NASH is characterized by severe hepatic fibrosis that potentiates cirrhosis and hepatocellular carcinoma. The MCD diet also potentiates severe liver fibrosis by reducing lipid secretion and antioxidant defenses, and adversely altering the gut microbiome to promote liver inflammation and damage. B, a dopamine D2 receptor agonist reduces adipose lipolysis and hepatic lipogenesis and inflammation. C improves a gut microbiome adverse to liver. C is also 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 against MCD diet induced liver fibrosis. C57B6 mice were fed an MCD diet for 8 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) daily for 4 weeks while maintained on the diet. A group of mice on normal diet were used as normal reference control. BC therapy led to significant reductions of serum ALT (85%), serum AST (33.4%), liver steatosis (65.4%), inflammation (86.7%), ballooning degeneration (60%), and NAFLD activity score (86.4%), as well as gene expression markers each of fibrosis (αSMA, TGFβ, COL1A, TXNIP) by 88-92%, inflammation (TNFa, IL1β, MCP1, iNOS) by 91-97%, ER stress (DDIT3, ATF, sXBP1, HSPA5) by 45-93%, steatosis (ACC1, PLIN2) by 31-97%, and fatty acid oxidation (PPARα, PGC1α, CPT1, UCP1) by 65-86, and reduced the percent fibrosis area by 92.7% relative to vehicle (and resultantly similar to normal diet mice) (all above: P<0.05) and by amounts greater than B or C alone or additively. This study demonstrates the positive interactive effects of bromocriptine and curcumin on advanced liver fibrosis in an MCD diet model of NASH.


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

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