Ye Chen, Xiao Wu, Jing Zhang, Guopin Pan, Xiaoyun Wang, Xiaosun Guo, Jianli Wang, Xiaopei Cui, Haiqing Gao, Mei Cheng, Jingwen Yang, Cheng Zhang, Fan Jiang
Author Information
Ye Chen: Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China.
Xiao Wu: Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China. ORCID
Jing Zhang: Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China.
Guopin Pan: Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China.
Xiaoyun Wang: Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China.
Xiaosun Guo: Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China.
Jianli Wang: Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Jinan, China.
Xiaopei Cui: Key Laboratory of Cardiovascular Proteomics of Shandong Province, Department of Geriatrics, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.
Haiqing Gao: Key Laboratory of Cardiovascular Proteomics of Shandong Province, Department of Geriatrics, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.
Mei Cheng: Key Laboratory of Cardiovascular Proteomics of Shandong Province, Department of Geriatrics, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.
Jingwen Yang: Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China.
Cheng Zhang: Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, Jinan, China. ORCID
Fan Jiang: Key Laboratory of Cardiovascular Proteomics of Shandong Province, Department of Geriatrics, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China. ORCID
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 Ca 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.
