Low density lipoprotein mimics insulin action on autophagy and glucose uptake in endothelial cells

Abstract

Elevated plasma low density lipoprotein (LDL) is an established risk factor for cardiovascular disease. In addition to being able to cross the endothelial barrier to become accumulated in subendothelial space and thereby initiate atherosclerosis, LDL may exert a direct effect on vascular endothelial cells through activation of LDL receptor and its downstream signaling. Whether LDL can modulate the signaling for autophagy in endothelial cells is not clear. The present study firstly demonstrated that LDL can suppress endothelial autophagy through activation of the PI3K/Akt/mTOR signaling pathway and can promote glucose uptake by translocating glucose transporter 1 (GLUT1) from cytoplasm to cell membrane, actions similar to those of insulin. A co-immunoprecipitation assay found that LDL receptor (LDLR) and insulin receptor (IR) formed a complex in HUVECs. Knock down of the insulin receptor by small interfering RNA blocked the suppression of autophagy by LDL, as well as the signaling pathway involved. We conclude that LDL may mimic the action of insulin in endothelial cells, which might partly explain the increased incidence of diabetes in patients receiving some LDL-lowering therapy.

Effect of Inhibition of GLUT1 Expression and Autophagy Modulation on the Growth and Migration of Laryngeal Carcinoma Stem Cells under Hypoxic and Low-Glucose Conditions

“…GLUT-1 overexpression promotes the proliferation, invasion, and metastasis of cancer cells, particularly under hypoxia and starvation conditions [6,7]. Activation of autophagy promotes the functions of CD133 + cells under hypoxia [15,16], likely by enhancing glucose uptake [21][22][23]. Therefore, we explored whether the increased proliferation and migration of CD133 + Tu212 cells were associated with elevated GLUT-1 expression and autophagy.…”

“…Autophagy modulates various metabolic pathways, including that centered on glucose [23]. Hypoxia and glucose deprivation may induce autophagy, promoting glucose uptake by upregulating GLUT-1 expression to increase the glycolytic ux and maintain nutrient uptake under stress conditions [21][22][23]40,41]. In airway progenitor cells, a lack of GLUT-1 impacts its recycling but not its expression, facilitating glucose uptake [40].…”

“…The expression of glucose transporter-1 (GLUT-1) is reportedly associated with autophagy activation in CSCs under hypoxic or nutrient-deprived conditions [17][18][19][20]. Autophagy may also affect cellular glucose uptake [21][22][23]. Beclin-1, an autophagy marker, plays an important role in the initiation of autophagy [24].…”

Effect of Inhibition of GLUT1 Expression and Autophagy Modulation on the Growth and Migration of Laryngeal Carcinoma Stem Cells Under Hypoxic and Low-Glucose Conditions

“…Previous studies showed that GLUT-1 overexpression promoted cancer cell proliferation, invasion and metastasis, especially in hypoxia and starvation conditions [6,7]. Besides, activated autophagy promoted the functions of CD133 + cells under hypoxia [15,16], probably by enhancing cell glucose intake [21][22][23].…”

Relationship Between Autophagy and Metabolic Syndrome Characteristics in the Pathogenesis of Atherosclerosis

“…MetS-induced autophagy dysregulation has been identified as a critical factor in endothelial dysfunction and atherosclerosis. LDL can suppress endothelial autophagy by activating the PI3K/Akt/mTOR pathway in ECs ( Zhu L. et al, 2019 ). In addition, ox-LDL can inhibit autophagic flux by suppressing the Sirtuin 1 (SIRT 1)/forkhead box protein O1 (FoxO1) pathway to promote apoptosis and adhesion molecule expression in ECs ( Wang et al, 2019 ; Wu Q. et al, 2019 ).…”