Sabine Rütti

Low- and High-Density Lipoproteins Modulate Function, Apoptosis, and Proliferation of Primary Human and Murine Pancreatic β-Cells

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.

Atherosclerotic mice exhibit systemic inflammation in periadventitial and visceral adipose tissue, liver, and pancreatic islets.

OBJECTIVE Atherosclerosis is a chronic inflammatory disease of major conduit arteries. Similarly, obesity and type 2 diabetes mellitus are associated with accumulation of macrophages in visceral white adipose tissue and pancreatic islets. Our goal was to characterize systemic inflammation in atherosclerosis with hypercholesterolemia, but without obesity. METHODS AND RESULTS We compared 22-week-old apolipoprotein E knockout (ApoE(-/-)) with wild-type mice kept for 14 weeks on a high cholesterol (1.25%) diet (CD, n=8) and 8-week-old ApoE(-/-) with wild-type mice kept on a normal diet (ND, n=8). Hypercholesterolemic, atherosclerotic ApoE(-/-) mice on CD exhibited increased macrophages and T-cells in plaques and periadventitial adipose tissue that revealed elevated expression of MIP-1alpha, IL-1beta, IL-1 receptor, and IL-6. Mesenteric adipose tissue and pancreatic islets in ApoE(-/-) mice showed increased macrophages. Expression of IL-1beta was enhanced in mesenteric adipose tissue of ApoE(-/-) mice on CD. Furthermore, these mice exhibited steatohepatitis with macrophage and T-cell infiltrations as well as increased MIP-1alpha and IL-1 receptor expression. Blood glucose, insulin and total body weight did not differ between the groups. CONCLUSIONS In hypercholesterolemic lean ApoE(-/-) mice, inflammation extends beyond atherosclerotic plaques to the periadventitial and visceral adipose tissue, liver, and pancreatic islets without affecting glucose homeostasis.

Are HDL receptors really located where we think they are in the liver

DOI:10.1097/MOL.0000000000000322 The central role played by HDLs in reverse cholesterol transport has been studied in detail over the past years. One of the many functions of HDLs is to facilitate the uptake of cholesterol from cells of peripheral organs and to deliver it to the liver where it is transferred to the bile for excretion. Scavenger receptor class B type 1 (SRB1), which is abundantly expressed in the liver, participates in the selective hepatic cholesterol uptake from mature HDL particles [1]. A second recently discovered pathway involves HDL particle uptake by the P2Y13 purinergic receptor [2]. How SRB1 binds to HDLs and unloads its cholesterol cargo remains to be precisely determined, as different mechanisms have been proposed, implicating or not HDL particle endocytosis [3,4]. The experiments studying the implication of SRB1 in reverse cholesterol transport have so far always considered that this occurs in hepatocytes. In our current understanding of reverse cholesterol transport, liver sinusoidal endothelial cells (LSECs) act as a hedgerow separating blood circulation from the space of Disse (the extracellular space located between endothelial cells and hepatocytes), allowing HDLs to passively move from the circulation to the hepatocytes where their cholesterol cargo is processed [5]. Given the known high capacity of LSECs to scavenge many different particles, Ganesan and colleagues [6 & ] evaluated the participation of these cells in HDL metabolism in a study recently published in Scientific Reports. Using two different approaches (high-resolution confocal microscopy of ultrathin section of mouse liver and flow cytometry of purified cell populations), they convincingly concluded that LSECs express substantially more SRB1 than hepatocytes. They explain the discrepancy between their findings and what has been described so far in the literature by technical limitations of earlier approaches. If hepatocytes really express almost no SRB1, how do HDLs enter hepatocytes to be metabolized and how is cholesterol eventually secreted into the bile? Different routes are possible. Ganesan and colleagues do not exclude that a very small amount of SRB1, not detectable with current technologies,

Genetics and molecular biology: HDL plasticity and diversity of functions.

DOI:10.1097/MOL.0000000000000242 It has become clear in recent years that one should not consider HDLs as a homogenous entity when studying their functions. It is now indeed recognized and well documented that the HDL pool in the blood is made of a variety of HDL particles that differ in terms of structure, composition, and signaling molecules they carry. More than 80 proteins and peptides and more than 200 lipid species have been detected in HDLs [1]. However, a single HDL particle only carries a distinct subset of these molecules. For example, less than 10% of HDL particles carry the bioactive sphingosine-1-phosphate (S1P) lipid [1]. The diversity in the composition of HDLs can potentially explain the variety of their functions ranging from reverse cholesterol transport to antioxidative, anti-inflammatory, and cytoprotective activities (recently reviewed in [2] and [3]). HDL particles are more plastic and dynamic than initially thought as recently highlighted by O’Neill et al. [4] in their study on patients with periodontitis. This human model is of interest because it involves a low-grade inflammation systemic status developing from a local inflammation site (the teeth). The etiology of the inflammation is therefore somehow simpler than what is seen in more complex diseases such as diabetes or the metabolic syndrome. Moreover, this model allows researchers to study the impact of low-grade inflammation in individuals that serve as their own controls after periodontitis is treated. In this study, periodontitis led to disturbed HDL vascular functions such as diminished paraoxonase activity and reduced ability to induce nitric oxide production by endothelial cells. Intriguingly, the cholesterol extraction capacity of HDLs was not affected by periodontitis, suggesting that only a subset of HDL functions and activities are affected by lowgrade inflammation. Although this study is in line with others (see [5–7] for recent publications) that showed disease-induced alterations in HDL functions, its salient point is that low-grade inflammation-associated perturbations in HDL functions and composition could be fully normalized with the resolution of the disease. Hence, HDLs are very plastic particles whose functions are dynamically

Involvement of 4E-BP1 in the Protection Induced by HDLs on Pancreatic β-Cells

High-density lipoproteins (HDLs) protect pancreatic -cells against apoptosis. This property might relate to the increased risk to develop diabetes in patients with low HDL blood levels. However, the mechanisms by which HDLs protect -cells are poorly characterized. Here we used a transcriptomic approach to identify genes differentially modulated by HDLs in -cells subjected to apoptotic stimuli. The transcript encoding 4E-binding protein (4E-BP)1 was up-regulated by serum starvation, and HDLs blocked this increase. 4E-BP1 inhibits cap-dependent translation in its nonor hypophosphorylated state but it loses this ability when hyperphosphorylated. At the protein level, 4E-BP1 was also up-regulated in response to starvation and IL-1 , and this was blunted by HDLs. Whereas an ectopic increase of 4E-BP1 expression induced -cell death, silencing 4E-BP1 increase with short hairpin RNAs inhibited the apoptotic-inducing capacities of starvation. HDLs can therefore protect -cells by blocking 4E-BP1 protein expression, but this is not the sole protective mechanism activated by HDLs. Indeed, HDLs blocked apoptosis induced by endoplasmic reticulum stress with no associated decrease in total 4E-BP1 induction. Although, HDLs favored the phosphorylation, and hence the inactivation of 4E-BP1 in these conditions, this appeared not to be required for HDL protection. Our results indicate that HDLs can protect -cells through modulation of 4E-BP1 depending on the type of stress stimuli. J Clin Endocrinol Metab, September 2009, 94(9):3618–3619 jcem.endojournals.org 3619