title: A liver-selective LXR inverse agonist that suppresses hepatic steatosis.
abstract: Fatty liver, which often accompanies obesity and type 2 diabetes, frequently leads to a much more debilitating hepatic disease including non-alcoholic steatohepatitis, cirrhosis, and hepatocellular carcinoma. Current pharmacological therapies lack conclusive efficacy and thus treatment options are limited. Novel therapeutics that suppress either hepatic lipogenesis and/or hepatic inflammation may be useful. Here, we describe the development of the first selective synthetic LXR inverse agonist (SR9238) and demonstrate that this compound effectively suppresses hepatic lipogenesis, inflammation, and hepatic lipid accumulation in a mouse model of non-alcoholic hepatosteatosis. SR9238 displays high potency for both LXRα and LXRβ (40-200 nM IC50) and was designed to display liver specificity so as to avoid potential side effects due to suppression of LXR in the periphery. Unexpectedly, treatment of diet-induced obese mice with SR9238 suppressed plasma cholesterol levels. These data indicate that liver-selective LXR inverse agonists may hold utility in the treatment of liver disease.
authors.affiliation: The Scripps Research Institute, Jupiter, FL 33458, USA.
authors.forename: Kristine
authors.initials: K
authors.lastname: Griffett
authors.forename: Laura A
authors.initials: LA
authors.lastname: Solt
authors.forename: Bahaa El-Dien M
authors.initials: Bel-D
authors.lastname: El-Gendy
authors.forename: Theodore M
authors.initials: TM
authors.lastname: Kamenecka
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Burris
mesh_terms: D000818:Animals; D002784:Cholesterol / Q000097:blood / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D054314:Drug Inverse Agonism; D005234:Fatty Liver / Q000188:drug therapy*; D006576:Heterocyclic Compounds, 4 or More Rings / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008099:Liver / Q000378:metabolism*; D000071518:Liver X Receptors; D051379:Mice; D008820:Mice, Obese; D015394:Molecular Structure; D009928:Organ Specificity; D057093:Orphan Nuclear Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D006576:Heterocyclic Compounds, 4 or More Rings; D000071518:Liver X Receptors; C000605213:NR1H3 protein, human; C000605214:Nr1h3 protein, mouse; D057093:Orphan Nuclear Receptors; C000593811:SR9238; D002784:Cholesterol