Promiscuous activity of the LXR antagonist GSK2033 in a mouse model of fatty liver disease.
The liver X receptor (LXR) functions as a receptor for oxysterols and plays a critical role in the regulation of glucose and lipid metabolism. We recently described a synthetic LXR inverse agonist that displayed efficacy in treatment of hepatic steatosis in a mouse model of non-alcoholic fatty liver disease (NAFLD). This compound, SR9238, was designed to display liver specificity so as to avoid potential detrimental effects on reverse cholesterol transport in peripheral tissues. Here, we examined the effects of a LXR antagonist/inverse agonist, GSK2033, which displays systemic exposure. Although GSK2033 performed as expected in cell-based models as a LXR inverse agonist, it displayed unexpected activity in the mouse NAFLD model. The expression of lipogenic enzyme genes such as fatty acid synthase and sterol regulatory binding protein 1c were induced rather than suppressed and no effect on hepatic steatosis was found. Further characterization of the specificity of GSK2033 revealed that it displayed a significant degree of promiscuity, targeting a number of other nuclear receptors that could clearly alter hepatic gene expression.
Department of Pharmacology & Physiology, Saint Louis University School of Medicine, St. Louis, MO 63104, USA.
Kristine
K
Griffett
Department of Pharmacology & Physiology, Saint Louis University School of Medicine, St. Louis, MO 63104, USA. Electronic address: burristp@slu.edu.
Thomas P
TP
Burris
D000818:Animals; D004195:Disease Models, Animal; D064429:Fatty Acid Synthases / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D057809:HEK293 Cells; D056945:Hep G2 Cells; D006576:Heterocyclic Compounds, 4 or More Rings / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D008099:Liver / Q000378:metabolism; D000071518:Liver X Receptors / Q000037:antagonists & inhibitors*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D065626:Non-alcoholic Fatty Liver Disease / Q000188:drug therapy*; D010455:Peptides / Q000737:chemistry; D051780:Sterol Regulatory Element Binding Protein 1 / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology*; D014280:Triglycerides / Q000737:chemistry; D000096926:Benzenesulfonamides
D064429:Fatty Acid Synthases; D006576:Heterocyclic Compounds, 4 or More Rings; D000071518:Liver X Receptors; D010455:Peptides; D051780:Sterol Regulatory Element Binding Protein 1; D013449:Sulfonamides; D014280:Triglycerides; C549350:2,4,6-trimethyl-N-((3'-(methylsulfonyl)-4-biphenylyl)methyl)-N-((5-(trifluoromethyl)-2-furanyl)methyl)benzenesulfonamide; D000096926:Benzenesulfonamides; C000605213:NR1H3 protein, human; C000605214:Nr1h3 protein, mouse; C000593811:SR9238; C497388:Srebf1 protein, mouse
Drug discovery; LXR; Lipogenesis; NASH; Nuclear receptor; Transcription
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