Metabolic and Hepatic Effects of Empagliflozin on Nonalcoholic Fatty Liver Mice

Shu Niu; Qingjuan Ren; Shuchun Chen; Xiaoyu Pan; Lin Yue; Xing Chen; Zelin Li; Ruoxi Zhen

doi:10.2147/DMSO.S422327

Metabolic and Hepatic Effects of Empagliflozin on Nonalcoholic Fatty Liver Mice

Diabetes Metab Syndr Obes. 2023 Aug 24:16:2549-2560. doi: 10.2147/DMSO.S422327. eCollection 2023.

Authors

Shu Niu^#¹, Qingjuan Ren^#¹, Shuchun Chen², Xiaoyu Pan^{2

3}, Lin Yue⁴, Xing Chen², Zelin Li², Ruoxi Zhen³

Affiliations

¹ Department of Endocrinology, Shijiazhuang People's Hospital, Shijiazhuang, Hebei, People's Republic of China.
² Department of Endocrinology, Hebei General Hospital, Shijiazhuang, Hebei, People's Republic of China.
³ Department of Internal Medicine, Hebei Medical University, Shijiazhuang, Hebei, People's Republic of China.
⁴ Department of Endocrinology, The Third Hospital of Shijiazhuang, Shijiazhuang, Hebei, People's Republic of China.

^# Contributed equally.

Abstract

Purpose: Among chronic liver diseases, non-alcoholic fatty liver disease (NAFLD) is one of the commonest. Although empagliflozin has several therapeutic uses in treating cardiovascular and renal disorders, its impacts and mechanisms on NAFLD are poorly understood. This research aimed to examine the metabolic regulatory mechanism through which empagliflozin protects against NAFLD.

Methods: Equal grouping of twenty-seven male C57BL/6J mice into those fed a normal diet (NCD), those fed a high-fat diet (HFD), and those fed an HFD with empagliflozin (Empa) was approached. HE, oil red O staining, and Masson staining were utilized for evaluating the pathological damage to the liver and the mice's liver and body weights. Lipids, blood glucose, and inflammation index were compared across the three groups. Liquid chromatography/mass spectrometry (LC-MS) has been employed for identifying liver metabolomics.

Results: The findings suggested that empagliflozin mitigated the inflammatory and oxidative stress response associated with the buildup of lipids caused by HFD. Differentially expressed metabolites (DEMs) were identified by metabonomics analysis as present in both the HFD/NCD and Empa/HFD groups. These DEMs were primarily found in lipids and organic acids like lysophosphatidylcholine (lysoPC), lecithin (PC), triglyceride (TG), palmitic acid, and L-isoleucine. Among the enriched pathways that were shown to be important were those involved in the metabolism of histidine, arachidonic acid, the control of lipolysis in adipocytes, and insulin resistance. There was a strong correlation between inflammation and oxidative stress in most of the metabolites. The inflammation and oxidative stress unbalance were ameliorated by empagliflozin.

Conclusion: NAFLD mice model showed considerable improvement in metabolic abnormalities and liver protection after treatment with empagliflozin. The process may include the overexpression of L-isoleucine and the downregulation of lysoPC, PC, TG, and palmitic acid to reduce liver harm caused by lipotoxicity.

Keywords: NAFLD; differentially expressed metabolites; empagliflozin; metabolomics; obesity.

Grants and funding

This study was supported by the Hebei Provincial Medical Science Research Project (20230218). This funding source did not influence the study outcomes, and the authors were free to interpret the data in accordance with a strict scientific rationale.