therapeutic strategies have focused on drug targets and delivery systems. At last, promising remedies to the current challenges are based on multi‐modal synergistic and targeted delivery therapies through mesenchymal stem cells, nanotechnology, and gut‐liver axis providing useful insights into anti‐fibrotic strategies for clinical use.

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Inhibition of ASGR1 decreases lipid levels by promoting cholesterol excretion

Cited by 77 publications

References 38 publications

ASGR1: an emerging therapeutic target in hypercholesterolemia

ASGR1: an emerging therapeutic target in hypercholesterolemia

Hepatocellular carcinoma risk-stratification based on ASGR1 in circulating epithelial cells for cancer interception

Prospective therapeutics for intestinal and hepatic fibrosis

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