Author: Boulahtouf, Abdelhay ; Garoche, Clémentine ; Legler, Juliette ; Grimaldi, Marina ; Bourguet, William ; Balaguer, Patrick ; Toporova, Lucia ; den Broeder, Marjo J. ; Chiavarina, Barbara

Endocrine disrupting chemicals (EDCs) are able to deregulate the hormone system, notably through interactions with nuclear receptors (NRs). The mechanisms of action and biological effects of many EDCs have mainly been tested on human and mouse but other species such as zebrafish and xenopus are increasingly used as a model to study the effects of EDCs. Among NRs, peroxisome proliferator-activated receptor γ (PPARγ) is a main target of EDCs, for which most experimental data have been obtained from human and mouse models. To assess interspecies differences, we tested known human PPARγ ligands on reporter cell lines expressing either human, mouse, zebrafish, or xenopus PPARγ. Using these cell lines, we were able to highlight major interspecies differences. Known hPPARγ pharmaceutical ligands modulated hPPARγ and mPPARγ activities in a similar manner, while xPPARγ was less responsive and zfPPARγ was not modulated at all by these compounds. On the contrary, human liver X receptor (hLXR) ligands GW 3965 and WAY-252623 were only active on zfPPARγ. Among environmental compounds, several molecules activated the PPARγ of the four species similarly, e.g., phthalates (MEHP), perfluorinated compounds (PFOA, PFOS), and halogenated derivatives of BPA (TBBPA, TCBPA), but some of them like diclofenac and the organophosphorus compounds tri-o-tolyl phosphate and triphenyl phosphate were most active on zfPPARγ. This study confirms or shows for the first time the h, m, x, and zfPPARγ activities of several chemicals and demonstrates the importance of the use of species-specific models to study endocrine and metabolism disruption by environmental chemicals.

01 Jan 2021·Emerging microbes & infectionsQ2 · MEDICINE

The liver X receptor agonist LXR 623 restricts flavivirus replication

Q2 · MEDICINE

ArticleOA

Author: Dorward, David W. ; Bloom, Marshall E. ; Carmody, Aaron ; Best, Sonja M. ; Mlera, Luwanika ; Chiramel, Abhilash I. ; Offerdahl, Danielle K.

The vector-borne flaviviruses (VBFVs) are well known for causing great misery and death in humans worldwide. The VBFVs include those transmitted by mosquitos, such as Zika virus (ZIKV), dengue virus; and those transmitted by ticks including the tick-borne flavivirus serocomplex and Powassan virus (POWV). Two of our recent reports showed that intracranial POWV infection in the reservoir host, Peromyscus leucopus, was restricted and caused no overt clinical disease. Several modes of analyses suggested activation of the LXR pathway. Activation of the LXR pathway leads to increased efflux of cholesterol from cells and consequent disturbances in membrane biogenesis. Because VBFV replication is dependent on membrane biogenesis, we evaluated the effect of an LXR agonist (LXR623) on POWV and ZIKV infection and observed that the compound impaired permissive replication of both viruses in a human neuroblastoma SK-N-SH cell line. The LXR agonist resulted in failure of the viruses to induce ER expansion and elaborate vesicle formation, suggesting that the efflux of cholesterol was part of the antiviral mechanism. We also observed that the LXR agonist contributed to the mechanism of virus suppression by increased expression of mRNAs encoding for the antiviral cytokines CXCL10, RANTES and IFN1β. In sharp contrast, a LXR antagonist (GSK2033) had no significant effect on VBFV replication. We conclude that LXR623 impairs flavivirus replication by stimulating cellular antiviral factors.

01 Dec 2020·Hepatology (Baltimore, Md.)Q1 · MEDICINE

Activation of the Liver X Receptor Pathway Inhibits HBV Replication in Primary Human Hepatocytes

Q1 · MEDICINE

Article

Author: Hu, Hui ; Gao, Lu ; Yan, Zhipeng ; Wu, Daitze ; Zeng, Jing ; Young, John A T

Background and Aims:

Hepatitis B virus (HBV) infection is ranked among the top health priorities worldwide. Accumulating evidence suggests that HBV infection and replication are closely associated with liver metabolism. The liver X receptors (LXRs), which belong to the superfamily of nuclear hormone receptors, are important physiological regulators of lipid and cholesterol metabolism. However, the association between the LXR pathway and HBV infection remains largely unclear.

Approach and Results:

In this study, the antiviral activity of LXR agonists was investigated using multiple HBV cellular models. We observed that in HBV‐infected primary human hepatocytes (PHHs), synthetic LXR agonists (T0901317, GW3965, and LXR‐623), but not an LXR antagonist (SR9238), potently inhibited HBV replication and gene expression, as demonstrated by substantial reductions in viral RNA, DNA, and antigen production following agonist treatment. However, covalently closed circular DNA (cccDNA) levels were not significantly reduced by the agonists. In addition, no rebound in viral replication was observed after treatment withdrawal, indicating a long‐lasting inhibitory effect. These results suggest that LXR agonists decrease the transcriptional activity of cccDNA. In contrast, no significant anti‐HBV effect was observed in HepG2‐derived cell lines. Interestingly, LXR agonist treatment strongly reduced cholesterol 7α‐hydroxylase 1 (CYP7A1) mRNA levels. Knockdown of CYP7A1 gene expression with small interfering RNA inhibited HBV activity in PHHs, suggesting CYP7A1 as a potential factor contributing to the antiviral effects of LXR agonists.

Conclusions:

We found that activation of the LXR pathway with synthetic LXR agonists could elicit potent anti‐HBV activity in PHHs, possibly through sustained suppression of cccDNA transcription. Our work highlights the therapeutic potential of targeting the LXR pathway for the treatment of chronic HBV infection.

News (Medical) associated with LXR-623

20 Sep 2007

·www.biospace.com

Karo Bio AB Development of Clinical Candidate LXR-623 Discontinued

STOCKHOLM, Sweden--(BUSINESS WIRE)--Regulatory News: Karo Bio announced today that it has been informed by its research partner, Wyeth Pharmaceuticals, a division of Wyeth, that development of LXR-623 has been discontinued. The compound had been in phase 1 testing for the treatment of atherosclerosis. While LXR-623 demonstrated efficacy on biomarkers for atherosclerosis, it had an unfavorable pro further development. Karo Bio and Wyeth remain committed to the research partnership and to advancing a new lead compound under the terms of the collaboration, which was recently extended until August 31, 2008. The collaboration between Karo Bio and Wyeth targets the Liver X Receptor (LXR), with the aim to develop new treatments for atherosclerosis. LXR regulates transport proteins, including ABCA1 and ABCG1, which promote reverse cholesterol transport (transport of cholesterol from peripheral tissues to the liver). Furthermore, it has been demonstrated that small molecular compounds that activate LXR have anti-atherogenic properties. "Unfortunately compounds do fail in the process but this is part of the development of pharmaceuticals. We remain optimistic about LXR as a target for treatment of atherosclerosis and for the prospects for new molecules for development. The learnings generated from the LXR-623 program will be valuable as additional potential compounds move forward. We have recently extended our collaboration with Wyeth and we are pleased with Wyeth's commitment to the program", says Per Olof Wallstrom, President of Karo Bio. Facts about Karo Bio Karo Bio is a drug discovery and development company specializing in nuclear receptors for the development of novel pharmaceuticals with focus on metabolic diseases. The company has expanded from being a drug discovery company by adding in-house preclinical and clinical development resources and competence for development of drugs to treat metabolic diseases. The company has a strong project portfolio with innovative molecules that primarily targets diseases such as diabetes, atherosclerosis and dyslipidemia. In all of these areas there are significant market opportunities and a growing need for new pharmaceuticals with new mechanisms of action. In addition to the proprietary projects Karo Bio has two strategic collaborations with international pharmaceutical companies and one biotech collaboration for development of innovative therapies for the treatment of common diseases. Karo Bio is listed on the OMX Nordic Exchange Stockholm AB since 1998 (Reuters: KARO.ST). This press release is also available online at: and This information was brought to you by Cision Contact: Per Olof Wallstrom President & Chief Executive Officer Telephone: +46 8 608 60 20 or Per Otteskog Senior Vice President Telephone: +46 8 608 60 18 Source: Karo Bio

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Indication	Highest Phase	Country/Location	Organization	Date
Atherosclerosis	Phase 1	-	Pfizer Inc.	-

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