Endothelial HMGB1 Is a Critical Regulator of LDL Transcytosis via an SREBP2–SR-BI Axis

Abstract

OBJECTIVE: LDL (low-density lipoprotein) transcytosis across the endothelium is performed by the SR-BI (scavenger receptor class B type 1) receptor and contributes to atherosclerosis. HMGB1 (high mobility group box 1) is a structural protein in the nucleus that is released by cells during inflammation; extracellular HMGB1 has been implicated in advanced disease. Whether intracellular HMGB1 regulates LDL transcytosis through its nuclear functions is unknown. Approach and Results: HMGB1 was depleted by siRNA in human coronary artery endothelial cells, and transcytosis of LDL was measured by total internal reflection fluorescence microscopy. Knockdown of HMGB1 attenuated LDL transcytosis without affecting albumin transcytosis. Loss of HMGB1 resulted in reduction in SR-BI levels and depletion of SREBP2 (sterol regulatory element-binding protein 2)—a transcription factor upstream of SR-BI. The effect of HMGB1 depletion on LDL transcytosis required SR-BI and SREBP2. Overexpression of HMGB1 caused an increase in LDL transcytosis that was unaffected by inhibition of extracellular HMGB1 or depletion of RAGE (receptor for advanced glycation endproducts)—a cell surface receptor for HMGB1. The effect of HMGB1 overexpression on LDL transcytosis was prevented by knockdown of SREBP2. Loss of HMGB1 caused a reduction in the half-life of SREBP2; incubation with LDL caused a significant increase in nuclear localization of HMGB1 that was dependent on SR-BI. Animals lacking endothelial HMGB1 exhibited less acute accumulation of LDL in the aorta 30 minutes after injection and when fed a high-fat diet developed fewer fatty streaks and less atherosclerosis. Conclusions: Endothelial HMGB1 regulates LDL transcytosis by prolonging the half-life of SREBP2, enhancing SR-BI expression. Translocation of HMGB1 to the nucleus in response to LDL requires SR-BI.

The Endothelium Is Both a Target and a Barrier of HDL’s Protective Functions

“…Estradiol inhibited endothelial SR-BI through activation of the G-protein coupled estrogen receptor and thereby LDL transport [ 34 ]. Similarly, the proinflammatory mediator high mobility group box 1 (HMGB1) regulated LDL transcytosis via SR-BI [ 35 ]. Whether these pathways also influence HDL transport is unknown and remains to be investigated.…”

Nuclear HMGB1 protects from non-alcoholic fatty liver diseases through negative regulation of liver X receptor

“…Additionally, Hi-C data demonstrated that HMGB1 binds to TAD (Topology Associated Domain) boundaries, known to regulate chromatin topology and consequently gene expression. In addition to this paper, a recent study has also evoked an RNA-binding property as a another functional layer for HMGB1 to regulate gene expression (26,43). Therefore, 3-D conformation and RNA binding clearly represent additional mechanisms by which HMGB1 could mediate its repressive effect on LXRα, which is therefore worthwhile to further investigate in the context of liver steatosis.…”

TNFɑ-induced LDL cholesterol accumulation involve elevated LDLR cell surface levels and SR-B1 downregulation in human arterial endothelial cells

“…5) signi cantly promoted Dil-LDL accumulation with or without TNF . SR-BI, on the other hand, has been reported to faciliate AP to BL transport of LDL in an LDLR-independent manner [110]. However, there is some controversy about the role of LDLR in tra cking ligand across the brain endothelium.…”