Hypermethylation of hepatic Gck promoter in ageing rats contributes to diabetogenic potential

Jiang, Minghong; Fei, J.; Lan, Michael S.; Li, Zhiqiang; Liu, Min-Jie; Fan, Weiwei; Gao, Xin; Lu, Daru

doi:10.1007/s00125-008-1034-8

Cited by 76 publications

(62 citation statements)

References 47 publications

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“…A chronically high secretion of insulin could explain our observation of low blood glucose and high GK activity. Alternatively, high level of hypoxia inducible factor (HIF)-1␣ (41) or hypomethylation of GK gene promoter region (42,43) are potential mechanisms accounting for high GK activity. On the other hand, high activity of GK should favor a greater availability of glucose-derived substrates for acetyl-CoA production from glycolysis.…”

Section: Discussionmentioning

confidence: 99%

Neonatal Exposure to Oxidants Induces Later in Life a Metabolic Response Associated to a Phenotype of Energy Deficiency in an Animal Model of Total Parenteral Nutrition

et al. 2010

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Failure to protect total parenteral nutrition (TPN) from ambient light exacerbates the generation of peroxides, which affects blood glucose and plasma triacylglyceride (TG) in neonates. Based on the concept that the origin of adult diseases can be traced back to perinatal life, it was hypothesized that neonatal exposure to peroxides may affect energy availability later in life. Three-day-old guinea pigs, fitted with a jugular catheter, were fed regular chow (sham) Ϯ i. T he association between oxidative stress and characteristic features of the metabolic syndrome, such as diabetes, hypertension, and dyslipidemia, is well documented (1-6). Human (7) and animal studies (8,9) suggest that the origin of the metabolic syndrome can be traced back to perinatal life, a time when newborn infants are at greater risk of oxidative stress caused by weak antioxidant defenses (10 -12) or exposure to an oxidative environment or both (13-18). Several reports suggest that, in neonates, oxidative stress triggers the events that lead to programming of adult diseases (19 -22).Total parenteral nutrition (TPN) represents a source of oxidants in the form of peroxides that can be calibrated either by applying or not photoprotecting. The peroxides are derived from interactions between dissolved oxygen and electron donors such as lipid, amino acid, or ascorbic acid (23,24). The reaction is catalyzed by photoexcited riboflavin (24). Therefore, the main active agents participating in the generation of peroxides in TPN are ambient light [(ϩ)L] and multivitamin preparations (MVP) (23,24). Photoprotection [(Ϫ)L] of TPN reduces the levels of peroxides by close to 50% (23,25,26). Absence of photoprotection of TPN is associated in preterm newborn infants with higher urinary peroxide concentrations (16), higher blood pressure in girl babies (15), and greater blood glucose and plasma triacylglycerol concentrations (13). Hence, peroxides contaminating TPN solutions are not completely quenched by newborns infants and are thought to be an agent initiating metabolic perturbations. We questioned whether these peroxides are linked to metabolic consequences later in life.Based on the concept that neonatal oxidative stress may interfere with metabolic programming (27), we hypothesized that neonatal exposure to peroxides such as those generated in solutions of parenteral nutrition, induces a permanent modification in lipid and glucose metabolism especially lipogenesis and/or glycolysis. Perturbations in lipid and glucose metabolism, which are fuels for energy production, could have longterm consequences on growth and physical activity, thereby affecting global development. The aim of this study was to measure in adult guinea pigs metabolic responses and spontaneous physical activity after a brief neonatal exposure to i.v. oxidant molecules limited to the first wk of life. A second objective was to assess if these modifications were related to the infusion of peroxides. MATERIALS AND METHODSExperimental design. The metabolic response and the levels...

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Section: Discussionmentioning

confidence: 99%

Neonatal Exposure to Oxidants Induces Later in Life a Metabolic Response Associated to a Phenotype of Energy Deficiency in an Animal Model of Total Parenteral Nutrition

et al. 2010

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“…Then PCR products were sequenced using a DNA sequencer (ABI PRISM 3730, Foster City, CA, USA). Methylation level was measured according to our previously reported method (Jiang et al, 2008(Jiang et al, , 2009). …”

Section: Quantification Of Methylation Level Of Mir-146a Promotermentioning

confidence: 99%

Dysregulated expression of miR‐146a contributes to age‐related dysfunction of macrophages

Jiang¹,

Xiang²,

Wang

et al. 2011

Aging Cell

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SummaryAge-associated immune dysfunction, characterized by increased systemic levels of cytokines, manifests as an increased susceptibility to infections. Thus, understanding these negative regulators of the immune response has paved the way to delineating signaling pathways that impact immune senescence. In the present study, we found that miR-146a, which negatively regulated the expression of IL-1b and IL-6, was highly expressed in aged mice. However, there was a lack of response to the stimulation of lipopolysaccharide (LPS) and proinflammatory cytokines in macrophages of aged mice. As a result, the negative feedback regulation loop with miR-146a involving down-regulation of inflammation factors was interrupted in aged mice. Aberrant NF-jB binding to the miR-146a promoter was demonstrated to be associated with the abnormal expression of miR-146a in aged mice. The DNA methyltransferase inhibitor (5-aza-2-deoxycytidine) and the histone deacetylase inhibitor [trichostatin A (TSA)] both significantly up-regulated miR-146a transcriptional activation by altering the DNA-binding activity of NF-jB in macrophages isolated from aged mice, which suggests that DNA methylation and histone acetylation are involved in the suppression of age-dependent miR-146a expression. Additionally, high levels of histone deacetylase (HDACs) expressions contributed to the inhibition of miR-146a expression in LPS-stimulated macrophages from aged mice in vitro. While the suppression of HDACs activities by TSA could improve LPS-induced inflammatory responses owing to up-regulation of miR-146a expression in macrophages from aged mice. These data indicate that the dysregulated expression of miR-146a results in the age-associated dysfunction of macrophages, and miR-146a may be a good target for the treatment of age-related inflammatory diseases.

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“…To quantify the degree of liver gene expression, we applied PCR array 56 Gck encodes glucokinase phosphorylates glucose as first step of glucose utilization in hepatocytes. 57 The role of glucokinase is to provide glucose 6-phosphate for the synthesis of glycogen and fatty acids. Gpd1, Hk2 and Pklr encode for glycolytic enzymes.…”

Section: Evidence For Liver Programmingmentioning

confidence: 99%

Effect of intrauterine growth retardation on liver and long-term metabolic risk

Cianfarani

Agostoni

Bedogni³

et al. 2012

Int J Obes

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Intrauterine growth retardation predisposes toward long-term morbidity from type 2 diabetes and cardiovascular disease. To explain this association, the concept of programming was introduced to indicate a process whereby a stimulus or insult at a critical period of development has lasting or lifelong consequences on key endocrine and metabolic pathways. Subtle changes in cell composition of tissues, induced by suboptimal conditions in utero, can influence postnatal physiological functions. There is increasing evidence, suggesting that liver may represent one of the candidate organs targeted by programming, undergoing structural, functional and epigenetic changes following exposure to an unfavorable intrauterine environment. The aim of this review is to provide insights into the molecular mechanisms underlying liver programming that contribute to increase the cardiometabolic risk in subjects with intrauterine growth restriction.

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Hypermethylation of hepatic Gck promoter in ageing rats contributes to diabetogenic potential

Cited by 76 publications

References 47 publications

Neonatal Exposure to Oxidants Induces Later in Life a Metabolic Response Associated to a Phenotype of Energy Deficiency in an Animal Model of Total Parenteral Nutrition

Neonatal Exposure to Oxidants Induces Later in Life a Metabolic Response Associated to a Phenotype of Energy Deficiency in an Animal Model of Total Parenteral Nutrition

Dysregulated expression of miR‐146a contributes to age‐related dysfunction of macrophages

Effect of intrauterine growth retardation on liver and long-term metabolic risk

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