Taurine is a liver <scp>X</scp> receptor‐α ligand and activates transcription of key genes in the reverse cholesterol transport without inducing hepatic lipogenesis

Hoang, Minh Hien; Jia, Yongyi; Jun, Hee-Jin; Lee, Ji Hae; Hwang, Kwang Yeon; Choi, Dal Woong; Um, Soo‐Jong; Lee, Boo Yong; You, Sung Hyun; Lee, Sung Joon

doi:10.1002/mnfr.201100611

Cited by 53 publications

(30 citation statements)

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“…Tau also prevented the development of NAFLD induced by a high-CHOL diet in hamsters [10] and in high-sucrose feeding rats [18]. This hepatic CHOL lowering effect may be due to a direct action of Tau on the liver X receptor (LXR)-α, increasing its transcription activity and enhancing the expression of genes involved in CHOL efflux and reducing CHOL accumulation in hepatocytes through augmentation of CHOL 7α-hydroxylase mRNA levels [22]. Therefore, reduced hepatic CHOL content in MTau and CTau rats without alteration in total CHOL plasma levels may be due to increased hepatic CHOL excretion and efflux, together with a possible alteration in plasma lipoprotein profile induced by Tau.…”

Section: Discussionmentioning

confidence: 93%

“…The normalization of the TG deposition in the livers of MTau rats was accompanied by an improvement in ChREBP and MTP mRNA levels, although other lipogenic genes and proteins were not regulated by Tau. In HepG2 cells, Tau was found to delay nuclear translocation of the SREBP-1c protein by upregulating the Insig2a gene; this effect reduces the cellular lipid content without alterations in the expression of genes related to fatty acid synthesis [22]. In addition, HepG2 cells incubated with 100 μM Tau presented enhanced ChREBP gene expression [22].…”

Section: Discussionmentioning

confidence: 96%

“…In HepG2 cells, Tau was found to delay nuclear translocation of the SREBP-1c protein by upregulating the Insig2a gene; this effect reduces the cellular lipid content without alterations in the expression of genes related to fatty acid synthesis [22]. In addition, HepG2 cells incubated with 100 μM Tau presented enhanced ChREBP gene expression [22]. The increase in ChREBP in MTau rats evidenced in our study possibly normalizes MTP mRNA expression, which contributes to ameliorate the transfer of lipids to ApoB in this group.…”

Section: Discussionmentioning

confidence: 98%

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Improvement in the expression of hepatic genes involved in fatty acid metabolism in obese rats supplemented with taurine

et al. 2015

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Section: Discussionmentioning

confidence: 93%

Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 98%

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Improvement in the expression of hepatic genes involved in fatty acid metabolism in obese rats supplemented with taurine

et al. 2015

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“…Other OTC metabolites, however, could play a role. Hepatic cells effi ciently convert OTC to taurine ( 60,61 ), which is an LXR ligand and has been shown to affect hepatic lipid metabolism ( 62 ). OTC could also generate sulfate ( 60,61 ) that, in turn, may affect hepatic functions such as drug detoxifi cation and protein posttranslational modifi cation.…”

Section: Discussionmentioning

confidence: 99%

Effect of Procysteine on aging-associated changes in hepatic GSH and SMase: evidence for transcriptional regulation of smpd3

Deevska

Sunkara

Karakashian

et al. 2014

Journal of Lipid Research

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Journal of Lipid Research Volume 55, 2014 2041GSH is the major antioxidant in the body responsible for maintaining the intracellular redox balance. Aging is accompanied by a progressive decline in the levels of GSH in humans ( 1-3 ) and rodents ( 4-7 ), as well as in senescent cells in culture ( 8 ), resulting in elevated reactive oxygen species (ROS) and a state of chronic oxidative stress. Dietary GSH supplementation has been considered as a potential treatment for various aging-related diseases that are linked to oxidative stress, including metabolic, cardiovascular, and Alzheimer's diseases, as well as various types of cancers ( 9-11 ). The direct delivery of GSH, however, is ineffi cient and could even be toxic; therefore, various precursors of GSH synthesis have been widely used instead ( 12 ).The availability of L -cysteine is the rate-limiting factor for GSH synthesis. Several cysteine pro-drugs, including L-2-oxothiazolidine-4-carboxylic acid (OTC), have been successfully used to elevate GSH levels ( 13 ). Administration of OTC has been shown to effectively elevate hepatic GSH concentration in healthy guinea pigs ( 14 ), as well as in rats and mice with experimentally induced GSH defi ciency due to acetaminophen and alcohol consumption ( 7,15,16 ). In humans, OTC supplementation leads to a significant increase in blood GSH in healthy volunteers ( 17, 18 ), as well as in dialysis and HIV patients ( 19-21 ). Typically, dietary OTC supplementation has benefi cial effects and protects against acetaminophen-, alcohol-, or thioacetamideinduced hepatic damage ( 15,16,22,23 ).Abstract In hepatocytes, aging-associated decline in GSH has been linked to activation of neutral SMase (nSMase), accumulation of bioactive ceramide, and infl ammation. In this study, we seek to test whether dietary supplementation with the cysteine precursor, L-2-oxothiazolidine-4-carboxylic acid (OTC), would correct the aging-associated differences in hepatic GSH, nSMase, and ceramide. Young and aged mice were placed on a diet that either lacked sulfurcontaining amino acids (SAAs) or had 0.5% OTC for 4 weeks. Mice fed standard chow were used as an additional control. SAA-defi cient mice exhibited signifi cant aging-associated differences in hepatic GSH, GSH/GSSG, ceramide, and nSMase. C24:1 ceramide, the major ceramide species in liver, was affected the most by aging, followed by the less abundant C16:0 ceramide. OTC supplementation eliminated the aging-associated differences in hepatic GSH and GSH/GSSG ratio. Surprisingly, however, instead of decreasing, the nSMase activity and ceramide increased in the OTC-fed mice irrespective of their age. These effects were due to elevated nSMase-2 mRNA and protein and appeared to be direct. Similar increases were seen in HepG2 cells following treatment with OTC. The OTC-fed aged mice also exhibited hepatic steatosis and triacylglyceride accumulation. These results suggest that OTC is a potent stimulant of nSMase-2 expression and that there may be unanticipated complications of OTC supplementation. ...

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“…Unfortunately, the trial was terminated due to adverse central nervous system effects. [19][20][21] LXR antagonists reported so far include riccardin C (4, antagonist of LXRβ), naringenin (5, antagonist of LXRα), genistein (6, inhibition of LXRα or activation of LXRβ), taurine (7, antagonist of LXRα), rhein (8, antagonist of LXRα/β), SR-9238 (9, antagonist of LXRα/β), and 10 (antagonist of LXRα), among others [22][23][24][25][26][27][28] (Fig. 1).…”

mentioning

confidence: 99%

Discovery and Synthesis of a Novel Series of Liver X Receptor Antagonists

Nian

Gan

Tan

et al. 2015

CHEMICAL & PHARMACEUTICAL BULLETIN

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Fourteen novel compounds were prepared and their antagonistic activities against liver X receptors (LXR) α/β were tested in vitro. Compound 26 had an IC 50 value of 6.4 µM against LXRα and an IC 50 value of 5.6 µM against LXRβ. Docking studies and the results of structure-activity relationships support the further development of this chemical series as LXRα/β antagonists.Key words liver X receptor α; liver X receptor β; antagonistic activity Nuclear receptors (NRs) are ligand-activated transcription factors that coordinate gene expression in response to the modulation of metabolism, development, proliferation, and inflammation.1,2) Liver X receptors (LXRs) belonging to the NR superfamily are activated by specific oxidized forms of cholesterol and intermediate products of the cholesterol biosynthetic pathway. 1,3,4) There are two LXR isoforms in mammals, termed LXRα and LXRβ. LXRα is abundantly expressed mainly in the liver, intestine, kidney, spleen, and adipose tissue, whereas LXRβ is more ubiquitously expressed, with particularly high levels in the developing brain. [5][6][7][8] Both isoforms share almost 80% homology of their amino acid sequences in their DNA-binding domain and ligand-binding domain. 5,7)The LXR consists of four domains: N-terminal ligandindependent activation function domain (AF-1); DNA-binding domain (DBD); hydrophobic ligand-binding domain (LBD); and C-terminal ligand-dependent transactivation sequence (AF-2).5,9,10) By forming heterodimers with retinoid X receptors (RXRs), LXRs bind to LXR response elements (LXREs) in the promoter or enhancer elements of LXR target genes. The activation of LXR-RXR heterodimers not only induces the expression of a variety of target genes (CYP7A, ABCA1, SREBP-1) that are involved in lipid and glucose metabolism, but also results in the inhibition of genes encoding inflammatory factors such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and interferon (IFN)-γ. 1,[11][12][13][14][15] In the last decade, GlaxoSmithKline and other several pharmaceutical companies have been active in developing synthetic LXR agonists (Fig. 1). T0901317 (1, Tularik) and GW3965 (2, GSK) exhibit nonselectivity for LXRα and LXRβ with high affinity.11,16-18) The first compound to enter the clinic was LXR-623 (3, Wyeth), an LXRα/β partial agonist for the potential treatment of atherosclerosis and dyslipidemia. Unfortunately, the trial was terminated due to adverse central nervous system effects.19-21) LXR antagonists reported so far include riccardin C (4, antagonist of LXRβ), naringenin (5, antagonist of LXRα), genistein (6, inhibition of LXRα or activation of LXRβ), taurine (7, antagonist of LXRα), rhein (8, antagonist of LXRα/β), SR-9238 (9, antagonist of LXRα/β), and 10 (antagonist of LXRα), among others 22-28) (Fig. 1).SR-9238 was the first selective synthetic LXR inverse agonist that displays a degree of LXRβ selectivity with an IC 50 value of 214 nM for LXRα and 43 nM for LXRβ, and this compound effectively suppressed hepatic lipogenesis, inflammation, and hepatic lipid...

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Taurine is a liver X receptor‐α ligand and activates transcription of key genes in the reverse cholesterol transport without inducing hepatic lipogenesis

Abstract: Taurine is a direct LXR-α ligand, represses cholesterol accumulation, and modulates the expression of genes involved in reverse cholesterol transport in macrophages, without inducing hepatic lipogenesis. The induction of Insig-2a suppressed the nuclear translocation of SREBP-1c.

Cited by 53 publications

References 53 publications

Improvement in the expression of hepatic genes involved in fatty acid metabolism in obese rats supplemented with taurine

Improvement in the expression of hepatic genes involved in fatty acid metabolism in obese rats supplemented with taurine

Effect of Procysteine on aging-associated changes in hepatic GSH and SMase: evidence for transcriptional regulation of smpd3

Discovery and Synthesis of a Novel Series of Liver X Receptor Antagonists

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