Liraglutide attenuates hepatic iron levels and ferroptosis in db/db mice

Bioengineered. 2022 Apr;13(4):8334-8348. doi: 10.1080/21655979.2022.2051858.

Abstract

Liver pathological changes are as high as 21%-78% in diabetic patients, and treatment options are lacking. Liraglutide is a glucagon-like peptide-1 (GLP-1) receptor that is widely used in the clinic and is approved to treat obesity and diabetes. However, the specific protection mechanism needs to be clarified. In the present study, db/db mice were used to simulate Type 2 diabetes mellitus (T2DM), and they were intraperitoneally injected daily with liraglutide (200 μg/kg/d) for 5 weeks. Hepatic function, pathologic changes, oxidative stress, iron levels, and ferroptosis were evaluated. First, liraglutide decreased serum AST and ALT levels, and suppressed liver fibrosis in db/db mice. Second, liraglutide inhibited the ROS production by upregulating SOD, GSH-PX, and GSH activity as well as by downregulating MDA, 4-HNE, and NOX4 expression in db/db mice. Furthermore, liraglutide attenuated iron deposition by decreasing TfR1 expression and increasing FPN1 expression. At the same time, liraglutide decreased ferroptosis by elevating the expression of SLC7A11 and the Nrf2/HO-1/GPX4 signaling pathway in the livers of db/db mice. In addition, liraglutide decreased the high level of labile iron pools (LIPs) and intracellular lipid ROS induced by high glucose in vitro. Therefore, we speculated that liraglutide played a crucial role in reducing iron accumulation, oxidative damage and ferroptosis in db/db mice.

Keywords: Liver; ferroptosis; high glucose; iron overload; liraglutide; oxidative stress.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Diabetes Mellitus, Type 2* / metabolism
  • Ferroptosis*
  • Humans
  • Iron
  • Liraglutide / pharmacology
  • Liver / metabolism
  • Mice
  • Reactive Oxygen Species / metabolism

Substances

  • Reactive Oxygen Species
  • Liraglutide
  • Iron

Grants and funding

This work was supported by Natural Science Foundation of Hebei Province [NO. C2019423117], Hebei Administration of Traditional Chinese Medicine [NO. 202111]. Hebei Province ‘333 Talents Project’ funding project [NO. A202101063].