2. Academic Validation
  3. Liraglutide attenuates type 2 diabetes mellitus-associated non-alcoholic fatty liver disease by activating AMPK/ACC signaling and inhibiting ferroptosis

Liraglutide attenuates type 2 diabetes mellitus-associated non-alcoholic fatty liver disease by activating AMPK/ACC signaling and inhibiting ferroptosis

  • Mol Med. 2023 Sep 28;29(1):132. doi: 10.1186/s10020-023-00721-7.
Tingli Guo 1 2,  Wenhui Yan 1 2,  Xin Cui 1 2,  Na Liu 1 2,  Xiaotong Wei 1 2,  Yuzhuo Sun 1 2,  KeXin Fan 3,  Jieyun Liu 1 2,  Yuanyuan Zhu 1 2,  Zhuanzhuan Wang 4,  Yilei Zhang 5 6 7,  Lina Chen 8 9 10 11
Affiliations

Affiliations

  • 1 Department of Pharmacology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, No. 76 Yanta West Road, Xi'an, 710061, Shaanxi, People's Republic of China.
  • 2 Institute of Cardiovascular Sciences, Translational Medicine Institute, Xi'an Jiaotong University Health Science Center, Xi'an, 710061, Shaanxi, China.
  • 3 Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, The Institute of Molecular and Translational Medicine, Xi'an Jiaotong University Health Science Center, No. 76 Yanta West Road, Xi'an, 710061, Shaanxi, People's Republic of China.
  • 4 Key Laboratory of Environment and Genes Related to Diseases, Xi'an Jiaotong University, Ministry of Education, Xi'an, 710061, Shaanxi, China.
  • 5 Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, The Institute of Molecular and Translational Medicine, Xi'an Jiaotong University Health Science Center, No. 76 Yanta West Road, Xi'an, 710061, Shaanxi, People's Republic of China. zhangyilei@xjtu.edu.cn.
  • 6 Key Laboratory of Environment and Genes Related to Diseases, Xi'an Jiaotong University, Ministry of Education, Xi'an, 710061, Shaanxi, China. zhangyilei@xjtu.edu.cn.
  • 7 Department of Thoracic Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, China. zhangyilei@xjtu.edu.cn.
  • 8 Department of Pharmacology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, No. 76 Yanta West Road, Xi'an, 710061, Shaanxi, People's Republic of China. chenlin@mail.xjtu.edu.cn.
  • 9 Institute of Cardiovascular Sciences, Translational Medicine Institute, Xi'an Jiaotong University Health Science Center, Xi'an, 710061, Shaanxi, China. chenlin@mail.xjtu.edu.cn.
  • 10 Key Laboratory of Environment and Genes Related to Diseases, Xi'an Jiaotong University, Ministry of Education, Xi'an, 710061, Shaanxi, China. chenlin@mail.xjtu.edu.cn.
  • 11 Department of Endocrinology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, China. chenlin@mail.xjtu.edu.cn.
PMID: 37770820 DOI: 10.1186/s10020-023-00721-7
Abstract

Background: Non-alcoholic fatty liver disease (NAFLD) is one of the most common complications of type 2 diabetes mellitus (T2DM). The pathogenesis of NAFLD involves multiple biological changes, including Insulin resistance, oxidative stress, inflammation, as well as genetic and environmental factors. Liraglutide has been used to control blood sugar. But the impact of liraglutide on T2DM-associated NAFLD remains unclear. In this study, we investigated the impact and potential molecular mechanisms of inhibiting Ferroptosis for liraglutide improves T2DM-associated NAFLD.

Methods: Mice were fed on high-fat-diet and injected with streptozotocin to mimic T2DM-associated NAFLD and gene expression in liver was analysed by RNA-seq. The fast blood glucose was measured during the period of liraglutide and ferrostatin-1 administration. Hematoxylin and eosin staining was used to evaluate the pathological changes in the liver. The occurrence of hepatic Ferroptosis was measured by lipid peroxidation in vivo. The mechanism of liraglutide inhibition Ferroptosis was investigated by in vitro Cell Culture.

Results: Liraglutide not only improved glucose metabolism, but also ameliorated tissue damage in the livers. Transcriptomic analysis indicated that liraglutide regulates lipid metabolism related signaling including AMPK and ACC. Furthermore, Ferroptosis inhibitor rather than other cell death inhibitors rescued liver cell viability in the presence of high glucose. Mechanistically, liraglutide-induced activation of AMPK phosphorylated ACC, while AMPK Inhibitor compound C blocked the liraglutide-mediated suppression of Ferroptosis. Moreover, Ferroptosis inhibitor restored liver function in T2DM mice in vivo.

Conclusions: These findings indicate that liraglutide ameliorates the T2DM-associated NAFLD, which possibly through the activation of AMPK/ACC pathway and inhibition of Ferroptosis.

Keywords

Ferroptosis; Lipid peroxidation; Liraglutide; Non-alcoholic fatty liver disease; Type 2 diabetes mellitus.

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