The Epigenetic Drug 5-Azacytidine Interferes with Cholesterol and Lipid Metabolism

Poirier, Steve; Samami, Samaneh; Mamarbachi, Maya; Demers, Annie; Chang, Ta−Yuan; Vance, Dennis E.; Hatch, Grant M.; Mayer, Gaétan

doi:10.1074/jbc.m114.563650

Cited by 38 publications

(34 citation statements)

References 55 publications

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Section: Epigenetics In Life Phase Transitionsmentioning

confidence: 99%

“…These two generations were also shorter, but as yet there is no link established between hypomethylation and body length. However, it should be noted that 5-azacytidine and other nucleoside analogues are not specific DNA methylation inhibitors and also affect other pathways (Gnyszka et al, 2013;Poirier et al, 2014).Further evidence for epigenetic inheritance in Drosophila and Daphnia is reviewed elsewhere (Youngson and Whitelaw, 2008), but the mechanisms of this 'soft' inheritance are generally not well understood.Evidence for epigenetics in locusts DNA methylationTo our knowledge, the earliest study on DNA methylation in locusts dates from 1951 (Wyatt, 1951), and reported that 0.96% of all cytosines are methylated in L. migratoria. Surprisingly, these early findings were followed by a 60 year gap.…”

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Epigenetics and locust life phase transitions

Ernst

Hiel

Depuydt

et al. 2015

Journal of Experimental Biology

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Insects are one of the most successful classes on Earth, reflected in an enormous species richness and diversity. Arguably, this success is partly due to the high degree to which polyphenism, where one genotype gives rise to more than one phenotype, is exploited by many of its species. In social insects, for instance, larval diet influences the development into distinct castes; and locust polyphenism has tricked researchers for years into believing that the drastically different solitarious and gregarious phases might be different species. Solitarious locusts behave much as common grasshoppers. However, they are notorious for forming vast, devastating swarms upon crowding. These gregarious animals are shorter lived, less fecund and transmit their phase characteristics to their offspring. The behavioural gregarisation occurs within hours, yet the full display of gregarious characters takes several generations, as does the reversal to the solitarious phase. Hormones, neuropeptides and neurotransmitters influence some of the phase traits; however, none of the suggested mechanisms can account for all the observed differences, notably imprinting effects on longevity and fecundity. This is why, more recently, epigenetics has caught the interest of the polyphenism field. Accumulating evidence points towards a role for epigenetic regulation in locust phase polyphenism. This is corroborated in the economically important locust species Locusta migratoria and Schistocerca gregaria. Here, we review the key elements involved in phase transition in locusts and possible epigenetic regulation. We discuss the relative role of DNA methylation, histone modification and small RNA molecules, and suggest future research directions. KEY WORDS: Locust phase, Polyphenism, Locust swarming, Locusta migratoria, Schistocerca gregaria, Apis mellifera, Invertebrate, DNA methylation, Histone modification, Methylome IntroductionThe term epigenetics tends to take a variety of meanings (Haig, 2004;Jablonka and Lamb, 2002). In its narrow sense, it can be defined as 'meiotically and mitotically heritable changes in gene expression, not based on DNA sequence alterations ' (Riggs et al., 1996). In a broader sense, it can also be interpreted as 'modifications of chromosome structure ' (Bird, 2007). Independent of the interpretation, however, epigenetics did not receive much attention in insect research until recent years.The most prominent epigenetic mechanisms, namely (1) methylation of cytosine in DNA, (2) modifications of histone proteins and (3) nucleosome positioning and regulation by noncoding RNA, were only rarely the focus of the entomology field. This may have been due to the general low, often almost undetectable, levels of methylation in insects and other invertebrates REVIEW Functional Genomics and Proteomics Lab, KU Leuven, Naamsestraat 59, bus 2465, B-3000 Leuven, Belgium.*Author for correspondence (Liliane.Schoofs@bio.kuleuven.be) (Glastad et al., 2011), including the prime model organisms Drosophila melanogaster and Caenorhabdi...

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Section: Epigenetics In Life Phase Transitionsmentioning

confidence: 99%

mentioning

confidence: 99%

Epigenetics and locust life phase transitions

Ernst

Hiel

Depuydt

et al. 2015

Journal of Experimental Biology

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“…Among the genes found to be elevated in Slfn2 eka/eka in comparison to wild‐type monocytes are: ACAT2 , which codes for the ER membrane‐bound sterol O ‐acyltransferase 2, which produces intracellular cholesteryl esters from long‐chain fatty acyl CoA and cholesterol; AGPAT9 (1‐acylglycerol‐3‐phosphate O ‐acyltransferase 9, the gene encoding for GPAT3), which regulates triacylglycerol biosynthesis and cytosolic lipid droplet formation; meteorin‐like ( METRNL ), which is highly expressed in activated monocytes and during adipogenesis and encodes for a protein that promotes lipid metabolism and inhibits adipose inflammation . Furthermore, our gene profile analysis showed that Slfn2 eka/eka monocytes have highly reduced levels of the genes ALOX15 , FABP4 and HPGD , which have regulatory roles in fatty acid and cholesterol metabolism, fatty acid uptake/transport and lipid/prostaglandin metabolism, respectively.…”

Section: Resultsmentioning

confidence: 99%

Slfn2 mutation‐induced loss of T‐cell quiescence leads to elevated de novo sterol synthesis

et al. 2017

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Acquisition of a 'quiescence programme' by naive T cells is important to provide a stress-free environment and resistance to apoptosis while preserving their responsiveness to activating stimuli. Therefore, the survival and proper function of naive T cells depends on their ability to maintain quiescence. Recently we demonstrated that by preventing chronic unresolved endoplasmic reticulum (ER) stress, Schlafen2 (Slfn2) maintains a stress-free environment to conserve a pool of naive T cells ready to respond to a microbial invasion. These findings strongly suggest an intimate association between quiescence and stress signalling. However, the connection between ER stress conditions and loss of T-cell quiescence is unknown. Here we demonstrate that homeostasis of cholesterol and lipids, is disrupted in T cells and monocytes from Slfn2-mutant, elektra, mice with higher levels of lipid rafts and lipid droplets found in these cells. Moreover, elektra T cells had elevated levels of free cholesterol and cholesteryl ester due to increased de novo synthesis and higher levels of the enzyme HMG-CoA reductase. As cholesterol plays an important role in the transition of T cells from resting to active state, and ER regulates cholesterol and lipid synthesis, we suggest that regulation of cholesterol levels through the prevention of ER stress is an essential component of the mechanism by which Slfn2 regulates quiescence.

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“…It eradicated the berberine effect on HNF1α and PCSK9 gene transcription process [55]. A diminished expression of PCSK9 and of other key genes involved in cholesterol and lipid metabolism was obtained in vitro and in vivo (in mouse liver) using 5-azacytidine, a DNA-hypomethylating agent [56], utilized in the treatment of myelodysplastic syndrome and acute myeloid leukemia. This drug inhibits de novo pyrimidine synthesis, followed by a disruption of lipid and cholesterol metabolism [56].…”

Section: Other Drugs That Influence Pcsk9 Metabolismmentioning

confidence: 99%

The Regulation of Proprotein Convertase Subtilisin/ Kexin Type 9 and Its Liver Involvement

Mihăilă

2017

BJMMR

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Introduction: Anti-proprotein convertase subtilisin/kexin type 9 (PCSK9) antibodies have been very effective to lower low-density lipoprotein (LDL)-cholesterol. They attracted the attention on PCSK9 enzyme role in multiple pathways and underlined the complex correlations between lipid metabolism and various other liver or extrahepatic diseases, that are insufficiently known. Hepatocyte nuclear factor 1, sterol regulatory element-binding protein (SREBP) 1c and SREBP2 are the main modulators of liver PCSK9 gene and protein expression, processes that can also be influenced by some natural and synthetic compounds (as berberine, or bortezomib and rosuvastatin, respectively), endoplasmic reticulum stress, metabolic status and the diurnal pattern. Aim: This minireview is an analysis of PCSK9 involvement in liver pathology. Results and Conclusion: PCSK9 is a key enzyme which increases LDL-receptor degradation. Hepatitis C virus (HCV) enters into hepatocytes in combination with lipoproteins through LDLreceptors and negatively modulates the PCSK9 expression to reduce LDL-receptor degradation and increase HCV entry into hepatocyte. PCSK9 modulates the hepatic CD81-a mediator of postattachment process. The greater the liver lipid accumulation the higher the plasma levels of PCSK9, which were observed in non-alcoholic fatty liver disease. A decreased expression of PCSK9 and an increased expression of LDL-receptor were shown in liver samples from patients Mini-review Article

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The Epigenetic Drug 5-Azacytidine Interferes with Cholesterol and Lipid Metabolism

Cited by 38 publications

References 55 publications

Epigenetics and locust life phase transitions

Epigenetics and locust life phase transitions

Slfn2 mutation‐induced loss of T‐cell quiescence leads to elevated de novo sterol synthesis

The Regulation of Proprotein Convertase Subtilisin/ Kexin Type 9 and Its Liver Involvement

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