Effects of the synthetic liver X receptor agonist T0901317 on the growth hormone and thyroid hormone axes in male rats

Davies, J. S.; Kotokorpi, Pia; Lindahl, Ulrika; Oscarsson, Jan; Wells, Timothy; Mode, Agneta

doi:10.1007/s12020-008-9067-9

Cited by 6 publications

(4 citation statements)

References 56 publications

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“…Our observation that stimulation of LXRα by TO increased the expression of hDIO1 in HepG2 cells was inconsistent with previous in vivo observations that TO decreases hepatic expression of Dio1 in rat and mouse models [37,38]. Importantly, there is a large difference in the sequences of this gene’s promoter regions between human and rodent; TREs have not been identified in the promoter regions of rat or mouse Dio1 , whereas two TREs are present in the promoter region of human DIO1 [3].…”

Section: Discussioncontrasting

confidence: 99%

Regulation of type 1 iodothyronine deiodinase by LXRα

et al. 2017

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The iodothyronine deiodinases are selenoenzymes that regulate the activity of thyroid hormone via specific inner- or outer-ring deiodination. In humans, type 1 deiodinase (D1) is highly expressed in the liver, but the mechanism by which its gene expression is regulated remains to be elucidated. Liver X receptor α (LXRα), a transcription factor of the nuclear receptor superfamily, is highly expressed in the liver, where it functions as a sensor for excess intracellular oxysterols. LXRα interacts with other nuclear receptors on promoters of genes that contain a binding core sequence for nuclear receptors. In addition, it is reported that the promoter of the gene encoding human D1 (hDIO1) contains the core sequence for one of nuclear receptors, thyroid hormone receptor (TR). We investigated the involvement of LXRα in the regulation of hDIO1, in the liver. We performed hDIO1 promoter–reporter assays using a synthetic LXR agonist, T0901317, and compared promoter activity between a human liver carcinoma cell line, HepG2, and a clone of human embryonic kidney cells, TSA201. We defined the region between nucleotides −131 and −114, especially nucleotides −126 and −125, of the hDIO1 promoter as critical for basal and LXRα-mediated specific transcriptional activation in HepG2 cells. An increase in hDIO1 expression was observed in LXRα-stimulated cells, but absent in cycloheximide-treated cells, indicating that new protein synthesis is required for LXRα-mediated regulation of hDIO1. On the other hand, electrophoretic mobility shift assays revealed that LXRα and RXRα bound to the hDIO1 promoter. We also demonstrated that LXRα and TRβ compete with each other on this specific region of the promoter. In conclusion, our results indicated that LXRα plays a specific and important role in activation of TH by regulating D1, and that LXRα binds to and regulates the hDIO1 promoter, competing with TRβ on specific sequences within the promoter.

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Section: Discussioncontrasting

confidence: 99%

Regulation of type 1 iodothyronine deiodinase by LXRα

et al. 2017

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“…This intervention may be especially effective by promoting both efficient cholesterol recycling and removal of inflammation-promoting myelin debris (Lefterov et al, 2007; Zelcer et al, 2007) that may help combat age-related reduction of successful remyelination (Shen et al, 2008; Shields et al, 1999). Such interventions may have serious systemic side effects however (Cheng et al, 2008a; Davies et al, 2008). …”

Section: Future Directions and Treatment Implicationsmentioning

confidence: 99%

Alzheimer's disease as homeostatic responses to age-related myelin breakdown

Bartzokis

2011

Neurobiology of Aging

479

515

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The amyloid hypothesis (AH) of Alzheimer’s disease (AD) posits that the fundamental cause of AD is the accumulation of the peptide amyloid beta (Aβ) in the brain. This hypothesis has been supported by observations that genetic defects in amyloid precursor protein (APP) and presenilin increase Aβ production and cause familial AD (FAD). The AH is widely accepted but does not account for important phenomena including recent failures of clinical trials to impact dementia in humans even after successfully reducing Aβ deposits. Herein, the AH is viewed from the broader overarching perspective of the myelin model of the human brain that focuses on functioning brain circuits and encompasses white matter and myelin in addition to neurons and synapses. The model proposes that the recently evolved and extensive myelination of the human brain underlies both our unique abilities and susceptibility to highly prevalent age-related neuropsychiatric disorders such as late onset AD (LOAD). It regards oligodendrocytes and the myelin they produce as being both critical for circuit function and uniquely vulnerable to damage. This perspective reframes key observations such as axonal transport disruptions, formation of axonal swellings/sphenoids and neuritic plaques, and proteinaceous deposits such as Aβ and tau as by-products of homeostatic myelin repair processes. It delineates empirically testable mechanisms of action for genes underlying FAD and LOAD and provides “upstream” treatment targets. Such interventions could potentially treat multiple degenerative brain disorders by mitigating the effects of aging and associated changes in iron, cholesterol, and free radicals on oligodendrocytes and their myelin.

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“…In addition, others have shown that LDLr Ϫ / Ϫ mice transplanted with LXR ␣ ␤ Ϫ / Ϫ bone marrow demonstrate a 3-fold increase in atherosclerosis in the absence of changes in plasma lipids. (154) Unfortunately, systemic administration of fi rst generation LXR agonists results in elevated plasma triglycerides, fatty liver (155,156) , and disturbance of growth hormone and thyroid axes (157). These studies show that cholesterol mobilization from the vascular macrophage constitutes an important step in atheroprotection.…”

Section: Lxrmentioning

confidence: 99%

The HDL hypothesis: does high-density lipoprotein protect from atherosclerosis?

Vergeer

Holleboom

Kastelein

et al. 2010

Journal of Lipid Research

199

122

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This article is available online at http://www.jlr.org the imagination. Because of a general consensus that HDL protects against atherosclerosis, what we shall term the HDL hypothesis, strategies have been developed to raise plasma HDL levels or to improve HDL function. However, it is increasingly questioned whether such interventions will indeed reduce the risk of atherosclerosis. This review summarizes the reported evidence that supports the HDL hypothesis. EPIDEMIOLOGYA low plasma HDL-C concentration is among the strongest, statistically independent risk factors for cardiovascular disease (CVD) (2). In a widely cited meta-analysis of four large studies (total number of individuals studied: 15,252), a 1 mg/dl increase of HDL-C levels was reported to be associated with a 2-3% decreased CVD risk (3). This result provides an epidemiological argument in favor of therapeutically raising HDL-C levels. One may draw parallels with the detrimental consequences of elevated lowdensity lipoprotein cholesterol (LDL-C) levels and blood pressure, which have been successfully controlled through therapy, resulting in signifi cant reductions of cardiovascular mortality and morbidity (4, 5) . It should be noted, however, that the associations between elevated LDL-C and blood pressure and increased CVD risk refl ect causal relationships, whereas such a relation between low HDL-C levels and increased CVD is not undisputed (6, 7). This is related to the fact that HDL-C levels are infl uenced by many different variables that also affect CVD risk: 1 ) Men have on average lower HDL-C levels than women (8). (1) reported that plasma levels of high-density lipoprotein cholesterol (HDL-C) were reduced in patients with coronary artery disease. In 1977, Gordon et al. (2) subsequently showed that low HDL-C is a risk factor for coronary heart disease in the Framingham study. These important fi ndings have given rise to a large number of diverse HDL studies over the last few decades. The numerous different and apparently unrelated beneficial effects that have since been ascribed to HDL appeal to

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Effects of the synthetic liver X receptor agonist T0901317 on the growth hormone and thyroid hormone axes in male rats

Cited by 6 publications

References 56 publications

Regulation of type 1 iodothyronine deiodinase by LXRα

Regulation of type 1 iodothyronine deiodinase by LXRα

Alzheimer's disease as homeostatic responses to age-related myelin breakdown

The HDL hypothesis: does high-density lipoprotein protect from atherosclerosis?

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