The unfolded protein response is a negative regulator of scavenger receptor class B, type I (SR-BI) expression.
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.
Department of Medical Chemistry, Center for Pathobiochemistry and Genetics, Medical University of Vienna, Währingerstraße 10, 1090 Vienna, Austria.
Tanja
T
Eberhart
Department of Medical Chemistry, Center for Pathobiochemistry and Genetics, Medical University of Vienna, Währingerstraße 10, 1090 Vienna, Austria.
Karin
K
Eigner
Department of Medical Chemistry, Center for Pathobiochemistry and Genetics, Medical University of Vienna, Währingerstraße 10, 1090 Vienna, Austria.
Yüksel
Y
Filik
Department of Medical Chemistry, Center for Pathobiochemistry and Genetics, Medical University of Vienna, Währingerstraße 10, 1090 Vienna, Austria.
Stefanie
S
Fruhwürth
Department of Medical Chemistry, Center for Pathobiochemistry and Genetics, Medical University of Vienna, Währingerstraße 10, 1090 Vienna, Austria.
Herbert
H
Stangl
Department of Medical Chemistry, Center for Pathobiochemistry and Genetics, Medical University of Vienna, Währingerstraße 10, 1090 Vienna, Austria. Electronic address: clemens.roehrl@meduniwien.ac.at.
Clemens
C
Röhrl
D002318:Cardiovascular Diseases / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D002784:Cholesterol / Q000737:chemistry; D015536:Down-Regulation; D004721:Endoplasmic Reticulum / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress; D005786:Gene Expression Regulation; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000166:cytology; D006706:Homeostasis; D006801:Humans; D008055:Lipids / Q000737:chemistry; D034741:RNA, Small Interfering / Q000378:metabolism; D051122:Scavenger Receptors, Class B / Q000378:metabolism*; D056811:Unfolded Protein Response
D008055:Lipids; D034741:RNA, Small Interfering; C495124:SCARB1 protein, human; D051122:Scavenger Receptors, Class B; D002784:Cholesterol
Cholesterol; Endoplasmic reticulum stress (ER stress); HDL; Unfolded protein response (UPR)