HDL inhibits endoplasmic reticulum stress-induced apoptosis of pancreatic β-cells in vitro by activation of Smoothened

Abstract

Loss of pancreatic β-cell mass and function as a result of sustained endoplasmic reticulum (ER) stress is a core step in the pathogenesis of diabetes mellitus type 2. The complex control of β-cells and insulin production involves hedgehog 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 β-cell apoptosis. We investigated the mechanism by which HDL inhibits ER stress and apoptosis induced by thapsigargin, a sarco/ER Ca 2+ -ATPase inhibitor, in β-cells of a rat insulinoma cell line, INS1e. We further explored effects on the hedgehog signaling receptor Smoothened (Smo) with pharmacologic agonists and inhibitors. Interference with sterol synthesis or efflux enhanced βcell apoptosis and abrogated the anti-apoptotic activity of HDL. During ER stress, HDL facilitated the efflux of specific oxysterols, including 24-hydroxycholesterol (24-OHC). Supplementation of reconstituted HDL with 24-OHC enhanced and-in cells lacking ATP-binding cassette transporter ABCG1 or the 24-OHC synthesizing enzyme CYP46A1-restored the protective activity of HDL. Inhibition of Smo countered the beneficial effects of HDL but also LDL, and Smo agonists decreased β-cell apoptosis in the absence of ABCG1 or CYP46A1. The translocation of the Smo-activated transcription factor gliomaassociated 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 β-cell death involves the transport, generation and mobilization of oxysterols for activation of the hedgehog signalling receptor Smo.

HDL Cholesterol and Non-Cardiovascular Disease: A Narrative Review

“…The molecular mechanisms underlying the potential beneficial functions of HDLs in β-cells are largely unknown. Intriguingly, however, a recent study found that a potential protective effect of HDL to reverse endoplasmic stress and β-cell death may involve a complex cascade of the transport, generation, and mobilization of oxysterols for the activation of the hedgehog signaling receptor Smoothened [ 124 ].…”

β-Cell Dysfunction, Hepatic Lipid Metabolism, and Cardiovascular Health in Type 2 Diabetes: New Directions of Research and Novel Therapeutic Strategies

“…Local expression of ApoC-III within the pancreatic islets has led to β-cell failure in mice [ 53 ]. In contrast, it was found that high-density lipoprotein (HDL) expression in β-cell had a protective role against ER stress [ 102 ].…”

Protection against Glucolipotoxicity by High Density Lipoprotein in Human PANC-1 Hybrid 1.1B4 Pancreatic Beta Cells: The Role of microRNA

“…By contrast, high-density lipoprotein (HDL) [ 5 , 6 , 7 , 8 ], its major apolipoprotein (apo), apoA-I [ 7 , 9 , 10 , 11 ], and/or the ATP binding cassette (ABC) transporters with which they interact [ 12 , 13 , 14 , 15 , 16 ], can provide protection to beta cells and pancreatic islets in experimental models, findings generally supported by clinical data [ 17 , 18 , 19 , 20 , 21 ]. Studies variously link these protective functions with sterol removal or efflux from beta cells [ 8 , 12 , 13 , 14 , 15 , 16 ]; others report cholesterol- and/or transporter-independent effects of apoA-I and HDL [ 7 , 10 ], while conflicting reports exist regarding beta cell function in carriers of loss of function (LOF) mutations in ABCA1 [ 22 , 23 ]. Some of these divergent outcomes may be attributed to the heterogeneous nature of HDL and its cargo molecules [ 24 , 25 ], and to the widely differing concentrations of apoA-I (10 μg protein mL −1 to 900 μg mL −1 ) and/or HDL (50 μg protein mL −1 to 1 mg mL −1 ) used, or required, to demonstrate the protective effect of this lipoprotein in human and rodent beta cell models (reviewed in [ 5 ]).…”

“…Certainly, numerous cell signalling pathways are altered in beta cells by exposure to apoA-I and HDL, including G protein coupled receptor (GPCR) activation of adenyl cyclase, protein kinase A and forkhead box protein 01 (Fox01) [ 9 ], calcium signalling [ 7 ], and activation of hedgehog (Hh) receptor Smoothened (SMO) [ 8 ], protein kinase B [ 26 ] and sphingosine-1-phosphate receptors (S1PR1-3) [ 5 , 24 , 27 ]. Transcription factors, such as the Liver X receptor (LXR), peroxisome proliferator activator receptor alpha (PPARα), FOXO1 and BTB domain and CNC homolog 1 (BACH1) have also emerged as key factors orchestrating cellular responses to fatty acids such as palmitate [ 3 ].…”

“…By contrast, high-density lipoprotein (HDL) [5][6][7][8], its major apolipoprotein (apo), apoA-I [7,[9][10][11], and/or the ATP binding cassette (ABC) transporters with which they interact [12][13][14][15][16], can provide protection to beta cells and pancreatic islets in experimental models, findings generally supported by clinical data [17][18][19][20][21]. Studies variously link these protective functions with sterol removal or efflux from beta cells [8,[12][13][14][15][16]; others report cholesterol-and/or transporter-independent effects of apoA-I and HDL [7,10], while conflicting reports exist regarding beta cell function in carriers of loss of function (LOF) mutations in ABCA1 [22,23].…”