Abstract-Apolipoprotein E (apoE) is synthesized in the liver and in macrophages, and it has antiatherogenic properties that are mediated, at least in part, through the regulation of plasma cholesterol homeostasis. Previous data suggest that apoE also has antiinflammatory properties that may contribute to protection against atherosclerosis independent of its role in lipid metabolism. In this study, apoE knockout and C57BL/6 mice were stimulated with low-dose lipopolysaccharide (LPS) and other Toll-like receptor (TLR) agonists. We show that apoE modulates the systemic type I inflammatory response in vivo. The proinflammatory cytokines tumor necrosis factor ␣, interleukin (IL)-6, IL-12, and interferon-␥ were upregulated to a significantly greater extent in apoE-deficient mice than in wild-type mice at both the mRNA and protein levels following administration of LPS. In contrast, hypercholesterolemic low-density lipoprotein receptor/apobec-1 double knockout mice had a similar cytokine response as wild-type mice, eliminating hypercholesterolemia as a cause for the exaggerated cytokine response. Importantly, reconstitution of apoE expression in the liver of apoE-deficient mice normalized the LPS-induced plasma protein levels of IL-12p40.
The excess accumulation of lipids in islets is thought to contribute to the development of diabetes in obesity by impairing -cell function. However, lipids also serve a nutrient function in islets, and fatty acids acutely increase insulin secretion. A better understanding of lipid metabolism in islets will shed light on complex effects of lipids on -cells. Adipose differentiation-related protein (ADFP) is localized on the surface of lipid droplets in a wide range of cells and plays an important role in intracellular lipid metabolism. We found that ADFP was highly expressed in murine -cells. Moreover, islet ADFP was increased in mice on a high-fat diet (3.5-fold of control) and after fasting (2.5-fold of control), revealing dynamic changes in ADFP in response to metabolic cues. ADFP expression was also increased by addition of fatty acids in human islets. The downregulation of ADFP in MIN6 cells by antisense oligonucleotide (ASO) suppressed the accumulation of triglycerides upon fatty acid loading (56% of control) along with a reduction in the mRNA levels of lipogenic genes such as diacylglycerol O-acyltransferase-2 and fatty acid synthase. Fatty acid uptake, oxidation, and lipolysis were also reduced by downregulation of ADFP. Moreover, the reduction of ADFP impaired the ability of palmitate to increase insulin secretion. These findings demonstrate that ADFP is important in regulation of lipid metabolism and insulin secretion in -cells. MIN6 cells; oleic acid; palmitic acid; high-fat diet; fasting THE CURRENT EPIDEMIC OF OBESITY is feared to increase the prevalence of type 2 diabetes due to its contribution to insulin resistance (38). However, excess adiposity and dyslipidemia commonly seen in obesity may have an additional role in the development of diabetes by directly damaging -cells (45). Indeed, prolonged exposure to elevated levels of fatty acids impairs insulin secretion in vivo and ex vivo, a phenomenon termed "lipotoxicity" (16,47,50,56). Ceramide generation, an increase in reactive oxygen species, 12/15-lipoxygenase activation, and atypical protein kinase C activation are some of the mechanisms proposed for islet dysfunction and lipid-induced apoptosis (5, 44, 51, 52). On the other hand, lipids serve a nutrient function and are the principal energy source in islets deprived of exogenous nutrients (34, 54). Not only does acute exposure to fatty acids augment insulin secretion ex vivo, but a rise in fatty acids also facilitates glucose-stimulated insulin secretion (GSIS) after fasting in vivo (10). The activation of cell surface fatty acid receptor G protein-coupled receptor 40 (GPR40) plays a significant role in the augmentation of insulin secretion by fatty acids. However, cellular uptake of fatty acids is also believed to contribute to the insulin secretion by provision of lipid metabolites, including long-chain acyl-CoA and diacylglycerides (25,43,65). Thus, fatty acids play complex and seemingly contradictory roles in -cells, which calls for a better understanding of fatty acid uptake, storage...
HDL and its associated apo, APOE, inhibit S-phase entry of murine aortic smooth muscle cells. We report here that the antimitogenic effect of APOE maps to the N-terminal receptor-binding domain, that APOE and its N-terminal domain inhibit activation of the cyclin A promoter, and that these effects involve both pocket protein-dependent and independent pathways. These antimitogenic effects closely resemble those seen in response to activation of the prostacyclin receptor IP. Indeed, we found that HDL and APOE suppress aortic smooth muscle cell cycle progression by stimulating Cox-2 expression, leading to prostacyclin synthesis and an IP-dependent inhibition of the cyclin A gene. Similar results were detected in human aortic smooth muscle cells and in vivo using mice overexpressing APOE. Our results identify the Cox-2 gene as a target of APOE signaling, link HDL and APOE to IP action, and describe a potential new basis for the cardioprotective effect of HDL and APOE. Conflict of interest:The authors have declared that no conflict of interest exists. Nonstandard abbreviations used: smooth muscle cells (SMCs); cyclin-dependent kinase (cdk); retinoblastoma protein (pRb); cAMP response element (CRE); cAMP response element-binding protein (CREB); electrophoretic mobility shift assay (EMSA); 6-keto-prostaglandin F1α (6-keto-PGF1α); recombinant adenovirus encoding the human APOE3 cDNA (AdAPOE3).
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