Liver Selective LXR Inverse Agonists as Effective Therapeutics for Liver Disease

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: SUN 723-739-Lipids: Therapeutics & Case Reports
Sunday, June 16, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board SUN-728
Kristine Griffett*, Laura A Solt, Bahaa El-Dien M El-Gendy, Theodore M Kamenecka and Thomas P Burris
The Scripps Research Institute, Jupiter, FL
Nuclear receptors are ligand-activated transcription factors that regulate the expression of target genes that control diverse aspects of physiology including development, reproduction, metabolism, and circadian rhythm.  The Liver X Receptors (LXRα and LXRβ) belong to the nuclear receptor superfamily and play a key role in lipid metabolism and inflammation.  Non-alcoholic fatty liver disease (NAFLD) is associated with increased hepatic lipogenesis and often progresses to the more aggressive nonalcoholic steatohepatitis (NASH), cirrhosis and hepatocellular carcinomas (HCC).  Fatty liver diseases can occur in overweight and obese individuals, however recent finding show that individuals with normal BMI and children may also be affected.  Current treatment options typically center around lifestyle changes, focusing on alteration of diet and weight loss, but these treatments tend to be inadequate for a large number of patients.  We have developed a novel liver-specific LXR inverse agonist SR9238 that effectively recruits the corepressor to LXR target genes leading to suppression of their transcription. We hypothesized that either blocking activation of lipogenic enzyme expression or active suppression of these genes with an inverse agonist would lead to a potential treatment for NAFLD and NASH.  Thus far, our data indicates that SR9238 suppresses NAFLD and inflammation in a diet-induced obese mouse model.  Currently, we are investigating this compound in an in vivo model of NASH and genetic obesity.  SR9238 may prove to be an effective tool compound to develop an effective treatment of NASH and more severe liver diseases.

Nothing to Disclose: KG, LAS, BEDME, TMK, TPB

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