Modes-of-Action Related to Repeated Dose Toxicity: Tissue-Specific Biological Roles of PPAR<i>γ</i>Ligand-Dependent Dysregulation in Nonalcoholic Fatty Liver Disease

Sharif, Merilin Al; Alov, Petko; Vitcheva, Vessela; Pajeva, Ilza; Tsakovska, Ivanka

doi:10.1155/2014/432647

Cited by 22 publications

(11 citation statements)

References 66 publications

(104 reference statements)

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“…Genes were selected; for example, Gsr , Gpx and Gss [17] that are involved in oxidative stress response pathway. Genes were also selected from immune pathway [18, 19], cell cycle regulation pathways [20] and DNA methylation pathways (S1 Table) [21, 22]. CpGs within the promoter region of the selected genes were targeted for methylation analysis (S2 Table).…”

Section: Methodsmentioning

confidence: 99%

Changes in DNA Methylation in Mouse Lungs after a Single Intra-Tracheal Administration of Nanomaterials

Tabish¹,

Poels²,

Byun³

et al. 2017

PLoS ONE

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AimsThis study aimed to investigate the effects of nanomaterial (NM) exposure on DNA methylation.Methods and ResultsIntra-tracheal administration of NM: gold nanoparticles (AuNPs) of 5-, 60- and 250-nm diameter; single-walled carbon nanotubes (SWCNTs) and multi-walled carbon nanotubes (MWCNTs) at high dose of 2.5 mg/kg and low dose of 0.25 mg/kg for 48 h to BALB/c mice. Study showed deregulations in immune pathways in NM-induced toxicity in vivo. NM administration had the following DNA methylation effects: AuNP 60 nm induced CpG hypermethylation in Atm, Cdk and Gsr genes and hypomethylation in Gpx; Gsr and Trp53 showed changes in methylation between low- and high-dose AuNP, 60 and 250 nm respectively, and AuNP had size effects on methylation for Trp53.ConclusionEpigenetics may be implicated in NM-induced disease pathways.

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Section: Methodsmentioning

confidence: 99%

Changes in DNA Methylation in Mouse Lungs after a Single Intra-Tracheal Administration of Nanomaterials

Tabish¹,

Poels²,

Byun³

et al. 2017

PLoS ONE

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“…Rats treated with Dex only had a TAG increment in the liver, but the same did not happen with the DFO group, suggesting an attenuator effect of FO. Some data suggest that PPAR-γ expression can be related to the increment of fat accumulation in liver in high fat diet experimental models (Fraulob et al 2012;Al Sharif et al 2014).…”

Section: R a F Tmentioning

confidence: 99%

Fish oil supplementation attenuates changes in plasma lipids caused by dexamethasone treatment in rats

Barbosa

Francisco

Motta

et al. 2016

Appl. Physiol. Nutr. Metab.

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Dexamethasone is an anti-inflammatory glucocorticoid that may alter glucose and lipid homeostasis when administered in high doses or for long periods of time. Omega-3 fatty acids, present in fish oil (FO), can be used as potential modulators of intermediary glucose and lipid metabolism. Herein, we evaluate the effects of FO supplementation (1 g·kg(-1) body weight (BW)) on glucose and lipid metabolism in rats treated with dexamethasone (0.5 mg·kg(-1) BW) for 15 days. Adult male Wistar rats were distributed among 4 groups: control (saline, 1 mL·kg(-1) BW and mineral oil, 1 g·kg(-1) BW), DEX (dexamethasone and mineral oil), FO (fish oil and saline), and DFO (fish oil and dexamethasone). Dexamethasone and saline were administered intraperitoneally, and fish oil and mineral oil were administered by gavage. We evaluated functional and molecular parameters of lipid and glycemic profiles at 8 days and at the end of treatment. FO supplementation increased hepatic docosahexaenoic acid (DEX: 5.6% ± 0.7%; DFO: 10.5% ± 0.8%) and eicosapentaenoic acid (DEX: 0.3% ± 0.0%; DFO: 1.3% ± 0.1%) contents and attenuated the increase of plasma triacylglycerol, total cholesterol, and non-high-density lipoprotein cholesterol concentrations in DFO rats compared with DEX rats. These effects seem not to depend on hepatic expression of insulin receptor substrate 1, protein kinase B, peroxisome proliferator-activated receptor γ coactivator 1-α, and peroxisome proliferator-activated receptor γ. There was no effect of supplementation on body weight loss, fasting glycemia, and glucose tolerance in rats treated with dexamethasone. In conclusion, we show that FO supplementation for 15 days attenuates the dyslipidemia induced by dexamethasone treatment.

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“…In contrast, expression of seven genes ( Pparg , Cd36 , Slc2a4 , Atox1 , Skp1 , Angptl3 , and Pnpla3 ) showed a gender-specific bias. The aberrant expression of PPARγ [ 51 ] is associated with NAFLD [ 52 – 54 ], and liver-specific loss of PPARγ is known to markedly attenuate the pathogenesis of NAFLD [ 55 , 56 ]. The PPARγ activates SREBP-1c, a master transcription factor that promotes de novo lipid synthesis [ 57 ].…”

Section: Discussionmentioning

confidence: 99%

Sex-specific differences in hepatic steatosis in obese spontaneously hypertensive (SHROB) rats

et al. 2018

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BackgroundPatients with metabolic syndrome, who are characterized by co-existence of insulin resistance, hypertension, hyperlipidemia, and obesity, are also prone to develop non-alcoholic fatty liver disease (NAFLD). Although the prevalence and severity of NAFLD is significantly greater in men than women, the mechanisms by which gender modulates the pathogenesis of hepatic steatosis are poorly defined. The obese spontaneously hypertensive (SHROB) rats represent an attractive model of metabolic syndrome without overt type 2 diabetes. Although pathological manifestation caused by the absence of a functional leptin receptor has been extensively studied in SHROB rats, it is unknown whether these animals elicited sex-specific differences in the development of hepatic steatosis.MethodsWe compared hepatic pathology in male and female SHROB rats. Additionally, we examined key biochemical and molecular parameters of signaling pathways linked with hyperinsulinemia and hyperlipidemia. Finally, using methods of quantitative polymerase chain reaction (qPCR) and western blot analysis, we quantified expression of 45 genes related to lipid biosynthesis and metabolism in the livers of male and female SHROB rats.ResultsWe show that all SHROB rats developed hepatic steatosis that was accompanied by enhanced expression of SREBP1, SREBP2, ACC1, and FASN proteins. The livers of male rats also elicited higher induction of Pparg, Ppara, Slc2a4, Atox1, Skp1, Angptl3, and Pnpla3 mRNAs. In contrast, the livers of female SHROB rats elicited constitutively higher levels of phosphorylated JNK and AMPK and enhanced expression of Cd36.ConclusionBased on these data, we conclude that the severity of hepatic steatosis in male and female SHROB rats was mainly driven by increased de novo lipogenesis. Moreover, male and female SHROB rats also elicited differential severity of hepatic steatosis that was coupled with sex-specific differences in fatty acid transport and esterification.Electronic supplementary materialThe online version of this article (10.1186/s13293-018-0202-x) contains supplementary material, which is available to authorized users.

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Modes-of-Action Related to Repeated Dose Toxicity: Tissue-Specific Biological Roles of PPARγLigand-Dependent Dysregulation in Nonalcoholic Fatty Liver Disease

Cited by 22 publications

References 66 publications

Changes in DNA Methylation in Mouse Lungs after a Single Intra-Tracheal Administration of Nanomaterials

Changes in DNA Methylation in Mouse Lungs after a Single Intra-Tracheal Administration of Nanomaterials

Fish oil supplementation attenuates changes in plasma lipids caused by dexamethasone treatment in rats

Sex-specific differences in hepatic steatosis in obese spontaneously hypertensive (SHROB) rats

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