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Endocrine and Metabolic Side Effects
Published in Ayse Serap Karadag, Berna Aksoy, Lawrence Charles Parish, Retinoids in Dermatology, 2019
Ayse Serap Karadag, Emin Ozlu, Bodo C. Melnik
Evidence derived from rats indicates that RAR and RXR ligands can act synergistically to induce hypertriglyceridemia through distinct mechanisms of action (138). DrugBank screening revealed alitretinoin and bexarotene are liver X receptor (LXR) modulators (139). Both retinoids are able to induce hypertriglyceridemia (49,117,141). Dose-response studies demonstrated that plasma concentrations observed in clinical trials are sufficient for LXR activation and thus could account for LXR-mediated side effects such as hyperlipidemia (139). Many liver LXR/RXR-related genes including Scd-1 and Srebf1 are associated with increased TG and were highly expressed in rat liver after bexarotene administration (143). Studies in mice confirmed that hypertriglyceridemic action of bexarotene occurs via the RXR/LXR heterodimer and show that RXR heterodimers can act with a selective permissivity on target genes of specific metabolic pathways in the liver (144). Another target gene of RXR agonists is apolipoprotein C-III (apoC-III) (145). apoC-III promotes the assembly and secretion of TG-rich VLDL particles from hepatic cells under lipid-rich conditions (146). In addition, apoC-III strongly inhibits hepatic uptake of VLDL and intermediate density lipoproteins (IDL), overriding the opposite influence of apolipoprotein E when both are present (147).
Beneficial Effects of Omega-3 Fatty Acids on Cardiovascular Disease
Published in Catherina Caballero-George, Natural Products and Cardiovascular Health, 2018
Estela Guerrero De León, Mahabir Prashad Gupta, Juan Antonio Morán-Pinzón
There are three isoforms of SREBPs: SREBP-1a and -1c, which originate from the same gene, and SREBP-2. All of them are activated in response to a decrease in free cholesterol content in the endoplasmic reticulum (ER). SREBP-2 stimulates primarily transcription of genes related to cholesterol biosynthesis and LDL receptor (rLDL). SREBP-1c is the predominant form of SREBP-1 in most tissues, and together with SREBP-1a, regulates the synthesis of FAs, TGs and phospholipids. Most of the lipogenic effects of insulin depend upon the induced expression of SREBP-1c and the subsequent stimulation of the FA synthesis pathway. The expression of SREBP-1c is also stimulated by the liver X receptor (LXR), through two LXR binding sites (LXRE) present in the SREBP-1c promoter (Desvergne et al., 2006) (Figure 1.2). In contrast to these signaling events, high levels of PUFAs suppress the expression of SREBP-1c and ChREBP, the latter being a sensitive factor for glucose concentration that promotes lipogenesis from carbohydrates. However, these transcription factors are not regulated by the direct binding of fatty acids but rather respond to changes in gene transcription. For example, PUFAs decrease the transcription of SREBP-1c and ChREBP secondary to competition with oxysterols, a positive regulator of the SREBP-1 and ChREBP genes, which bind to the LXR (Ou et al., 2001).
Maturation, Barrier Function, Aging, and Breakdown of the Blood–Brain Barrier
Published in Shamim I. Ahmad, Aging: Exploring a Complex Phenomenon, 2017
Elizabeth de Lange, Ágnes Bajza, Péter Imre, Attila Csorba, László Dénes, Franciska Erdő
In the brain, excess cholesterol is metabolized into 24S-hydroxycholesterol (24S-OH-chol) and eliminated into the circulation across the BBB. 24S-OH-chol is a natural agonist of the nuclear liver X receptors (LXRs) involved in peripheral cholesterol homeostasis. The effects of this oxysterol on the pericytes have demonstrated that pericytes express LXR nuclear receptors and their target gene ATP-binding cassette, subfamily A, member 1 (ABCA1), known to be one of the major transporters involved in peripheral lipid homeostasis. Furthermore, pericytes are able to internalize the amyloid-β peptides which accumulate in the brain of AD patients (Saint-Pol et al. 2012).
Activation of liver X receptors ameliorates alterations in testicular function in rats exposed to electromagnetic radiation
Published in Alexandria Journal of Medicine, 2021
Nevertyty Mohamed Mahmoud, Randa Salah Gomaa, Amal Elsayd Salem
Liver X receptors (LXRs) are nuclear receptor superfamily and ligand-activated transcription factors that exist in two isoforms: LXRα and LXRβ [12]. LXRs are involved in several physiological processes such as lipid metabolism and cholesterol homeostasis. In addition, they have been reported to play important roles in the modulation of inflammation [13]. LXRα and LXRβ are expressed in the mouse and human testes. In the mouse, LXRα is mainly expressed in Leydig cells, and LXRβ in Sertoli cells, while both are expressed in germ cells. LXR αβ-/- mice become prematurely infertile with increased apoptosis of germ cells, reduced germ cell proliferation, and low testosterone levels [14]. In humans, both LXRα and LXRβ are expressed in testicular biopsy specimens and are expected to have a similar role as in the mouse, so they may be related to premature infertility [15]. Moreover, LXRs exert anti-inflammatory effects by inhibiting production of pro-inflammatory cytokines either directly or indirectly [16].
Transcriptional regulation of CYP3A4 by nuclear receptors in human hepatocytes under hypoxia
Published in Drug Metabolism Reviews, 2020
Xuechun Yuan, Hui Lu, Anpeng Zhao, Yidan Ding, Qiong Min, Rong Wang
The liver X receptor (LXR) consists of two isoforms LXRα and LXRβ (NR1H3 and NR1H2), which are capable of maintaining the lipid homeostasis by regulating the transcription of relevant genes (Duniec-Dmuchowski et al. 2007). LXRα has been proved to up-regulate the CYP3A4 gene in HepaRG cells and primary human hepatocytes through binding with the responsive elements for PXR-mediated CYP3A4 transcription. Nevertheless, the activation of LXRα would disturb even weaken the transcription of PXR-dependent CYP3A4, probably due to their competence for RXRα to form heterodimers. Furthermore, nutritional, physiological and disease conditions influencing LXR would be possibly one of the determinants for basal and xenobiotic-responsive expression of CYP3A4 in human livers (Watanabe et al. 2013). It is not hard to speculate hypoxic condition may affect regular function of LXR so as to influence PXR-mediated processes including CYP3A4 regulation.
Alterations of drug-metabolizing enzymes and transporters under diabetic conditions: what is the potential clinical significance?
Published in Drug Metabolism Reviews, 2018
Feng Chen, De-Yi Li, Bo Zhang, Jie-Yu Sun, Fang Sun, Xing Ji, Jin-Chun Qiu, Robert B. Parker, S. Casey Laizure, Jing Xu
Located on the apical membrane of enterocytes and hepatocytes, ABCG5 and ABCG8 limit intestinal absorption and facilitate biliary secretion of cholesterol and phytosterols. This heterodimer transporter is positively regulated by Liver X receptor. Mutated ABCG5/G8 genes could cause sitosterolemia (abnormal accumulation of cholesterol and plant sterols in the circulation), thereby leading to premature cardiovascular disease (Yu et al. 2014). The hepatic mRNA expression of ABCG5/G8 was decreased in SI rats with declined cholesterol output (Bloks et al. 2004), but increased in SI mice (Aleksunes et al. 2013). Both mRNA and protein expression of ABCG5/G8 in jejunum of the SI rats were found to be suppressed, whist campesterol and β-sitosterol concentrations in rat plasma were decreased (Bloks et al. 2004).