NASH involves a combination of hepatic and gastrointestinal (GI) pathophysiologies comprising hepatic lipotoxicity and nitro/oxidative stress and a “leaky," proinflammatory GI environment that collude to induce the disease. B, a dopamine D2 receptor agonist is known to reduce plasma hyperFFAemia, and hepatic lipogenesis and inflammation. C has been demonstrated to reduce GI inflammation and leakiness, and is known to augment brain dopaminergic activity. We therefore investigated if B and C combination therapy that engages different pathological targets of NASH may provide an additive/synergistic benefit for NASH in a mouse model. C57B6 mice were maintained on 40 kcal% fat diet with 5% fructose drinking water for 20 weeks to induce NASH with fibrosis then randomized to 4 treatment groups: Vehicle, B (10mg/kg), C (100mg/kg), and combination of B and C (BC) (N=8/gr) daily for 4 weeks while maintained on the diet. A group of mice on normal diet was used as normal reference control. BC treatment led to significant reductions of hyperglycemia (21.8%), microbiome dysbiosis (38.1%), serum ALT (26.5%), obesity (10.1%), and liver steatosis (66.7%), inflammation (93.3%), ballooning (85.0%), NAFLD activity score (80.0%), as well as of four gene expression markers each of fibrosis (αSMA, TGFβ, COL1A, TXNIP) by 26-40%, inflammation (TNFa, IL1β, MCP1, iNOS) by 41-81%, ER stress (DDIT3, ATF, sXBP1, HSPA5) by 28-40%, steatosis (SREBP1c, FASN, ACC1, PLIN2) by 28-42%, and fatty acid oxidation (PPARα, PGC1α, CPT1, UCP1) by 24-84% and increased antioxidant gene expression (NQO, GPX1, CAT, HMOX1) by 29-70%, and reduced the percent fibrosis area by 80% relative to vehicle (and resultantly similar to normal diet mice) (all above: P<0.05) and by amounts greater than either B or C alone or additively. This is the first study to demonstrate the positive interactive effects of bromocriptine and curcumin on NASH in a mouse obesogenic dietary model of the disease and it offers a potential safe means of treating NASH.


T. Tsai: Employee; Self; VeroScience LLC. A. Cincotta: Employee; Self; VeroScience LLC.

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