Identification and characterization of a novel mouse peroxisome proliferator-activated receptor a-regulated and starvation-induced gene, Ppsig

Sun, Yan; Ng, Lui; Lam, Wun; Lo, Clive; Chan, Pui-Ting; Yuen, Yee-Lok; Wong, Paul; Tsang, D.; Cheung, Wing‐Tai; Lee, Susanna Sau-Tuen

doi:10.1016/j.biocel.2008.01.006

Cited by 19 publications

(21 citation statements)

References 23 publications

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“…ChIP-seq experiments have reported that 38% of estrogen receptora-binding elements were found within introns along with an additional 38% being further than 10 kb from the TSS (Levy et al, 2008). Other examples of nuclear receptors with identified response elements within an intronic region include the androgen receptor (Zheng et al, 2006), the vitamin D receptor (Zella et al, 2006), and peroxisome proliferator-activated receptora (Sun et al, 2008). In addition, androgen regulation of the Nrf2-target gene GSTP1 appears to be dependent upon a 500-bp region of the fifth intron of the gene (Ikeda et al, 2002); however, to our knowledge, this is the first example of Nrf2 itself potentially regulating a target gene through an intronic response element.…”

Section: Canet Et Almentioning

confidence: 99%

Identification of a Functional Antioxidant Response Element within the Eighth Intron of the HumanABCC3Gene

et al. 2014

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The ATP-binding cassette (ABC) family of transporters, including ABCC3, is a large family of efflux pumps that plays a pivotal role in the elimination of xenobiotics from the body. ABCC3 has been reported to be induced during hepatic stress conditions and through the progression of some forms of cancer. Several lines of evidence have implicated the transcription factor nuclear factor (erythroid-derived 2)-like 2 (Nrf2) in this induction. However, although rodent models have been investigated, a functional antioxidant response element (ARE) in the human ABCC3 gene has not been identified. The purpose of this study was to identify and characterize the ARE(s) responsible for mediating the Nrf2-dependent induction of the human ABCC3 gene. A high-throughput chromatin immunoprecipitation-sequencing analysis performed in A549 cells revealed a specific interaction between Nrf2 and the eighth intron of the human ABCC3 gene rather than the more prototypical flanking region of the gene. Subsequent in silico analysis of the intron identified two putative ARE elements that contained the core consensus ARE sequence commonly found in several Nrf2-responsive genes. Functional characterization of these two AREs using luciferase-reporter constructs with ARE mutant constructs revealed that one of these putative AREs is functionally active. Finally, DNA pull-down assays confirmed specific binding of these intronic AREs by Nrf2 in vitro. Our findings identify a functional Nrf2 response element within the eighth intron of the ABCC3 gene, which may provide mechanistic insight into the induction of ABCC3 during antioxidant response stimuli.

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Section: Canet Et Almentioning

confidence: 99%

Identification of a Functional Antioxidant Response Element within the Eighth Intron of the HumanABCC3Gene

et al. 2014

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“…Given that RetSat is a direct PPAR target and that ablation of RetSat expression results in impaired activation of PPAR␥, we were especially interested in the effect of dihydroretinoids on activation of PPARs (Sun et al, 2008;Schupp et al, 2009). Our screen revealed that dihydroretinoids do not activate PPAR␥ or PPAR␤/␦ but do show low antagonistic activity for PPAR␣ at high concentrations.…”

Section: Downloaded Frommentioning

confidence: 99%

“…Expression of RetSat in the liver and kidney is dramatically up-regulated during fasting (Sun et al, 2008), whereas in adipose tissue, it is highly up-regulated during adipocyte differentiation (Schupp et al, 2009). Both observations can be explained by the fact that RetSat expression is controlled by PPAR␣ in liver and kidney and by PPAR␥ in fat through a peroxisome proliferator-response element found in intron 1 of the RETSAT gene (Sun et al, 2008;Schupp et al, 2009). Receptors PPAR␣ and PPAR␥ are key participants in the regulation of lipid metabolism and adipocyte differentiation, respectively, and are pharmacological targets for hypolipidemic (fibrate) and antidiabetic (thiazolidinedione) drug classes.…”

mentioning

confidence: 99%

Activation of Retinoic Acid Receptors by Dihydroretinoids

Moise¹,

Álvarez²,

Domínguez³

et al. 2009

Mol Pharmacol

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Vitamin A-derived metabolites act as ligands for nuclear receptors controlling the expression of a number of genes. Stereospecific saturation of the C 13 -C 14 double bond of all-transretinol by the enzyme, retinol saturase (RetSat), leads to the production of (R)-all-trans-13,14-dihydroretinol. In liver and adipose tissue, expression of RetSat is controlled by peroxisome proliferator-activated receptors (PPAR) ␣ and ␥, respectively. Expression of RetSat in adipose tissue is also required for PPAR␥ activation and adipocyte differentiation, but the involved mechanism is poorly understood. In this study, we examined the potential of (R)-all-trans-13,14-dihydroretinol and its metabolites to control gene transcription via nuclear receptors. Using a cell-based transactivation assay to screen 25 human nuclear receptors for activation, we found that dihydroretinoids have a narrow transcriptional profile limited primarily to activation of retinoic acid receptors (RARs). Although (R)-alltrans-13,14-dihydroretinoic acid exhibited comparable potency to retinoic acid in promoting the interaction of RARs with a coactivator peptide in vitro, its potency in activating RARcontrolled genes in cell-based assays was much lower than that of retinoic acid. As an explanation for the weak RAR agonist activity of dihydroretinoids in cell-based assays, we propose that both delivery of ligand to the nucleus and RAR activation favor retinoic acid over dihydroretinoids. Discrimination between the cognate ligand, retinoic acid, and close analogs such as dihydroretinoids, occurs at multiple levels and may represent a mechanism to modulate retinoid-dependent physiological processes.

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“…RetSat was shown to have an interesting relationship with several important metabolic pathways, such as the fasting response, insulin signaling, and lipid metabolism [16–19]. Increased lipid peroxidation and ROS production is an early pathological feature of HFD-induced insulin resistance [27, 28].…”

Section: Resultsmentioning

confidence: 99%

“…The expression of RetSat is induced by PPARα and PPARγ, important transcriptional regulators of lipid metabolism [16, 17], and is often deregulated in diabetic patients and in various models of insulin resistance [18]. Moreover, in vitro studies have uncovered the requirement of RetSat in the adipogenic differentiation of 3T3-L1 cells [17].…”

Section: Introductionmentioning

confidence: 99%

Retinol saturase modulates lipid metabolism and the production of reactive oxygen species

Pang

Wang

Jurczak

et al. 2017

Archives of Biochemistry and Biophysics

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Retinol saturase (RetSat) catalyzes the saturation of double bonds of all-trans-retinol leading to the production of dihydroretinoid metabolites. Beside its role in retinoid metabolism, there is evidence that RetSat modulates the cellular response to oxidative stress and plays critical roles in adipogenesis and the accumulation of lipids. Here, we explore the relationship between RetSat, lipid metabolism and oxidative stress using in vitro and in vivo models with altered expression of RetSat. Our results reveal that RetSat is a potent modulator of the cellular response to oxidative stress and the generation of reactive oxygen species (ROS). The levels of reactive aldehydes products of lipid peroxidation, as measured based on thiobarbituric acid reactivity, are increased in RetSat overexpressing cells and, conversely, reduced in cells and tissues with reduced or absent expression of RetSat compared to controls. Despite increased weight gain, neutral lipid accumulation and alterations in hepatic lipid composition, RetSat−/− mice exhibit normal responses to insulin. In conclusion, our findings further expand upon the role of RetSat in oxidative stress and lipid metabolism and could provide insight in the significance of alterations of RetSat expression as observed in metabolic disorders.

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Identification and characterization of a novel mouse peroxisome proliferator-activated receptor a-regulated and starvation-induced gene, Ppsig

Cited by 19 publications

References 23 publications

Identification of a Functional Antioxidant Response Element within the Eighth Intron of the HumanABCC3Gene

Identification of a Functional Antioxidant Response Element within the Eighth Intron of the HumanABCC3Gene

Activation of Retinoic Acid Receptors by Dihydroretinoids

Retinol saturase modulates lipid metabolism and the production of reactive oxygen species

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