Soat1 mediates the mouse strain effects on cholesterol loading-induced endoplasmic reticulum stress and CHOP expression in macrophages.

Autor: Luo M; Department of Cardiovascular Medicine, Second Xiangya Hospital, Central South University, Changsha, China; Department of Cardiovascular & Metabolic Sciences, Cleveland Clinic Lerner Research Institute, Cleveland, OH, USA., Opoku E; Department of Cardiovascular & Metabolic Sciences, Cleveland Clinic Lerner Research Institute, Cleveland, OH, USA., Traughber CA; Department of Cardiovascular & Metabolic Sciences, Cleveland Clinic Lerner Research Institute, Cleveland, OH, USA; Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine -Case Western Reserve University, Cleveland, OH, USA., Hai Q; Department of Cardiovascular & Metabolic Sciences, Cleveland Clinic Lerner Research Institute, Cleveland, OH, USA., Robinet P; Department of Cardiovascular & Metabolic Sciences, Cleveland Clinic Lerner Research Institute, Cleveland, OH, USA., Berisha S; Department of Cardiovascular & Metabolic Sciences, Cleveland Clinic Lerner Research Institute, Cleveland, OH, USA., Smith JD; Department of Cardiovascular & Metabolic Sciences, Cleveland Clinic Lerner Research Institute, Cleveland, OH, USA; Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine -Case Western Reserve University, Cleveland, OH, USA. Electronic address: smithj4@ccf.org.
Jazyk: angličtina
Zdroj: Biochimica et biophysica acta. Molecular and cell biology of lipids [Biochim Biophys Acta Mol Cell Biol Lipids] 2021 Jan; Vol. 1866 (1), pp. 158825. Date of Electronic Publication: 2020 Oct 06.
DOI: 10.1016/j.bbalip.2020.158825
Abstrakt: We previously demonstrated that AKR vs. DBA/2 mouse bone marrow derived macrophages have higher levels of free cholesterol and lower levels of esterified cholesterol after cholesterol loading, and that AKR, but not DBA/2, macrophages induced C/EBP homologous protein (CHOP) expression after cholesterol loading. We earlier determined that the free and esterified cholesterol level effect is due to a truncation in the sterol O-acyltransferase 1 (Soat1) gene, encoding acetyl-coenzyme A acetyltransferase 1 (ACAT1). Here we examined the mechanism for the differential induction of CHOP by cholesterol loading. CHOP was induced in both strains after incubation with tunicamycin, indicating both strains have competent endoplasmic reticulum stress pathways. CHOP was induced when DBA/2 macrophages were cholesterol loaded in the presence of an ACAT inhibitor, indicating that the difference in free cholesterol levels were responsible for this strain effect. This finding was confirmed in macrophages derived from DBA/2 embryonic stem cells. Cholesterol loading of Soat1 gene edited cells, mimicking the AKR allele, led to increased free cholesterol levels and restored CHOP induction. The upstream pathway of free cholesterol induced endoplasmic reticulum stress was investigated; and, RNA-dependent protein kinase-like endoplasmic reticulum kinase (PERK) and inositol-requiring enzyme 1 α protein kinase (IRE1α) pathways were required for maximal CHOP expression.
(Copyright © 2020 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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