REGULATORY MECHANISMS
David M. Gibson, Robert A. Harris in Metabolic Regulation in Mammals, 2001
opposed by insulin which is released from the endocrine pancreas as blood glucose rises during feeding. Insulin signals the synthesis and storage of glycogen and triglyceride by targeting enzymes directly (dephosphorylation) and by synthesis of a set of enzymes catalyzing lipogenesis (specific gene expression). The insulin receptor initiates two distinct, signal pathways that achieve these ends and other outcomes (recruitment of glucose transporters, general enhancement of protein synthesis and abatement of apoptosis). Many other specialized cell functions are elicited by receptor-linked signal pathways, e.g. transient release of Ca7 ' (into the cytosol from the endoplasmic reticulum) which targets a group of regulatory enzymes. Intracellular nuclear receptors are essentially endocrine-sensitive protein transcription factors that directly influence gene expression. Certain receptors of this kind respond to intracellular feedback signaling: PPAR-« by binding polyunsaturated fatty acids and SREBP-2 released by low membrane cholesterol levels.
The principal targets for drug action
Hugh McGavock in How Drugs Work, 2017
Nuclear receptors linked to gene transcription, which are coupled via DNA. These produce their effect very slowly, over a period of hours or even days. Steroid hormones, oestrogens and thyroxine are examples of hormones/drugs that affect nuclear receptors, seeFigure 9.1b. Endogenous hormones and some drugs pass through the cell membrane and attach to receptors in the cytoplasm. he receptor plus ligand complex then moves across the nuclear membrane into the nucleus. Once inside the nucleus it binds to specific parts of chromosomal DNA, resulting in messenger RNA production and protein synthesis (seeFigure 9.1b). Steroids, oestrogen and thyroxine act via nuclear receptors, tamoxifen blocks intracellular oestrogen receptors, and slows the progression of breast malignancy.
Alitretinoin
Sarah H. Wakelin, Howard I. Maibach, Clive B. Archer in Handbook of Systemic Drug Treatment in Dermatology, 2015
Alitretinoin (9-cis-retinoic acid) is an endogenously occurring retinoid which is structurally related to vitamin A. It acts as a pan-agonist at retinoid receptors, binding with high affinity to both retinoic acid receptors (RARs) and retinoid X receptors (RXR). The latter are capable of binding to a range of different nuclear receptors to modulate gene expression (Figure 1). The precise mode of action of alitretinoin in chronic hand eczema remains unclear, but retinoids are known to affect multiple processes at a cellular level including proliferation, differentiation and apoptosis. They may also have anti-inflammatory and immunomodulatory effects, including suppression of nitric oxide and tumour necrosis factor (TNF)-alpha production, impairment of T-cell activation and down-regulation of chemokine synthesis (CXCL9 and CXCL10), thereby impairing the recruitment of inflammatory leukocytes. Alitretinoin has been shown to suppress the expression of co-stimulatory molecules on the surface of antigen-presenting cells, which may be of relevance to a therapeutic effect in contact dermatitis. In contrast to isotretinoin, alitretinoin only has a minimal effect on sebum secretion.
The therapeutic potential of PROTACs
Published in Expert Opinion on Therapeutic Patents, 2021
Andrew B. Benowitz, Katherine L. Jones, John D. Harling
Nuclear receptors function as important signal transduction mechanisms within cells, playing a key role in sensing stimulating ligands and then regulating gene transcription in response to those ligands. It has been well characterized that the presence of excess signaling ligands or mutations in nuclear receptors resulting in inappropriate transcriptional program activation or propagation can exacerbate human disease, and approved medicines that antagonize these receptors have proven to be valuable treatment options for patients. However, patient benefit can be limited upon prolonged treatment with these medicines, and it has been hypothesized that degrading nuclear receptors through a PROTAC strategy may provide superior patient benefit versus antagonism [17]. To this end, multiple reports describing the PROTAC-mediated degradation of the androgen receptor (AR) for the treatment of prostate cancer [18–20], as well as the estrogen receptor (ER) for the treatment of breast cancer [21–23] have been disclosed.
Liver X receptor: a potential target in the treatment of atherosclerosis
Published in Expert Opinion on Therapeutic Targets, 2022
Shreya R. Savla, Kedar S Prabhavalkar, Lokesh K Bhatt
LXRs are ligand-activated transcription factors of the nuclear hormone receptor superfamily. Nuclear receptors are transcription factors involved in various physiological processes [8]. Nuclear receptors, like LXRs, the peroxisome proliferator-activator receptors (PPARs), and the farnesoid X receptors (FXRs), respond to cellular changes associated with levels of endogenous lipid ligands by regulation of gene expressions encoding the proteins that play a role in lipid metabolism. The family of LXRs comprise two isotypes, LXR alpha (LXRα) and beta (LXRβ), which are encoded by genes Nr1h3 and Nr1h2, respectively. LXRα and LXRβ show a high level of sequence homology but differ in tissue distribution. Metabolically active cells and tissues, like intestine, liver, macrophages, and adipose tissue, exhibit a high level of LXRα expression. LXRα is restricted to the myeloid lineage in hematopoietic cells. On the other hand, LXRβ exhibits a ubiquitous expression profile. The two isotypes of LXR, namely LXR α and β, show an overlapping expression pattern that is non-identical to each other [4].
Understanding mitochondrial biogenesis through energy sensing pathways and its translation in cardio-metabolic health
Published in Archives of Physiology and Biochemistry, 2018
Abhijit Nirwane, Anuradha Majumdar
Nuclear receptor superfamily constitutes a group of 48 transcription factors in humans, which includes the receptors for steroid hormones, thyroid hormone, lipophilic vitamins and cholesterol metabolites (Burris et al.2013). The nuclear receptors are divided into two broad groups, conventional hormone receptors whose ligands have been identified and orphan nuclear receptors whose ligands are yet to be discovered (reviewed by Alaynick 2008). Nuclear receptors after activation regulates expression of several genes involved in energy metabolism. This is achieved by their specific interactions with coactivator and corepressor molecules (Kressler et al. 2002, Sonoda et al. 2008). Substantial evidences from past reports highlighted the pivotal role of PPAR-α, a nuclear receptor, in body energy homoeostasis and inflammatory response (Wang and Wan 2008, Tyagi et al.2011, Contreras et al.2013). High levels of PPAR-α is native to liver, brown adipose tissue, heart, kidney and skeletal muscle (Ferré 2004). Fibrates, pharmacologically classified as cholesterol lowering compounds, targets PPAR-α to increase hepatic fatty acid oxidation (Staels et al.1998). Further, PPAR-α binds with retinoid X receptors (RXR) in conjugation with its co-activator PGC-1α to switch on the mitochondrial fatty acid oxidative genes in variety of tissues (Vega et al. 2000) (Figure 8). Dietary restriction is also known to increase PPAR-α expression contributing fatty acid homeostasis (Contreras et al. 2013, Montagner et al. 2016).
Related Knowledge Centers
- DNA
- Gene Expression
- Molecular Biology
- Protein
- Steroid Hormone
- Thyroid Hormones
- Hormone
- Vitamin
- Gene
- Developmental Biology