1345-P: Low-Dose Colchicine/Metformin Combination Ameliorates NASH via Regulating AMPK/NRF2/GDF15 Axis in Mice

Abstract

Nonalcoholic steatohepatitis (NASH) , a complex metabolic disease by multifactorial pathogenesis is demanded multiple pharmacological modes of action for robust treatment strategies. Colchicine has shown efficacy in various clinical settings which inflammation is a key component, however growing evidences suggest that the therapeutic effect of colchicine is multifaceted by intervening in several different pathways involved in inflammation. Here, we investigated the novel therapeutic effects of low-doses of colchicine (LDC) -metformin (LDC-Met) combination to targeting NASH. To induce NASH disorder, C57BL/6J male mice were fed a CDHFD (choline-deficient high fat diet) for 12 weeks, then were orally administrated by LDC-Met with CDHFD for an additional 12 weeks. In CDHFD induced NASH mice models, LDC-Met markedly decreased the NAS and fibrosis score along with reducing serum level of liver enzymes and total cholesterol increased by CDHFD feeding. Consistent with these data, hepatic gene expression of steatosis, fibrosis, inflammation and apoptosis markers increased by CDHFD was noticeably inhibited by LDC-Met. Interestingly, significant increased circulating GDF15 was found in LDC-Met group, which was accompanied by increased hepatic GDF15 expression. Additionally, LDC-Met significantly augmented hepatic phosphorylation of AMPK and NRF2 in CDHFD-fed mice and NLRP3 inflammasome activity were negatively controlled by LDC-Met. Finally, LDC-Met noticeably reduced CDHFD-induced total body weight gain by approximately 20%, along with epididymal white adipose tissue (eWAT) weight reduction. Taken together, we found that the combination of LDC-Met has the best synergistic effect on NASH resolution, suggesting significant implications for potential drug repurposing and new drug development. Moreover, this novel combination elevates circulating levels of GDF15, which is necessary to obtain beneficial effects on energy balance and body weight. Disclosure S.Ham: None. H.Cho: None. C.Jeong: None. J.Youn: None.