CHA – 204-2 PDF
June 30, 2020 | by admin
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Nuclear receptors NRs are members of a superfamily of ligand-regulated and orphan transcription factors that regulate gene expression in response to nutritional and physiological stimuli. NRs are separated into distinct classes.
First, there are classic hormone receptors that bind specific hormones, such as the glucocorticoids GCsthyroid hormones, and estrogen. The GCs and tri-iodothyronine, acting via the glucocorticoid receptor GR and thyroid hormone receptor TR respectively, are important regulators of genes involved in metabolic fuel homeostasis during development and in response to metabolic stress.
Estrogen-related receptors ERRs also play critical roles in the regulation of cellular energy metabolism. Secondly, there are NRs that function as metabolic sensors, binding to substrate and end-product component molecules of metabolic pathways such as lipids and fatty acids FA. In this review, we focus on how PGC-1s coordinate the regulation of metabolite-responsive NRs and therefore the expression of genes controlling nutrient handling. Histone acetylation allows trans -acting factors to associate with cognate DNA binding sites and activate transcription.
Histone acetyltransferases HATs function to acetylate and remodel chromatin, leading to increased access to target genes by transcriptional machinery. Activation through ligand binding induces a conformational change leading to dissociation of corepressors and recruitment of protein complexes containing HAT activity that enhance gene transcription via modification of local chromatin structure Fig.
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Journal of Endocrinology2; The PGC-1s are a small family of transcriptional coactivators that play a critical role in the control of glucose, lipid, and energy metabolism. There are three known isoforms of PGC This allows for a coordinated transcriptional response to nutrient and physiological signals. All three isoforms of PGC-1 play a common role in control of mitochondrial physiology and FA oxidation, but also regulate differing metabolic pathways in an isoform-specific manner.
In turn, the NRFs induce expression of genes that regulate mitochondrial DNA and function and induce mitochondrial biogenesis. However, an extra level of regulation is exerted through post-translational modifications. Of interest, nonobese diabetic Goto-Kakizaki rats, a rodent model of diabetes, have decreased hepatic PRMT activity associated with impaired arginine methylation, and transfection with PRMT siRNA attenuates insulin signaling to gluconeogenic gene expression Iwasaki Interestingly, this pathway was not activated by classical gluconeogenic stimuli, including the GCs and glucagon, and is thought to represent an entirely separate parallel pathway for induction of gluconeogenic gene expression Rodgers et al.
In addition these mice exhibited reduced hepatic insulin sensitivity, which was associated with impaired insulin-stimulated Akt activation Estall et al. Interestingly, acute disruption of hepatic PGC-1 expression using an RNAi adenovirus has opposing effects, leading to enhanced insulin sensitivity, in part reflecting reduced expression of the mammalian tribbles homolog TRIB3 Koo et al.
There is a potential inhibitory role for GCN5 in this system. These may include pancreatic islets, linking insulin secretion with insulin action in liver and skeletal muscle. The expression level and compartmentalization of lipin-1 controls the assembly and secretion of hepatic very low-density lipoprotein VLDL; Bou Khalil et al.
Map of Kutchan-cho Hotels & Kutchan-cho Map
chx In the nucleus, lipin-1 acts as a transcriptional coativator linked to FA oxidation Fig. Conversely, a mutation in lipin-1 is responsible for the fatty liver dystrophic fld mouse phenotype, which includes hepatic steatosis, impaired FA oxidation, and hyperlipidemia Reue Of interest, it has been reported recently that the lipogenic transcription factor SREBP-1 is involved in the regulation of lipin-1 expression Fig.
In addition, lipin-1 gene expression is induced by T, an activating ligand for the LXR Ishimoto et al. This, in turn, leads to inhibition of Akt signaling and insulin resistance Fig. Microarray analyses of MIN6 cells overexpressing SIRT1 identified 41 downregulated and 24 upregulated fha, while analysis of MIN6 cell lines constitutively expressing siRNAs against the Sirt1 gene revealed 24 upregulated and 18 downregulated transcripts Moynihan et al.
Downregulation fha UCPs is proposed to reduce uncoupling and allow a more efficient ATP production under circumstances of limited access to nutrients, which could be explained by a more efficient oxidative phosphorylation, lowered production of ROS, and reduced oxidative damage. The potential importance of the GC in regulating lipin-1 expression in adipose tissue may therefore extend to regulating lipin-1 expression or function in the pancreatic islet.
LXR activation ca thought to be predominantly insulin-sensitizing Cao et al.
Thus, as well as acting as sensors of cellular cholesterol and modulating the expression of 204–2 concerned with cellular cholesterol handling, the LXRs enhance expression of genes involved in FA biosynthesis and TAG secretion. As in liver, LXR activation in adipocytes stimulates lipid accumulation Juvet et al. It has been proposed that, in liver, glucose at physiological concentrations is a high-affinity LXR ligand Mitro et al.
PPAR control: it’s SIRTainly as easy as PGC
This may explain why both low-fat and high-carbohydrate diets can induce hypertriglyceridemia. Glycerol kinase allows glycerol 3-phosphate production from glycerol, thereby enhancing the capacity for FA esterification to TAG.
TZDs trigger the dismissal of corepressor HDAC complexes and the recruitment of coactivators to the glycerol kinase gene. In contrast, lipin-1 promotes adipocyte TAG storage see above. Lipin-1 deficiency in fld mice causes lipodystrophy characterized by impaired adipose tissue development Reue et al. High adipose tissue lipin-1 expression is also associated with enhanced insulin sensitivity in man Yao-Borengasser et al.
This enhanced insulin sensitivity may reflect an increased ability of adipose tissue to act as a sink for lipid, preventing excessive lipid deposition in liver and skeletal muscles which impairs insulin action. Epigenetic modification, including DNA methylation, represents a molecular mechanism linking environmental events to altered gene expression and the development of disease states, including T2DM see e.
The full therapeutic significance of this observation has yet to be established. Thus, lipin-1 may be a promising target for therapeutic intervention for metabolic disorders such as fatty liver and resolution of insulin resistance.
Alterations in lipin-1 function in adipose tissue are therefore likely to impact the efficacy of the TZDs in the treatment of insulin resistance. A recent study on nondiabetic Chinese females demonstrated that LPIN1 mRNA levels in abdominal visceral adipose tissue negatively correlated with body mass index, body fat percentage and plasma TAG and leptin levels Chang et al.
However, no single nucleotide polymorphism of the LPIN1 gene was associated with type 2 diabetes in the population investigated in this study, leading the authors to conclude that the LPIN1 gene was not a major susceptibility 204–2 for T2DM Chang et al. It seems likely that the opposing actions of lipin-1 occur in response to different physiological stimuli and therefore further studies are required to establish which lipindirected pathway is dysregulated during the onset of metabolic disease.
This 2004-2 provide chx information with respect to development of therapeutic strategies for modulation of this pathway.
More recently small molecular weight molecules, including SRT and SRT, that selectively activate SIRT1 and are fold more potent activators than and structurally unrelated to resveratrol have been identified Milne et al. SRT opposes hyperinsulinemia and the impairment in glucose tolerance introduced by high-fat feeding in mice to an extent similar to that achieved with rosiglitazone Milne et al.
The consumption of saturated fat has been linked with the development of a number of disease states, including T2DM, cardiovascular disease dha atherosclerosis. Modest SIRT1 overexpression protects against hepatic steatosis and glucose intolerance induced by high-fat feeding Banks et al. Antisense oligonucleotide knockdown of hepatic SIRT1 reduced fasting hyperglycemia by normalizing basal hepatic glucose production, increasing hepatic insulin sensitivity in a rat model of T2DM streptozotocin injection followed by 4 weeks of fructose and high-fat feedingwhich led to the suggestion that novel SIRT1 inhibitors targeted to the liver could prove beneficial in the treatment of T2DM Erion et al.
Thus, consideration must be given to these potential pitfalls of strategies for mitigation of metabolic disorders involving modulation of SIRT1 activity. The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.
Introduction Nuclear receptors NRs are members of a superfamily of ligand-regulated and orphan transcription factors that regulate gene expression in response to nutritional and physiological stimuli. Fha of interest The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the cga reported.