Characterization of Cholesterol Homeostasis in Telomerase-immortalized Tangier Disease Fibroblasts Reveals Marked Phenotype Variability

Kannenberg, Frank; Gorzelniak, Kerstin; Jäger, Kathrin; Fobker, Manfred; Rust, Stephan; Repa, Joyce J.; Roth, Michael G.; Björkhem, Ingemar; Walter, Michael

doi:10.1074/jbc.m113.500256

Cited by 11 publications

(10 citation statements)

References 51 publications

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“…To further examine the function of Abca1 was critical for inflammatory repression, we reconstituted iBMDM from myeloid-specific Abca1−/− mice with wild-type Abca1 or two different Abca1 point mutants that lacks cholesterol efflux ability, N935S and C1477R ( Singaraja et al, 2006 ; Kannenberg et al, 2013 ). When Abca1 -deficient cells were reconstituted with wild-type Abca1, inflammatory gene expression was repressed by LXR activation; however, this effect was lost in cells expressing the N935S or C1477R mutants ( Figure 4C ).…”

Section: Resultsmentioning

confidence: 99%

LXRs link metabolism to inflammation through Abca1-dependent regulation of membrane composition and TLR signaling

Ito

Hong

Rong

et al. 2015

eLife

225

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The liver X receptors (LXRs) are transcriptional regulators of lipid homeostasis that also have potent anti-inflammatory effects. The molecular basis for their anti-inflammatory effects is incompletely understood, but has been proposed to involve the indirect tethering of LXRs to inflammatory gene promoters. Here we demonstrate that the ability of LXRs to repress inflammatory gene expression in cells and mice derives primarily from their ability to regulate lipid metabolism through transcriptional activation and can occur in the absence of SUMOylation. Moreover, we identify the putative lipid transporter Abca1 as a critical mediator of LXR's anti-inflammatory effects. Activation of LXR inhibits signaling from TLRs 2, 4 and 9 to their downstream NF-κB and MAPK effectors through Abca1-dependent changes in membrane lipid organization that disrupt the recruitment of MyD88 and TRAF6. These data suggest that a common mechanism-direct transcriptional activation-underlies the dual biological functions of LXRs in metabolism and inflammation.DOI: http://dx.doi.org/10.7554/eLife.08009.001

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Section: Resultsmentioning

confidence: 99%

LXRs link metabolism to inflammation through Abca1-dependent regulation of membrane composition and TLR signaling

Ito

Hong

Rong

et al. 2015

eLife

225

224

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“…Finally atheroprotective LXR-dependent SREBP1c signaling was normal in TT1, but was suppressed in TT2 cells. These and prior results may help to understand the differential susceptibility to CHD in TD [24]. …”

Section: Introductionmentioning

confidence: 93%

“…Investigators compared the effects of an ABCA1 mutation that produced an apparent lack of atherosclerosis (TD family 1, N935S) with an ABCA1 mutation with a functional ABCA1 knockout that was associated with severe atherosclerosis (TD family 2, Leu(548):Leu(575)-End), using primary and telomerase-immortalized fibroblasts [24]. Telomerase-immortalized TD fibroblasts of family 1 (TT1) showed 30% residual cholesterol efflux capacity in response to apoA-I, whereas telomerase-immortalized TD fibroblasts of family 2 (TT2) showed only 20%.…”

Section: Introductionmentioning

confidence: 99%

High-density lipoprotein metabolism, composition, function, and deficiency

Schaefer

Anthanont

Asztalos

2014

Current Opinion in Lipidology

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Purpose of review Our purpose was to examine recent advances in our knowledge of high density lipoprotein (HDL) metabolism, composition, function, and coronary heart disease (CHD), as well as marked HDL deficiency states due to mutations at the apolipoprotein (apo) A-I, ATP binding cassette transfer protein A1 (ABCA1), and lecithin cholesterol acyltransferase (LCAT) gene loci. Recent findings It has been documented that apoA-I, myeloperoxidase (MPO), and paraoxonase 1 (PON1) form a complex in HDL that is critical for HDL binding and function. MPO has a negative impact on HDL function, while PON1 has a beneficial effect. Patients that lack apoA-I develop markedly premature CHD. Patients that lack ABCA1 transporter function have only very small discoidal preβ-1 HDL, and develop hepatosplenomegaly, intermittent neuropathy and premature CHD, although significant heterogeneity for these disorders has been reported. Patients with LCAT deficiency have abnormal small discoidal low density lipoproteins and HDL particles, and develop kidney failure. Enzyme replacement therapy is being developed for the latter disorder. Summary Recent data indicates that proteins other than apoA-I and apoA-II such as MPO and PON1 have important effects on HDL function. There has been considerable recent progress made in our understanding of HDL protein content and function.

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“…Numerous findings in humans have shown that telomere shortening correlates with the degree of atherosclerosis in vivo [ 15 ]. Experimental data suggest that the activation of telomerase can delay and—at least in part—reverse the senescent phenotype [ 15 , 117 , 118 ]. The pathologically vicious circle between replicative aging and inflammation by atherosclerosis could be reversed by a telomerase-based therapy [ 119 ].…”

Section: Telomerase As a Target For Regenerative Medicinementioning

confidence: 99%

Therapeutic Targeting of Telomerase

Jäger

Walter

2016

Genes

Self Cite

114

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Telomere length and cell function can be preserved by the human reverse transcriptase telomerase (hTERT), which synthesizes the new telomeric DNA from a RNA template, but is normally restricted to cells needing a high proliferative capacity, such as stem cells. Consequently, telomerase-based therapies to elongate short telomeres are developed, some of which have successfully reached the stage I in clinical trials. Telomerase is also permissive for tumorigenesis and 90% of all malignant tumors use telomerase to obtain immortality. Thus, reversal of telomerase upregulation in tumor cells is a potential strategy to treat cancer. Natural and small-molecule telomerase inhibitors, immunotherapeutic approaches, oligonucleotide inhibitors, and telomerase-directed gene therapy are useful treatment strategies. Telomerase is more widely expressed than any other tumor marker. The low expression in normal tissues, together with the longer telomeres in normal stem cells versus cancer cells, provides some degree of specificity with low risk of toxicity. However, long term telomerase inhibition may elicit negative effects in highly-proliferative cells which need telomerase for survival, and it may interfere with telomere-independent physiological functions. Moreover, only a few hTERT molecules are required to overcome senescence in cancer cells, and telomerase inhibition requires proliferating cells over a sufficient number of population doublings to induce tumor suppressive senescence. These limitations may explain the moderate success rates in many clinical studies. Despite extensive studies, only one vaccine and one telomerase antagonist are routinely used in clinical work. For complete eradication of all subpopulations of cancer cells a simultaneous targeting of several mechanisms will likely be needed. Possible technical improvements have been proposed including the development of more specific inhibitors, methods to increase the efficacy of vaccination methods, and personalized approaches. Telomerase activation and cell rejuvenation is successfully used in regenerative medicine for tissue engineering and reconstructive surgery. However, there are also a number of pitfalls in the treatment with telomerase activating procedures for the whole organism and for longer periods of time. Extended cell lifespan may accumulate rare genetic and epigenetic aberrations that can contribute to malignant transformation. Therefore, novel vector systems have been developed for a ‘mild’ integration of telomerase into the host genome and loss of the vector in rapidly-proliferating cells. It is currently unclear if this technique can also be used in human beings to treat chronic diseases, such as atherosclerosis.

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Characterization of Cholesterol Homeostasis in Telomerase-immortalized Tangier Disease Fibroblasts Reveals Marked Phenotype Variability

Cited by 11 publications

References 51 publications

LXRs link metabolism to inflammation through Abca1-dependent regulation of membrane composition and TLR signaling

LXRs link metabolism to inflammation through Abca1-dependent regulation of membrane composition and TLR signaling

High-density lipoprotein metabolism, composition, function, and deficiency

Therapeutic Targeting of Telomerase

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