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Isolated Hepatic Perfusion as a Treatment for Liver Metastases of Uveal Melanoma
Published on: January 25, 2015
Discovery of tissue selective liver X receptor agonists for the treatment of atherosclerosis without causing hepatic
Chanjuan Li1, Hao Chen1, Xinying Chen1
1School of Pharmaceutical Sciences, Sun Yat-Sen University, 132 East Circle Road at University City, Guangzhou, 510006, China.
Abstract:
Liver X Receptor (LXR) is a potential drug target for atherosclerosis. One of the major challenges in taking LXR modulators to the clinic is steatosis. It was reported that sterol LXR agonists selectively activate LXR in the intestine and macrophage cells rather than in the liver. We hypothesize that sterol LXR agonists may selectively inhibit atherosclerosis without causing hepatic lipogenesis. Thus, based on LXR structure, 12 sterol compounds were designed and tested in a dual-luciferase reporter gene experiment. It was confirmed that compounds 4 and 6 were LXR agonists. Further experiments demonstrated that compounds 4 and 6 inhibit the formation of macrophage foam cells without inducing triglyceride accumulation in either hepatocytes or adipocytes. In vivo studies demonstrated that compound 4 promotes reverse cholesterol transport without inducing hepatic lipogenesis. Thus, we report that these compounds with sterol scaffolds can be promising leads for the treatment of atherosclerosis without inducing steatosis.
Insights
New sterol compounds targeting Liver X Receptor (LXR) show promise for treating atherosclerosis by inhibiting foam cell formation without causing liver fat accumulation (steatosis). These findings offer a potential therapeutic strategy with reduced side effects.
Area of Science:
- Biochemistry
- Pharmacology
- Medical Chemistry
Background:
- Liver X Receptor (LXR) is a key target for atherosclerosis treatment.
- Hepatic steatosis (fatty liver) is a major challenge limiting LXR modulator clinical use.
- Sterol LXR agonists may selectively target atherosclerosis without liver side effects.
Purpose of the Study:
- To design and evaluate novel sterol compounds as selective LXR agonists.
- To assess the efficacy of these compounds in inhibiting atherosclerosis progression.
- To determine if these compounds cause steatosis or hepatic lipogenesis.
Main Methods:
- Design of 12 sterol compounds based on LXR structure.
- Dual-luciferase reporter gene assay to confirm LXR agonism.
- In vitro studies on macrophage foam cell formation and triglyceride accumulation in hepatocytes/adipocytes.
- In vivo studies to assess reverse cholesterol transport and hepatic lipogenesis.
Main Results:
- Compounds 4 and 6 were identified as potent LXR agonists.
- Compounds 4 and 6 inhibited macrophage foam cell formation.
- No significant triglyceride accumulation was observed in hepatocytes or adipocytes.
- Compound 4 promoted reverse cholesterol transport in vivo without inducing hepatic lipogenesis.
Conclusions:
- Sterol-scaffolded compounds selectively activate LXR.
- These compounds are effective in preclinical models of atherosclerosis.
- They offer a potential therapeutic approach for atherosclerosis without inducing steatosis.
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