1. Academic Validation
  2. 2-Geranyl-1-methoxyerythrabyssin II alleviates lipid accumulation and inflammation in hepatocytes through AMPK activation and AKT inhibition

2-Geranyl-1-methoxyerythrabyssin II alleviates lipid accumulation and inflammation in hepatocytes through AMPK activation and AKT inhibition

  • Arch Pharm Res. 2023 Oct;46(9-10):808-824. doi: 10.1007/s12272-023-01464-z.
Yiyuan Xi 1 2 3 Soeun Kim 2 Thi Thanh Thuy Nguyen 2 Phil Jun Lee 2 Jujia Zheng 1 3 Zhuofeng Lin # 4 Namki Cho # 5
Affiliations

Affiliations

  • 1 The Clinical Research Center, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China.
  • 2 Research Institute of Pharmaceutical Sciences, College of Pharmacy, Chonnam National University, Gwangju, 61186, Korea.
  • 3 Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China.
  • 4 Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China. zhuofenglin@wzmc.edu.cn.
  • 5 Research Institute of Pharmaceutical Sciences, College of Pharmacy, Chonnam National University, Gwangju, 61186, Korea. cnamki@jnu.ac.kr.
  • # Contributed equally.
Abstract

A growing proportion of the global adult and pediatric populations are currently affected by nonalcoholic steatohepatitis (NASH), leading to rising rates of liver fibrosis and hepatocellular carcinoma without effective pharmacotherapy. Here, we investigated whether 2-geranyl-1-methoxyerythrabyssin II (GMET), isolated from Lespedeza bicolor, could alleviate lipid accumulation and inflammatory responses in a NASH model. GMET exhibited potent in vitro and in vivo effects against lipid accumulation and attenuated inflammatory responses without cytotoxicity. Mechanistically, GMET inhibits Acetyl-CoA Carboxylase (ACC), sterol regulatory element-binding proteins-1c (SREBP1), and mammalian target of rapamycin (mTOR), and activates PPARα by activating AMP-activated kinase (AMPK), leading to the alleviation of lipid accumulation. In addition, GMET suppresses the NF-κB pathway by activating AMPK and inhibiting the activated protein kinase B (Akt)/IκB-kinase (IKK) pathway, leading to the inhibition of the inflammatory response in hepatocytes. All these protective effects of GMET on lipid accumulation and inflammation in vivo and in vitro were largely abolished by co-treatment with dorsomorphin, an AMPK Inhibitor. In conclusion, GMET alleviated lipid accumulation and inflammation to preserve normal hepatocyte function in steatohepatitis. Thus, GMET is a novel potential multi-targeting compound to improve steatohepatitis.

Keywords

AMPK; Inflammation; Lespedeza bicolor; Lipid accumulation; Nonalcoholic steatohepatitis; Pterocarpan.

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