The unfolded protein response is a negative regulator of scavenger receptor class B, type I (SR-BI) expression

https://doi.org/10.1016/j.bbrc.2016.09.110Get rights and content
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Highlights

  • The HDL-receptor SR-BI is down-regulated by the unfolded protein response.

  • Reduced SR-BI expression results in impaired selective lipid uptake from HDL.

  • SR-BI down-regulation provides partial protection from ER stress.

Abstract

Scavenger receptor class B, type I (SR-BI) is the main receptor for high-density lipoprotein (HDL) and an emerging atheroprotective candidate. A central function of SR-BI is the delivery of HDL-derived cholesterol to the liver for subsequent excretion into the bile. Here, we investigated the regulation of SR-BI by the unfolded protein response (UPR), an adaptive mechanism induced by endoplasmic reticulum (ER) stress, which is frequently activated in metabolic disorders.

We provide evidence that induction of acute ER stress by well-characterized chemical inducers leads to decreased SR-BI expression in hepatocyte-derived cell lines. This results in a functional reduction of selective lipid uptake from HDL. However, the regulation of SR-BI by ER stress is not a direct consequence of altered cellular cholesterol metabolism. Finally, we show that SR-BI down-regulation by the UPR might be a compensatory mechanism to provide partial adaption to ER stress.

The observed down-regulation of SR-BI by ER stress in hepatic cells might contribute to the unfavorable effects of metabolic disorders on cholesterol homeostasis and cardiovascular diseases.

Keywords

HDL
Cholesterol
Endoplasmic reticulum stress (ER stress)
Unfolded protein response (UPR)

Abbreviations

ATF6
activating transcription factor 6
CHOP
C/EBP-homologous protein
ERdJ4
endoplasmic reticulum DNA J domain containing protein 4
GRP78
78 kDa glucose-regulated protein
HDL
high-density lipoprotein
IRE1
inositol-requiring enzyme 1
PERK
protein kinase RNA-like endoplasmic reticulum kinase
RCT
reverse cholesterol transport
SR-BI
scavenger receptor class B, type I
SREBP
sterol regulatory element binding protein
UPR
unfolded protein response

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1

Present address: Department of Molecular and Clinical Medicine, University of Gothenburg, Sweden.