A Liver-Selective LXR Inverse Agonist That Suppresses Hepatic Steatosis

Griffett, Kristine; Solt, Laura A.; Elgendy, Bahaa; Kamenecka, Theodore M.; Burris, Thomas P.

doi:10.1021/cb300541g

Cited by 100 publications

(139 citation statements)

References 30 publications

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“…A recent study found that the LXRa antagonist 22-S-hydroxycholesterol counteracted T090-induced lipogenesis and lipid formation in myotubes from type 2 diabetic patients (Kase et al, 2007). Hepatospecific inhibition of LXR using an inverse agonist also inhibited NAFLD development induced by a high-fat diet (Griffett et al, 2013). Published studies indicate that there is good correlation between the level of LXRa expression and NAFLD.…”

Section: Discussionmentioning

confidence: 99%

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Cinnamamides, Novel Liver X Receptor Antagonists that Inhibit Ligand-Induced Lipogenesis and Fatty Liver

Sim

Kim

Lee

et al. 2015

J Pharmacol Exp Ther

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Liver X receptor (LXR) is a member of the nuclear receptor superfamily, and it regulates various biologic processes, including de novo lipogenesis, cholesterol metabolism, and inflammation. Selective inhibition of LXR may aid the treatment of nonalcoholic fatty liver diseases. In the present study, we evaluated the effects of three cinnamamide derivatives on ligand-induced LXRa activation and explored whether these derivatives could attenuate steatosis in mice. N-(4-trifluoromethylphenyl) 3,4-dimethoxycinnamamide (TFCA) decreased the luciferase activity in LXRE-tkLuc-transfected cells and also suppressed ligand-induced lipid accumulation and expression of the lipogenic genes in murine hepatocytes. Furthermore, it significantly attenuated hepatic neutral lipid accumulation in a ligand-induced fatty liver mouse system. Modeling study indicated that TFCA inhibited activation of the LXRa ligand-binding domain by hydrogen bonding to Arg305 in the H5 region of that domain. It regulated the transcriptional control exerted by LXRa by influencing coregulator exchange; this process involves dissociation of the thyroid hormone receptor-associated proteins (TRAP)/DRIP coactivator and recruitment of the nuclear receptor corepressor. These results show that TFCA has the potential to attenuate ligand-induced lipogenesis and fatty liver by selectively inhibiting LXRa in the liver.

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Section: Discussionmentioning

confidence: 99%

“…For example, the grapefruit flavonoid naringenin inhibits ligand-induced LXRa activation by suppressing the action of Trap220 coactivator (Goldwasser et al, 2010). The synthetic LXR inverse agonist SR9238 increases the interaction between NCoR and LXR and decreases the Trap220 interaction (Griffett et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Cinnamamides, Novel Liver X Receptor Antagonists that Inhibit Ligand-Induced Lipogenesis and Fatty Liver

Sim

Kim

Lee

et al. 2015

J Pharmacol Exp Ther

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“…One of these candidates, SR9328, has been shown to suppress fat production, eliminate inflammation and reverse fat accumulation in mouse livers 3 . But researchers do not yet know how effective this drug will be in the presence of fibrosis and cirrhosis, which do not develop in these mice.…”

Section: Damage Controlmentioning

confidence: 99%

Fatty liver disease: The liver labyrinth

Morgan

2014

Nature

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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).…”

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confidence: 99%

“…27) In this paper, we describe the discovery and further structural development of LXR antagonists based on the fibrate skeleton. Both molecules activated LXRs in a luciferase reporter gene assay (GAL4) tested in HEK-293 cells.…”

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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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A Liver-Selective LXR Inverse Agonist That Suppresses Hepatic Steatosis

Cited by 100 publications

References 30 publications

Cinnamamides, Novel Liver X Receptor Antagonists that Inhibit Ligand-Induced Lipogenesis and Fatty Liver

Cinnamamides, Novel Liver X Receptor Antagonists that Inhibit Ligand-Induced Lipogenesis and Fatty Liver

Fatty liver disease: The liver labyrinth

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

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