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Research Progress on the Involvement of ANGPTL4 and Loss-of-Function Variants in Lipid Metabolism and Coronary Heart Disease: Is the “Prime Time” of ANGPTL4-Targeted Therapy for Coronary Heart Disease Approaching?

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Abstract

Background

Multiple genetic studies have confirmed the definitive link among the loss-of-function variants of angiogenin-like protein 4 (ANGPTL4), significantly decreased plasma triglyceride (TG) levels, and reduced risk of coronary heart disease (CHD). The potential therapeutic effect of ANGPTL4 on dyslipidemia and CHD has been widely studied.

Objective

This review provides a detailed introduction to the research progress on the involvement of ANGPTL4 in lipid metabolism and atherosclerosis and evaluates the efficacy and safety of ANGPTL4 as a therapeutic target for CHD.

Relevant Findings

By inhibiting lipoprotein lipase (LPL) activity, ANGPTL4 plays a vital role in the regulation of lipid metabolism and energy balance. However, the role of ANGPTL4 in regulating lipid metabolism is tissue-specific. ANGPTL4 acts as a locally released LPL inhibitor in the heart, skeletal muscle and small intestine, while ANGPTL4 derived from liver and adipose tissue mainly acts as an endocrine factor that regulates systemic lipid metabolism. As a multifunctional protein, ANGPTL4 also inhibits the formation of foam cells in macrophages, exerting an anti-atherogenic role. The function of ANGPTL4 in endothelial cells is still uncertain. The safety of ANGPTL4 monoclonal antibodies requires further evaluation due to their potential adverse effects.

Conclusion

The biological characteristics of ANGPTL4 are much more complex than those demonstrated by genetic studies. Future studies must elucidate how to effectively reduce the risk of CHD while avoiding potential atherogenic effects and other complications before the “prime time” of ANGPTL4-targeted therapy arrives.

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Funding

This work was supported by National Natural Scientific Funding of China (No. 81672264 and No. 81871858).

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  1. Department of Cardiology, The Second Xiangya Hospital, Central South University, 139 Middle Renmin Road, Changsha, 410000, Hunan, China

    Jingmin Yang, Xiao Li & Danyan Xu

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  1. Jingmin Yang
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Danyan Xu conceived of the scope of the review and helped revise the manuscript. Jingmin Yang was involved in the collection of the relevant references and drafted the manuscript. Xiao Li helped revise the manuscript and created the figure and table. All authors read and approved the final manuscript.

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Correspondence to Danyan Xu.

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Yang, J., Li, X. & Xu, D. Research Progress on the Involvement of ANGPTL4 and Loss-of-Function Variants in Lipid Metabolism and Coronary Heart Disease: Is the “Prime Time” of ANGPTL4-Targeted Therapy for Coronary Heart Disease Approaching?. Cardiovasc Drugs Ther 35, 467–477 (2021). https://doi.org/10.1007/s10557-020-07001-0

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