Euphorbia factor L3 ameliorates hepatic steatosis by activating LKB1-AMPK signaling pathway-regulated lipid metabolism.

Hepatic steatosis is a chronic progressive condition that leads to multiple severe liver disorders. However, current therapeutic options are limited for available drugs. Screening active natural products for curing hepatic steatosis provide novel chemical scaffolds for drug development and chemical probes to reveal novel mechanisms in the development of hepatic steatosis. Here, we established an in vitro cell model for measuring hepatic lipid content and screened a series of euphorane-type diterpenoids to identify active diterpenoids for decreasing hepatic lipids. Interestingly, among these diterpenoids, euphorbia factor L3 (EFL3) exhibited the most pronounced lipid-lowering activity, both in cultured hepatocytes and in HFD-induced mice with hepatic steatosis. Mechanistic studies demonstrated that EFL3 activated the LKB1-AMPK signaling pathway in hepatocytes, leading to downregulation of the lipogenic factors SREBP-1c, ACC1, and FASN, and leading to upregulation of fatty acid oxidation-related proteins SIRT1, PGC-1α, PPARα, and CPT1A. These changes improved cellular lipid metabolism and ultimately ameliorated hepatic steatosis in mice. In summary, this study supports the key role of LKB1-AMPK pathway in regulation of hepatic steatosis and reveals that EFL3 could be considered as a novel compound for drug development against hepatic steatosis.