బయోమోలిక్యులర్ రీసెర్చ్ & థెరప్యూటిక్స్ జర్నల్

నైరూప్య

Manassantin A and B are Potential Therapeutic Agents for Treating Nonalcoholic Fatty Liver Disease

John Min1, Sin-Hee Han², Ae-Jin Choi², Faridoddin Mirshahi¹, Shunlin Ren¹, Jason D. Kang3, Phillip B. Hylemon3, Hae-Ki Min¹*, Arun J. Sanyal¹*

Manassantin (MNS) has been reported to have various biological activities including repression of Hypoxia-Inducible Factor 1 (HIF-1), anti-inflammatory, and anti-plasmodial properties. Here, we investigated whether MNS has the potential to serve as a therapeutic agent for treating Non-Alcoholic Fatty Liver Disease (NAFLD) via regulation of hepatic AMPK and ERK1/2, gp130/Stat3, inflammation, and autophagy pathways. In NAFLD patients, AMPKα (Thr172) phosphorylation levels were suppressed, whereas ERK1/2 phosphorylation levels were increased. In addition, IL-6 levels were directly correlated with ERK1/2 activation and were inversely related to decreases in AMPKα (Thr172) phosphorylation. MNS increased activation of AMPKα by increasing cellular AMP: ATP ratio, decreased ERK1/2 and PKC-θ phosphorylation, and decreased p62 and LC3 protein expression in palmitate (PA) or IL-6-treated human hepatocytes. PA or IL-6-induced-Stat3 phosphorylation levels were markedly suppressed in MNS-A or MNS-B treated-hepatocytes. There were no changes in histology and body weight in normal mice that were treated with MNS-B for 2 weeks. However. MNS-B upregulated hepatic AMPK phosphorylation and inhibited ERK phosphorylation in these mice showing that the compound may cause an energy deficient state in the normal animal model. This energy-deficient state may prove to be key in ameliorating diet-induced NAFLD. These results strongly suggest that MNS-A and MNS-B, plant-based compounds, modulate nutrient and inflammatory signaling pathways involved in NAFLD and appear to be promising therapeutic agents for treating NAFLD.