ApoE genotype-specific inhibition of apoptosis

DeKroon, Robert M.; Mihovilovic, Mirta; Goodger, Zoe V.; Robinette, Jennifer B.; Sullivan, Patrick M.; Saunders, Ann M.; Strittmatter, Warren J.

doi:10.1194/jlr.m300097-jlr200

Cited by 34 publications

(26 citation statements)

References 28 publications

(28 reference statements)

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“…Similarly, apoE's effect on preventing lymphocyte death increases the immune response, enhancing the proinflammatory response to polymicrobial infections, and, thus, increased mortality. Our findings support reports which demonstrate that inhibition of apoptosis by lipoproteins depends on APOE genotype (41), and that apoptotic cells and fragments accumulate markedly in a range of tissues in apoE-deficient mice (42). The predominant Th1 response observed in serum from septic rats treated with apoE correlates with our observations of decreased apoptosis and Th2 induction.…”

Section: Discussionsupporting

confidence: 81%

Apolipoprotein E-Mediated Immune Regulation in Sepsis

Kattan

Kasravi

Elford

et al. 2008

The Journal of Immunology

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Lipids and lipoproteins have emerged as key constituents of the immune response to microbial infection. We, therefore, sought to understand the complex interaction between lipoprotein metabolism and sepsis. Apolipoprotein E (apoE), a component of plasma lipoproteins, has been suggested to bind and traffic Ags for NKT cell activation. However, apoE’s role in sepsis has not been demonstrated. In this study, we examined the effect of exogenous apoE in a rat model of septic peritonitis, induced by cecal ligation and puncture. We demonstrate that 48 h after serial injections of apoE, septic mortality increased in a dose-dependent manner. While sepsis resulted in increased splenic and decreased hepatic and circulating NKT cell populations, serial injections of apoE for 24 h after cecal ligation and puncture increased the frequency, cell number, and BrdU uptake in splenic and hepatic NKT cell populations, while concomitantly depleting these populations in the circulation. These changes were correlated with elevated alanine amino transferase levels, an indicator of liver injury. Interestingly, while sepsis increased hepatic T cell apoptosis and necrosis, apoE reversed these changes. apoE also promoted increases in predominantly Th1 cytokine levels in sera and a decrease in IL-4, the main NKT cell-derived Th2 cytokine. Consequently, apoE treatment is associated with increased sepsis-induced mortality, and increased NKT cell frequency and proliferation in the liver and spleen, with concomitant decreases in these NKT cell parameters in the peripheral circulation. apoE treatment also promoted a Th1 cytokine response, increased the degree of liver injury, and decreased apoptosis in hepatic lymphocytes.

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Section: Discussionsupporting

confidence: 81%

Apolipoprotein E-Mediated Immune Regulation in Sepsis

Kattan

Kasravi

Elford

et al. 2008

The Journal of Immunology

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“…5,20 ApoE4-VLDL binding to CLL cells may enhance leukemia cell apoptosis initiated by various means (for example, chemotherapy) and improve overall survival.…”

Section: Discussionmentioning

confidence: 99%

“…3 Lipoprotein particles in sera also modulate apoptotic cell death. 4,5 High-density lipoprotein particles, interacting through a sphingosine-1-phosphate receptor 3 (S1P 3 ), inhibit apoptosis by activating the PI-3-K/Akt pathway. 4 Very low density lipoprotein (VLDL) particles containing apolipoprotein E4 (apoE4) (but not the apoE3 or apoE2 isoforms) inhibit this pathway.…”

Section: Introductionmentioning

confidence: 99%

Apolipoprotein E genotype as a determinant of survival in chronic lymphocytic leukemia

et al. 2008

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Survival of chronic lymphocytic leukemia (CLL) cells requires sustained activation of the antiapoptotic PI-3-K/Akt pathway, and many therapies for CLL cause leukemia cell death by triggering apoptosis. Blood lipoprotein particles are either pro-or antiapoptotic. High-density lipoprotein particles are antiapoptotic through sphingosine-1-phosphate receptor 3-mediated activation of the PI-3-K/Akt pathway. Apolipoprotein E4 (apoE4)-very low density lipoproteins (VLDL) increase apoptosis, but the apoE2-VLDL and apoE3-VLDL isoforms do not. As increased B-cell apoptosis favors longer survival of CLL patients, we hypothesized that APOE4 genotype would beneficially influence the clinical course of CLL. We report here that women (but not men) with an APOE4 genotype had markedly longer survival than non-APOE4 patients. VLDL is metabolized to low-density lipoprotein through lipoprotein lipase. Higher levels of lipoprotein lipase mRNA in these CLL patients correlated with shorter survival. The beneficial effect of APOE4 in CLL survival is likely mediated through APOE4 allele-specific regulation of leukemia cell apoptosis. The APOE allele and genotype distribution in these CLL patients is the same as in unaffected control populations, suggesting that although APOE genotype influences CLL outcome and response to therapy, it does not alter susceptibility to developing this disease.

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“…Caspase 3/7 activity was measured using the Apo-ONE assay developed by Promega (Madison, WI) using a 1:200 dilution of substrate as reported previously (9). Caspase activity (%) was determined by subtracting the relative fluorescence units obtained in the presence of 20% FCS from that obtained in SFM and assigning 100% caspase activation to this difference.…”

Section: Caspase 3/7 Activity Assaymentioning

confidence: 99%

“…Cells were grown to near confluence on 96-well plates (Phoenix Research Products, Hayword, CA). To induce apoptosis, fetal calf serum (FCS)-containing medium was removed and cells were washed with RPMI, as reported previously (9). Each well received 70 ml of a) serum-free medium (SFM), consisting of RPMI 1640 supplemented with 0.2 mg/ml hydrocortisone and 1.0 mg/ml ascorbic acid (Sigma); b) SFM supplemented with 20% characterized FCS (HyClone, Logan, UT); or c) SFM supplemented with the indicated concentrations of lipoproteins.…”

Section: Cell Culture and Induction Of Apoptosismentioning

confidence: 99%

High-fat/high-cholesterol diet promotes a S1P receptor-mediated antiapoptotic activity for VLDL

Mihovilovic

Robinette

DeKroon

et al. 2007

Journal of Lipid Research

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Withdrawing growth factors or serum from endothelial cells leads to the activation of effector caspases 3 and 7, resulting in apoptotic cell death. HDL protects against caspase induction through sphingosine-1-phosphate (S1P) receptors. This anti-caspase activity of HDL is antagonized by VLDL from apolipoprotein E4 (apoE4) (genotype, APOE4/4; apolipoprotein, apoE) targeted replacement (TR) mice, but not by VLDL from TR APOE3/3 mice, and requires the binding of apoE4-VLDL to an LDL receptor family member. In the absence of HDL, apoE4-VLDL and apoE3-VLDL from TR mice have limited antiapoptotic activity. In contrast, we show here that a high-fat/highcholesterol/cholate diet (HFD) radically alters this biological activity of VLDL. On HFD, both apoE3-VLDL and apoE4-VLDL (HFD VLDL) inhibit caspase 3/7 activation initiated by serum withdrawal. This activity of HFD VLDL is independent of an LDL receptor family member but requires the activation of S1P 3 receptors, as shown by the ability of pharmacological block of S1P receptors by VPC 23019 and by small interfering RNA-mediated downregulation of S1P 3 receptors to inhibit HFD VLDL anticaspase activity.-Mihovilovic, M., J. B. Robinette, R. M. DeKroon, P. M. Sullivan, and W. J. Strittmatter. High-fat/highcholesterol diet promotes a S1P receptor-mediated antiapoptotic activity for VLDL. J. Lipid Res. 2007. 48: 806-815.

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ApoE genotype-specific inhibition of apoptosis

Cited by 34 publications

References 28 publications

Apolipoprotein E-Mediated Immune Regulation in Sepsis

Apolipoprotein E-Mediated Immune Regulation in Sepsis

Apolipoprotein E genotype as a determinant of survival in chronic lymphocytic leukemia

High-fat/high-cholesterol diet promotes a S1P receptor-mediated antiapoptotic activity for VLDL

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