sr9238 and Disease-Models--Animal

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.

Topics: Animals; Disease Models, Animal; Fatty Acid Synthases; Gene Expression Regulation; HEK293 Cells; Hep G2 Cells; Heterocyclic Compounds, 4 or More Rings; Humans; Inhibitory Concentration 50; Liver; Liver X Receptors; Male; Mice; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; Peptides; Sterol Regulatory Element Binding Protein 1; Sulfonamides; Triglycerides

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.

Topics: Animals; Cholesterol; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Inverse Agonism; Fatty Liver; Heterocyclic Compounds, 4 or More Rings; Humans; Liver; Liver X Receptors; Mice; Mice, Obese; Molecular Structure; Organ Specificity; Orphan Nuclear Receptors; Structure-Activity Relationship