2. Academic Validation
  3. Amino acid starvation-induced LDLR trafficking accelerates lipoprotein endocytosis and LDL clearance

Amino acid starvation-induced LDLR trafficking accelerates lipoprotein endocytosis and LDL clearance

  • EMBO Rep. 2022 Feb 3;23(3):e53373. doi: 10.15252/embr.202153373.
Ye Chen  # 1 2,  Xiao Wu  # 1 3 4,  Jing Zhang 1,  Guopin Pan 1,  Xiaoyun Wang 1,  Xiaosun Guo 1,  Jianli Wang 5,  Xiaopei Cui 2,  Haiqing Gao 2,  Mei Cheng 2,  Jingwen Yang 1,  Cheng Zhang 3 4,  Fan Jiang 2
Affiliations

Affiliations

  • 1 Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China.
  • 2 Key Laboratory of Cardiovascular Proteomics of Shandong Province, Department of Geriatrics, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.
  • 3 Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, Jinan, China.
  • 4 The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital of Shandong University, Jinan, China.
  • 5 Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Jinan, China.
  • # Contributed equally.
PMID: 34994492 DOI: 10.15252/embr.202153373
Abstract

Mammalian cells utilize Akt-dependent signaling to deploy intracellular GLUT4 toward cell surface to facilitate glucose uptake. Low-density lipoprotein receptor (LDLR) is the cargo receptor mediating endocytosis of Apolipoprotein B-containing lipoproteins. However, signaling-controlled regulation of intracellular LDLR trafficking remains elusive. Here, we describe a unique amino acid stress response, which directs the deployment of intracellular LDLRs, causing enhanced LDL endocytosis, likely via CA2+ and calcium/calmodulin-dependent protein kinase II-mediated signalings. This response is independent of induction of Autophagy. Amino acid stress-induced increase in LDL uptake in vitro is comparable to that by pravastatin. In vivo, acute AAS challenge for up to 72 h enhanced the rate of hepatic LDL uptake without changing the total expression level of LDLR. Reducing dietary Amino acids by 50% for 2 to 4 weeks ameliorated high fat diet-induced hypercholesterolemia in heterozygous LDLR-deficient mice, with reductions in both LDL and VLDL fractions. We suggest that identification of signaling-controlled regulation of intracellular LDLR trafficking has advanced our understanding of the LDLR biology, and may benefit future development of additional therapeutic strategies for treating hypercholesterolemia.

Keywords

amino acid starvation; calcium signaling; endocytic recycling; endocytosis; low-density lipoprotein receptor.

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