Transcriptomic Analysis Reveals the Protective Effects of Empagliflozin on Lipid Metabolism in Nonalcoholic Fatty Liver Disease

Abstract

Empagliflozin is a novel type of sodium-glucose cotransporter two inhibitor with diverse beneficial effects in the treatment of nonalcoholic fatty liver disease (NAFLD). Although empagliflozin impacts NAFLD by regulating lipid metabolism, the underlying mechanism has not been fully elucidated. In this study, we investigated transcriptional regulation pathways affected by empagliflozin in a mouse model of NAFLD. In this study, NAFLD was established in male C57BL/6J mice by administration of a high-fat diet; it was then treated with empagliflozin and whole transcriptome analysis was conducted. Gene expression levels detected by transcriptome analysis were then verified by quantitative real-time polymerase chain reaction, protein levels detected by Western Blot. Differential expression genes screened from RNA-Seq data were enriched in lipid metabolism and synthesis. The Gene Set Enrichment Analysis (GSEA) results showed decreased lipid synthesis and improved lipid metabolism. Empagliflozin improved NAFLD through enhanced triglyceride transfer, triglyceride lipolysis and microsomal mitochondrial β-oxidation. This study provides new insights concerning the mechanisms by which sodium-glucose cotransporter two inhibitors impact NAFLD, particularly in terms of liver lipid metabolism. The lipid metabolism-related genes identified in this experiment provide robust evidence for further analyses of the mechanism by which empagliflozin impacts NAFLD.

Integrated multi-omics analyses reveal effects of empagliflozin on intestinal homeostasis in high-fat-diet mice

“…Consistent with our previous study, the HFD-induced metabolic disturbance was improved by EMPA treatment (p < 0.05). 18 , 20

Figure 1 Mouse biochemistry parameters (A–J) (A) body weight, (B) fat mass, (C) fat/body weight, (D) serum triglyceride, (E) fasting glucose, (F) fasting insulin, (G) homeostatic model assessment of insulin resistance (HOMA-IR) index, (H) free fatty acids (FFA), (I) oral glucose tolerance test (OGTT), and (J) insulin tolerance test (ITT) curve. ∗p < 0.05, ∗∗p < 0.01, for (E) and (F), ∗HFD vs. CT p < 0.05, # EMPA vs. HFD, n = 5–6.

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“…We previously demonstrated that EMPA can protect against obesity-related cardiac dysfunction, nonalcoholic fatty liver disease, and chronic kidney disease via different mechanisms. 18 , 19 , 20 This protection was associated with improving metabolic disruption, including a reduced fat/body weight ratio and restored glucose homeostasis. Our study further confirmed that EMPA can reduce the fat/body weight ratio and alleviate impaired glucose/insulin tolerance.…”

“… 16 , 17 Our previous work showed that EMPA can improve obesity-related complications, including cardiac dysfunction, nonalcoholic fatty liver disease, and chronic kidney disease. 18 , 19 , 20 …”

Empagliflozin Attenuates Obesity-Related Kidney Dysfunction and NLRP3 Inflammasome Activity Through the HO-1–Adiponectin Axis

“…The RNA sequence and data analysis were prepared as previously described by our group (19). Differentially expressed genes (DEGs) were identified using limma packages in R 4.0.3 with the default parameters at (logFC) > 1, P.Value < 0.05 for the groups.…”

Empagliflozin Ameliorates Progression From Prediabetes to Diabetes and Improves Hepatic Lipid Metabolism: A Systematic Review

“…NAFLD pathophysiology depends on multiple constituents like hepatic lipid accumulation, IR, oxidative stress, endoplasmic reticulum stress, and other injuries. EMPA is found to be efficacious in minimizing all these aspects and thus reducing the NAFLD development [ 33 - 35 ].…”