CAV1-CAVIN1-LC3B-mediated autophagy regulates high glucose-stimulated LDL transcytosis

Xiangli Bai(Huazhong University of Science and Technology), Xiaoyan Yang(Huazhong University of Science and Technology), Xiong Jia(Huazhong University of Science and Technology), Yueguang Rong(Huazhong University of Science and Technology), Lulu Chen(Union Hospital), Tianshu Zeng(Union Hospital), Xiu‐Ling Deng(Union Hospital), Wenjing Li(Huazhong University of Science and Technology), Guangjie Wu(Huazhong University of Science and Technology), Ling Wang(Huazhong University of Science and Technology), Ye Li(Huazhong University of Science and Technology), Jing Zhang(Huazhong University of Science and Technology), Zhifan Xiong(Huazhong University of Science and Technology), Liang Xiong(Huazhong University of Science and Technology), Yumei Wang(Union Hospital), Lin Zhu(Huazhong University of Science and Technology), Ying Zhao(Huazhong University of Science and Technology), Si Jin(Huazhong University of Science and Technology)
Autophagy
August 26, 2019
10.1080/15548627.2019.1659613
Cited by 81Open Access
Full Text

Abstract

Diabetes is a recognized high-risk factor for the development of atherosclerosis, in which macroautophagy/autophagy is emerging to play essential roles. The retention of low-density lipoprotein (LDL) particles in subendothelial space following transcytosis across the endothelium is the initial step of atherosclerosis. Here, we identified that high glucose could promote atherosclerosis by stimulating transcytosis of LDL. By inhibiting AMPK-MTOR-PIK3C3 pathway, high glucose suppresses the CAV-CAVIN-LC3B-mediated autophagic degradation of CAV1; therefore, more CAV1 is accumulated in the cytosol and utilized to form more caveolae in the cell membrane and facilitates the LDL transcytosis across endothelial cells. For a proof of concept, higher levels of lipids were accumulated in the subendothelial space of umbilical venous walls from pregnant women with gestational diabetes mellitus (GDM), compared to those of pregnant women without GDM. Our results reveal that high glucose stimulates LDL transcytosis by a novel CAV1-CAVIN1-LC3B signaling-mediated autophagic degradation pathway. ABBREVIATIONS: ; CAV1: caveolin-1; CAVIN1: caveolae associated protein 1; CSD: the CAV1 scaffolding domain; GDM: gestational diabetes mellitus; IMD: intramembrane domain; LIR: LC3-interacting region; MAP1LC3/LC3: microtubule- associated protein 1 light chain 3; MFI: mean fluorescence intensity; MTOR: mechanistic target of rapamycin kinase; PIK3C3/VPS34: phosphatidylinositol 3-kinase catalytic subunit type 3; SQSTM1/p62: sequestosome 1.

Related Papers

AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1
Joungmok Kim, Mondira Kundu, Benoı̂t Viollet et al.|Nature Cell Biology|2011|7k
How to Interpret LC3 Immunoblotting
Noboru Mizushima, Tamotsu Yoshimori|Autophagy|2007|2.6k
Self-consumption: the interplay of autophagy and apoptosis
Guillermo Mariño, Mireia Niso‐Santano, Eric H. Baehrecke et al.|Nature Reviews Molecular Cell Biology|2014|2.1k
AMPK Phosphorylates and Inhibits SREBP Activity to Attenuate Hepatic Steatosis and Atherosclerosis in Diet-Induced Insulin-Resistant Mice
Li Yu, Shanqin Xu, Maria M. Mihaylova et al.|Cell Metabolism|2011|1.7k
The autophagosome: origins unknown, biogenesis complex
Christopher A. Lamb, Tamotsu Yoshimori, Sharon A. Tooze|Nature Reviews Molecular Cell Biology|2013|1.3k