Journal
JOURNAL OF LIPID RESEARCH
Volume 61, Issue 4, Pages 492-504Publisher
ELSEVIER
DOI: 10.1194/jlr.RA119000509
Keywords
adenosine 5 '-triphosphate binding cassette transporter; cytochrome P450 enzyme; high density lipoprotein; cholesterol efflux; cholesterol metabolism; oxysterols; lipoprotein receptors; hedgehog signaling
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Funding
- Swiss National Science Foundation (SNF) [CRSII3_154420, MRD 2014/267]
- Swiss Heart Foundation
- Forschungskredit of Universitat Zurich
- Ter Meulen Fund
- Royal Netherlands Academy of Arts and Sciences
- Swiss National Science Foundation (SNF) [CRSII3_154420] Funding Source: Swiss National Science Foundation (SNF)
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Loss of pancreatic beta-cell mass and function as a result of sustained ER stress is a core step in the pathogenesis of diabetes mellitus type 2. The complex control of beta-cells and insulin production involves hedgehog (Hh) signaling pathways as well as cholesterol-mediated effects. In fact, data from studies in humans and animal models suggest that HDL protects against the development of diabetes through inhibition of ER stress and beta-cell apoptosis. We investigated the mechanism by which HDL inhibits ER stress and apoptosis induced by thapsigargin, a sarco/ER Ca2+-ATPase inhibitor, in beta-cells of a rat insulinoma cell line, INS1e. We further explored effects on the Hh signaling receptor Smoothened (SMO) with pharmacologic agonists and inhibitors. Interference with sterol synthesis or efflux enhanced beta-cell apoptosis and abrogated the anti-apoptotic activity of HDL. During ER stress, HDL facilitated the efflux of specific oxysterols, including 24-hydroxycholesterol (OHC). Supplementation of reconstituted HDL with 24-OHC enhanced and, in cells lacking ABCG1 or the 24-OHC synthesizing enzyme CYP46A1, restored the protective activity of HDL. Inhibition of SMO countered the beneficial effects of HDL and also LDL, and SMO agonists decreased beta-cell apoptosis in the absence of ABCG1 or CYP46A1. The translocation of the SMO-activated transcription factor glioma-associated oncogene GLI-1 was inhibited by ER stress but restored by both HDL and 24-OHC. In conclusion, the protective effect of HDL to counter ER stress and beta-cell death involves the transport, generation, and mobilization of oxysterols for activation of the Hh signaling receptor SMO
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