A low high-density lipoprotein (HDL) plasma concentration and the abundance of small dense low-density lipoproteins (LDL) are risk factors for developing type 2 diabetes. We therefore investigated whether HDL and LDL play a role in the regulation of pancreatic islet cell apoptosis, proliferation, and secretory function. Isolated mouse and human islets were exposed to plasma lipoproteins of healthy human donors. In murine and human beta-cells, LDL decreased both proliferation and maximal glucose-stimulated insulin secretion. The comparative analysis of beta-cells from wild-type and LDL receptor-deficient mice revealed that the inhibitory effect of LDL on insulin secretion but not proliferation requires the LDL receptor. HDL was found to modulate the survival of both human and murine islets by decreasing basal as well as IL-1beta and glucose-induced apoptosis. IL-1beta-induced beta-cell apoptosis was also inhibited in the presence of either the delipidated protein or the deproteinated lipid moieties of HDL, apolipoprotein A1 (the main protein component of HDL), or sphingosine-1-phosphate (a bioactive sphingolipid mostly carried by HDL). In murine beta-cells, the protective effect of HDL against IL-1beta-induced apoptosis was also observed in the absence of the HDL receptor scavenger receptor class B type 1. Our data show that both LDL and HDL affect function or survival of beta-cells and raise the question whether dyslipidemia contributes to beta-cell failure and hence the manifestation and progression of type 2 diabetes mellitus.

LDL, HDL and cholesterol regulate the function and survival of β-cells. HDL also exerts antiobesity and insulin-sensitizing effects. Thus dyslipidemias may not only be consequences but also contributors to the pathogenesis and hence targets for prevention of T2DM.

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.

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