Amino acid starvation-induced LDLR trafficking accelerates lipoprotein endocytosis and LDL clearance.
Ye ChenXiao WuJing ZhangGuopin PanXiaoyun WangXiaosun GuoJianli WangXiaopei CuiHaiqing GaoMei ChengJingwen YangCheng ZhangFan JiangPublished in: EMBO reports (2022)
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 2+ 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.
Keyphrases
- low density lipoprotein
- amino acid
- stress induced
- protein kinase
- reactive oxygen species
- high fat diet induced
- cell surface
- signaling pathway
- insulin resistance
- drug induced
- oxidative stress
- cell death
- early onset
- intensive care unit
- type diabetes
- cardiovascular disease
- current status
- high glucose
- diabetic rats
- hepatitis b virus
- cardiovascular events
- bioinformatics analysis