1868-P: Bromocriptine (BC) Improves Hepatic Steatosis, Inflammation, and ER Stress in a Mouse Obesogenic Dietary Model of Nonalcoholic Steatohepatitis (NASH)

Abstract

The pathogenesis of NASH is a complex interaction among hepatic lipotoxicity, oxidative stress, mitochondrial dysfunction and ER stress leading to hepatic inflammation, cell death, and fibrosis. Bromocriptine, a dopamine D2 receptor agonist is known to reduce adipose lipolysis, plasma hyperFFAemia, and hepatic lipogenesis and inflammation. Also, the antidiabetes drug, bromocriptine-QR has been demonstrated to reduce cardiovascular events. Therefore, we investigated the impact of BC on hepatic pathophysiology in a mouse obesogenic dietary model of NASH. Six-week-old C57B6 male mice (N=8/gr) were maintained on a 40 kcal% fat diet with 5% fructose in the drinking water for 12 weeks to induce NASH then randomized to BC (10mg/kg) or vehicle daily treatment for an additional 3 weeks while maintained on the diet. A group of mice on normal diet was used as a normal reference control. Such BC therapy reduced plasma glucose (28.6%), insulin (31.4%), leptin (42.7%), cholesterol (21.9%) and body weight (14.2%) relative to vehicle (P<0.01). Also, plasma biomarkers of hepatic inflammation: elevated ALT, AST, and LPS, were reduced by BC (32.6, 38.8, and 38.1%, respectively, P<0.05) vs. vehicle. Treatment with BC significantly reduced four gene expression markers each for steatosis (SREBP1c, FASN, ACC1, PLIN2), fatty acid oxidation (PPARα, PGC1α, CPT1, UCP1), inflammation (TNFa, IL1β, MCP1, iNOS), ER stress (DDIT3, ATF, sXBP1, HSPA5), and fibrosis (αSMA, TGFβ, COL1A, TXNIP) by 16-76, 17-47, 31-75, 20-55, and 21-70%, respectively (P<0.05 for each gene). Finally, histological analysis of the liver revealed BC therapy reduced steatosis, inflammation, and ballooning degeneration resulting in a 63% reduced NAFLD activity score (2.6 vs. 7.1, P<0.01). The BC effects on NASH resulted in hepatic physiology closely resembling the normal diet control group. These results suggest that BC could be an effective therapy for NAFLD and NASH. Disclosure T. Tsai: Employee; Self; VeroScience LLC. A. Cincotta: Employee; Self; VeroScience LLC.