N-Acylthiadiazolines, a New Class of Liver X Receptor Agonists with Selectivity for LXRβ

Molteni, Valentina; Li, Xin; Nabakka, Juliet; Liang, Fang; Wityak, John; Koder, Alan; Vargas, Leo; Romeo, Russell D.; Mitro, Nico; Mak, Puiying A.; Seidel, H. Martin; Haslam, Jennifer A.; Chow, Donald; Tuntland, Tove; Spalding, Tracy A.; Brock, Ansgar; Bradley, Michelle N.; Castrillo, Antonio; Tontonoz, Peter; Sáez, Enrique

doi:10.1021/jm070453f

Cited by 59 publications

(58 citation statements)

References 27 publications

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“…De novo lipid biosynthesis was assessed by 14 C-acetate (GE Healthcare/Amersham; 57 mCi/mmol, 0.2 Ci/ l) incorporation assays in cells grown in 6-well plates. Briefl y, cells were serum starved for 2 h in 1 ml DMEM/glucose followed by the addition of 1 Ci of 14 C-acetate and incubated for 4 h at 37°C, 5% CO 2 .…”

Section: Lipids Biosynthesis Analysis and Mass Spectroscopymentioning

confidence: 99%

“…Briefl y, cells were serum starved for 2 h in 1 ml DMEM/glucose followed by the addition of 1 Ci of 14 C-acetate and incubated for 4 h at 37°C, 5% CO 2 . In some experiments, cells were pretreated for 30 min with either 50 M LY 294002 (PI3-kinase inhibitor), 50 M PD9805 [a mitogen-activated protein (MAP) kinase inhibitor], 0.1 M rapamycin (mTOR inhibitor), 10 M cerulenin (a fatty acid biosynthesis inhibitor), 20 g/ml lovastatin (a cholesterol biosynthesis inhibitor), 5 M H89 (protein kinase A inhibitor), 20 M compound C (AMP kinase inhibitor), or 10 M cytochalasin B (glucose transport inhibitor).…”

Section: Lipids Biosynthesis Analysis and Mass Spectroscopymentioning

confidence: 99%

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Effects of FoxO4 overexpression on cholesterol biosynthesis, triacylglycerol accumulation, and glucose uptake

Zhu

Mounzih

Chehab

et al. 2010

Journal of Lipid Research

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The initial clue between forkhead proteins ( 1 ) and metabolism originated from the nematode Caenorhabditis elegans when it was found that inactivation of the insulin receptor homolog daf-2 shifted the metabolism of the worm to fat storage, resulting in a prolonged life span ( 2 ). The O family of the forkhead transcription factors FoxO1, FoxO3a, and FoxO4 have been involved in the regulation of multiple biological pathways ( 3 ), such as cell survival ( 4 ), cell cycle ( 5 ), insulin sensitivity ( 6 ), and adipocyte differentiation ( 7 ). FoxO transcription factors are expressed at different levels in multiple tissues, with FoxO4 showing predominant expression in skeletal muscle, heart, and adipose tissue ( 1,8 ). Mouse knockout studies of FoxO1, FoxO3a, and FoxO4 revealed that homozygosity for FoxO1 led to embryonic lethality, whereas FoxO3a and FoxO4 were viable ( 9 ). These studies demonstrate that FoxO3a and FoxO4 cannot compensate for the loss of FoxO1; however, FoxO1 or other factors could compensate for certain aspects of FoxO3a and FoxO4 loss of function. FoxO3a homozygous null females showed an age-dependent infertility associated with abnormal follicular development, and transgenic mice overexpressing a constitutively active form of FoxO3a in oocytes had delayed oocyte Abstract The Forkhead transcription factors FoxO1, FoxO3a, and FoxO4 play a prominent role in regulating cell survival and cell cycle. Whereas FOXO1 was shown to mediate insulin sensitivity and adipocyte differentiation, the role of the transcription factor FoxO4 in metabolism remains ill defi ned. To uncover the effects of FoxO4, we generated a cellular model of stable FoxO4 overexpression and subjected it to microarray-based gene expression profi ling. While pathway analysis revealed a disruption of cholesterol biosynthesis gene expression, biochemical studies revealed an inhibition of cholesterol biosynthesis, which was coupled with decreased mRNA levels of lanosterol 14 ␣ demethylase (CYP51). FoxO4-mediated repression of CYP51 led to the accumulation of 24,25 dihydrolanosterol (DHL), which independently and unlike lanosterol inhibited cholesterol biosynthesis. Furthermore, FoxO4-overexpressing cells accumulated lipid droplets and triacylglycerols and had an increase in basal glucose uptake. Recapitulation of these effects was obtained following treatment with CYP51 inhibitors, which also induce DHL buildup. Moreover, DHL but not lanosterol strongly stimulated liver X receptor ␣ (LXR ␣ ) activity, suggesting that DHL and LXR ␣ mediate the downstream effects initiated by FoxO4. Together, these studies suggest that FoxO4 acts on CYP51 to regulate the late steps of cholesterol

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Section: Lipids Biosynthesis Analysis and Mass Spectroscopymentioning

confidence: 99%

Section: Lipids Biosynthesis Analysis and Mass Spectroscopymentioning

confidence: 99%

Effects of FoxO4 overexpression on cholesterol biosynthesis, triacylglycerol accumulation, and glucose uptake

Zhu

Mounzih

Chehab

et al. 2010

Journal of Lipid Research

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“…[19] Furthermore, the crystal structures of the ligand binding domains of these receptors have revealed that the same amino acids line the pocket in both receptors. [22] LXRα is most highly expressed in the liver, kidney, intestine and adipose tissue, while the expression of LXRβ is detectable in every tissue tested at a fairly consistent level. When compared using real-time quantitative PCR, the expression of mouse LXRβ in the liver is approximately 2-fold less than that of LXRα, while in other tissues LXRβ is the predominant receptor.…”

Section: The Nuclear Hormone Receptors Lxrα and Lxrβmentioning

confidence: 88%

“…Progress has been made to generate LXRβ-selective ligands, a remarkable advance considering the amino acid residues lining the ligand binding pockets of LXRα and LXRβ are identical. [22] However, because of this considerable difficulty, it is unclear to what extent selectivity between the isoforms can be achieved and whether selectivity obtained from in vitro screening will be maintained in an in vivo setting. A further challenge will be to design LXRβ-selective ligands with pharmacokinetic properties amenable to development.…”

Section: Benefits and Challenges Of Targeting Lxr For Therapeutic Modmentioning

confidence: 99%

Liver X receptors as therapeutic targets for managing cholesterol: implications for inflammatory conditions

Zhang

Chan

Cummins

2009

Clinical Lipidology

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SummaryAtherosclerosis is a disease characterized by excess cholesterol and inflammation in the blood vessels. The liver X receptors (alpha and beta) are members of the nuclear hormone receptor family that are activated by endogenous cholesterol metabolites. These receptors are widely expressed with a tissue distribution that includes the liver, intestine and macrophage. Upon activation, these receptors have been shown to increase reverse cholesterol transport from the macrophage back to the liver to aid in the removal of excess cholesterol. More recently, they have also been shown to inhibit the inflammatory response in macrophages. These functions are accomplished through direct regulation of gene transcription. Herein, we will describe the key benefits and potential risks of targeting the LXRs for the treatment of atherosclerosis.

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“…Structure-activity relationship (SAR) studies have been therefore conducted, resulting in the synthesis of different LXR agonists. Among them are acetyl-podocarpic acid and derivatives [79;80], 2-aryl-N-acyl indole [81], or N-acylthiadiazolines [82], anilinohexafluoroisopropanols [83], phenyl acetic acid substituted quinolines [12], acanthoic acid-related diterpenes [84], acidic heterocycles [85]. However, although most of these compounds are active on cholesterol metabolism, they also undesirably upregulate SREBP1-c gene expression, limiting therefore their development.…”

Section: Page 15 Of 35mentioning

confidence: 99%

Liver X receptor modulators: Effects on lipid metabolism and potential use in the treatment of atherosclerosis

Fiévet¹,

Staels²

2009

Biochemical Pharmacology

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To cite this version:C. Fiévet, B. Staels. Liver X Receptor modulators: Effects on lipid metabolism and potential use in the treatment of atherosclerosis. Biochemical Pharmacology, Elsevier, 2009, 77 (8) This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.Page 1 AbstractLiver X Receptors (LXRs) are nuclear receptors that play a crucial role in regulating the expression of genes involved in lipid metabolism. Ligand activation of LXRs improves cholesterol homeostasis via multiple coordinated effects, and this function is likely to explain in part the protective effects of LXR activation on atherosclerosis reported in animal models. However, LXR activation may also induce undesirable side effects, such as lipogenesis and hypertriglyceridemia. This review discusses the potential to develop LXR modulators as therapeutic agents for atherosclerosis.

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N-Acylthiadiazolines, a New Class of Liver X Receptor Agonists with Selectivity for LXRβ

Cited by 59 publications

References 27 publications

Effects of FoxO4 overexpression on cholesterol biosynthesis, triacylglycerol accumulation, and glucose uptake

Effects of FoxO4 overexpression on cholesterol biosynthesis, triacylglycerol accumulation, and glucose uptake

Liver X receptors as therapeutic targets for managing cholesterol: implications for inflammatory conditions

Liver X receptor modulators: Effects on lipid metabolism and potential use in the treatment of atherosclerosis

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