7月23日，華中農業大學動物科學技術學院、動物醫學院丁一副教授課題組通過篩選治療脂肪性肝炎的天然化合物，發現天麻素具有良好的安全性和抗脂肪性肝炎效果，並進一步探索了天麻素的作用機制。該研究以題為“Gastrodin improves nonalcoholic fatty liver disease via activation of the AMPK signaling pathway”線上發表在Hepatology上。
脂肪肝是動物（如牛、雞、猫等）和人常見的代謝性疾病之一，嚴重時引起脂肪性肝炎和肝硬化。儘管現代醫學發展迅速，人們在發掘其治療靶點方面取得了很大進展，但現時尚無獲得批准的有效治療藥物。該研究給小鼠飼喂高脂飲食（HFD）和高脂高膽固醇（HFHC），建立脂肪肝和脂肪肝炎模型，並使用天麻素治療。與對照組相比，天麻素治療小鼠的肝重量、肝臟和血清甘油三酯和膽固醇的含量、血清丙氨酸轉氨酶（ALT）和天冬氨酸轉氨酶（AST）的活性顯著降低，肝細胞的脂質蓄積和炎性反應顯著緩解，脂質蓄積、炎症和纖維化相關基因顯著下調（圖1）。
圖1天麻素緩解高脂飲食誘導的小鼠脂肪肝和肝炎
基因富集（GSEA）分析，發現天麻素主要啟動AMPK通路。進一步研究採用特异性的抑制劑（化合物C）和shRNA干擾，證實天麻素主要通過AMPK通路逆轉脂肪性肝炎。該研究篩選出脂肪肝炎的低毒高效治療藥物，發現了其新的作用靶點（圖2）。
圖2天麻素啟動AMPK訊號通路
華中農業大學動物醫學院博士生萬娟，碩士生張岩岩和博士後楊迪琦為本文共同第一作者，丁一副教授為本文通訊作者。本研究獲得國家自然科學基金專案資助。
原文連結：https://pubmed.ncbi.nlm.nih.gov/34297426/
英文摘要：
Background & aims:Nonalcoholic steatohepatitis（NASH）is currently one of the most common causes of liver transplantation and hepatocellular carcinoma.Thus far，there is still no effective pharmacological therapy for this disease.Recently，Gastrodin has demonstrated hepatoprotective effects in a variety of liver diseases.The aim of this study is to investigate the function of Gastrodin in NASH.
Approach and result:In our study，Gastrodin showed potent therapeutic effects on NASH both in vivo and in vitro.In high-fat diet（HFD）- or high-fat and high-cholesterol（HFHC）diet-fed mice，the liver weight，hepatic and serum triglyceride and cholesterol contents，the serum alanine aminotransferase（ALT）and aspartate aminotransferase（AST）activity levels were markedly reduced by Gastrodin treatment as compared to the corresponding vehicle groups.Notably，Gastrodin showed minimal effects on the function and histological characteristics of other major organs in mice.We further examined the effects of Gastrodin on lipid accumulation in primary mouse hepatocytes and human hepatocyte cell line，and observed that Gastrodin showed a significant decrease in lipid accumulation and inflammatory response in hepatocytes under metabolic stress.Furthermore，RNA-Seq analysis systemically indicated that Gastrodin suppressed the pathway and key regulators related to lipid accumulation，inflammation and fibrosis in the pathogenesis of NASH.Mechanistically，we found that Gastrodin protected against NASH by activating the AMPK pathway，which was supported by the result that the AMPK inhibitor compound C or AMPK knockdown blocked the Gastrodin-mediated hepatoprotective effect.
Conclusion:Gastrodin attenuates steatohepatitis by activating the AMPK pathway and represents a novel therapeutic for the treatment of NASH.
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