The trail to deadly membrane rafts

Läng, Florian

doi:10.1007/s00109-012-0975-z

Cited by 5 publications

(13 citation statements)

References 17 publications

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“…Furthermore, experiments in Abcc6 − / − mice showed a 25% reduction in plasma HDL cholesterol [20], confirming the potential role of ABCC6 in lipid homeostasis as described before [30]. Recently, Guo et al demonstrated that atorvastatin counteracts soft tissue mineralization in Abcc6-deficient mice [31]. Statins are widely used to inhibit HMG CoA reductase activity, the rate-limiting step in cholesterol biosynthesis, to reduce plasma low-density lipoprotein cholesterol (LDL-C) levels and CHD risk [32].…”

Section: Introductionsupporting

confidence: 59%

“…Therefore, our data indicate a conceivable role for ABCC6 in human cellular cholesterol and lipoprotein metabolism, observing significant differences between PXE fibroblasts and healthy controls. The results of our study provide a first hint, uncovering the molecular mechanisms underlying the positive outcome of statin treatment observed in Abcc6 −/− mice [31,52]. Moreover, newly published data including whole-genome sequencing of 89 individuals of polar and brown bears revealed that ABCC6 is one of the important genes which has been under high positive selection in polar bears, enabling to deal with life-long elevated LDL levels that are associated with high risk of heart disease in humans [53].…”

Section: Discussionmentioning

confidence: 98%

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ABCC6- a new player in cellular cholesterol and lipoprotein metabolism?

et al. 2014

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BackgroundDysregulations in cholesterol and lipid metabolism have been linked to human diseases like hypercholesterolemia, atherosclerosis or the metabolic syndrome. Many ABC transporters are involved in trafficking of metabolites derived from these pathways. Pseudoxanthoma elasticum (PXE), an autosomal-recessive disease caused by ABCC6 mutations, is characterized by atherogenesis and soft tissue calcification.MethodsIn this study we investigated the regulation of cholesterol biosynthesis in human dermal fibroblasts from PXE patients and healthy controls.ResultsGene expression analysis of 84 targets indicated dysregulations in cholesterol metabolism in PXE fibroblasts. Transcript levels of ABCC6 were strongly increased in lipoprotein-deficient serum (LPDS) and under serum starvation in healthy controls. For the first time, increased HMG CoA reductase activities were found in PXE fibroblasts. We further observed strongly elevated transcript and protein levels for the proprotein convertase subtilisin/kexin type 9 (PCSK9), as well as a significant reduction in APOE mRNA expression in PXE.ConclusionIncreased cholesterol biosynthesis, elevated PCSK9 levels and reduced APOE mRNA expression newly found in PXE fibroblasts could enforce atherogenesis and cardiovascular risk in PXE patients. Moreover, the increase in ABCC6 expression accompanied by the induction of cholesterol biosynthesis supposes a functional role for ABCC6 in human lipoprotein and cholesterol homeostasis.

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Section: Introductionsupporting

confidence: 59%

Section: Discussionmentioning

confidence: 98%

ABCC6- a new player in cellular cholesterol and lipoprotein metabolism?

et al. 2014

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“…The diseases closely resembles the human disorder in terms of histopathology, pathogenesis, lack of sex bias, and MHC class II association [14]. Diabetes can be detected in the LEW1.WR1 rat beginning at 14 days following virus infection [15]. We recently demonstrated that the innate immune system plays a key role in the mechanism triggering beta cell autoimmunity in the BioBreeding Diabetes Resistant and LEW1.WR1 rats [4, 15–17].…”

Section: Introductionmentioning

confidence: 99%

“…Diabetes can be detected in the LEW1.WR1 rat beginning at 14 days following virus infection [15]. We recently demonstrated that the innate immune system plays a key role in the mechanism triggering beta cell autoimmunity in the BioBreeding Diabetes Resistant and LEW1.WR1 rats [4, 15–17]. Indeed, activation of the innate immune system with TLR agonists, such as the viral mimic polyinosinic: polycytidylic acid (poly I:C) or CpG DNA, followed by infection with KRV substantially exacerbates diabetes [18, 19].…”

Section: Introductionmentioning

confidence: 99%

“…Moreover, infection with KRV leads to a robust proinflammatory response linked with the up-regulation of a vast array of proinflammatory cytokines and chemokines in the spleen, pancreatic lymph nodes and Peyer’s patches via mechanisms that involve TLR9 pathways [4, 17, 18]. Lastly, modulation of virus-induced innate immunity with steroids [18], IL-1 receptor antagonist [16], histone deacetylase inhibitors [15], or antibiotics [4] ameliorates disease development.…”

Section: Introductionmentioning

confidence: 99%

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Implication of the intestinal microbiome as a potential surrogate marker of immune responsiveness to experimental therapies in autoimmune diabetes

Needell

Dinarello

et al. 2017

PLoS ONE

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Type 1 diabetes (T1D) is an autoimmune proinflammatory disease with no effective intervention. A major obstacle in developing new immunotherapies for T1D is the lack of means for monitoring immune responsiveness to experimental therapies. The LEW1.WR1 rat develops autoimmunity following infection with the parvovirus Kilham rat virus (KRV) via mechanisms linked with activation of proinflammatory pathways and alterations in the gut bacterial composition. We used this animal to test the hypothesis that intervention with agents that block innate immunity and diabetes is associated with a shift in the gut microbiota. We observed that infection with KRV results in the induction of proinflammatory gene activation in both the spleen and pancreatic lymph nodes. Furthermore, administering animals the histone deacetylase inhibitor ITF-2357 and IL-1 receptor antagonist (Anakinra) induced differential STAT-1 and the p40 unit of IL-12/IL-23 gene expression. Sequencing of bacterial 16S rRNA genes demonstrated that both ITF-2357 and Anakinra alter microbial diversity. ITF-2357 and Anakinra modulated the abundance of 23 and 8 bacterial taxa in KRV-infected animals, respectively, of which 5 overlapped between the two agents. Lastly, principal component analysis implied that ITF-2357 and Anakinra induce distinct gut microbiomes compared with those from untreated animals or rats provided KRV only. Together, the data suggest that ITF-2357 and Anakinra differentially influence the innate immune system and the intestinal microbiota and highlight the potential use of the gut microbiome as a surrogate means of assessing anti-inflammatory immune effects in type 1 diabetes.

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Phospholipase C and D regulation of Src, calcium release and membrane fusion during Xenopus laevis development

Stith

2015

Developmental Biology

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This review emphasizes how lipids regulate membrane fusion and the proteins involved in three developmental stages: oocyte maturation to the fertilizable egg, fertilization and during first cleavage. Decades of work show that phosphatidic acid (PA) releases intracellular calcium, and recent work shows that the lipid can activate Src tyrosine kinase or phospholipase C during Xenopus fertilization. Numerous reports are summarized to show three levels of increase in lipid second messengers inositol 1,4,5-trisphosphate and sn 1,2-diacylglycerol (DAG) during the three different developmental stages. In addition, possible roles for PA, ceramide, lysophosphatidylcholine, plasmalogens, phosphatidylinositol 4-phosphate, phosphatidylinositol 5-phosphate, phosphatidylinositol 4,5-bisphosphate, membrane microdomains (rafts) and phosphatidylinositol 3,4,5-trisphosphate in regulation of membrane fusion (acrosome reaction, sperm-egg fusion, cortical granule exocytosis), inositol 1,4,5-trisphosphate receptors, and calcium release are discussed. The role of six lipases involved in generating putative lipid second messengers during fertilization is also discussed: phospholipase D, autotaxin, lipin1, sphingomyelinase, phospholipase C, and phospholipase A2. More specifically, proteins involved in developmental events and their regulation through lipid binding to SH3, SH4, PH, PX, or C2 protein domains is emphasized. New models are presented for PA activation of Src (through SH3, SH4 and a unique domain), that this may be why the SH2 domain of PLCγ is not required for Xenopus fertilization, PA activation of phospholipase C, a role for PA during the calcium wave after fertilization, and that calcium/calmodulin may be responsible for the loss of Src from rafts after fertilization. Also discussed is that the large DAG increase during fertilization derives from phospholipase D production of PA and lipin dephosphorylation to DAG.

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The trail to deadly membrane rafts

Cited by 5 publications

References 17 publications

ABCC6- a new player in cellular cholesterol and lipoprotein metabolism?

ABCC6- a new player in cellular cholesterol and lipoprotein metabolism?

Implication of the intestinal microbiome as a potential surrogate marker of immune responsiveness to experimental therapies in autoimmune diabetes

Phospholipase C and D regulation of Src, calcium release and membrane fusion during Xenopus laevis development

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