Effect of Empagliflozin on Thioacetamide-Induced Liver Injury in Rats: Role of AMPK/SIRT-1/HIF-1α Pathway in Halting Liver Fibrosis

Abstract

Hepatic fibrosis causes severe morbidity and death. No viable treatment can repair fibrosis and protect the liver until now. We intended to discover the empagliflozin’s (EMPA) hepatoprotective efficacy in thioacetamide (TAA)-induced hepatotoxicity by targeting AMPK/SIRT-1 activity and reducing HIF-1α. Rats were treated orally with EMPA (3 or 6 mg/kg) with TAA (100 mg/kg, IP) thrice weekly for 6 weeks. EMPA in both doses retracted the serum GGT, ALT, AST, ammonia, triglycerides, total cholesterol, and increased serum albumin. At the same time, EMPA (3 or 6 mg/kg) replenished the hepatic content of GSH, ATP, AMP, AMPK, or SIRT-1 and mitigated the hepatic content of MDA, TNF-α, IL-6, NF-κB, or HIF-1α in a dose-dependent manner. Likewise, hepatic photomicrograph stained with hematoxylin and eosin or Masson trichrome stain of EMPA (3 or 6 mg/kg) revealed marked regression of the hepatotoxic effect of TAA with minimal injury. Similarly, in rats given EMPA (3 or 6 mg/kg), the immunohistochemically of hepatic photomicrograph revealed minimal stain of either α-SMA or caspase-3 compared to the TAA group. Therefore, we concluded that EMPA possessed an antifibrotic effect by targeting AMPK/SIRT-1 activity and inhibiting HIF-1α. The present study provided new insight into a novel treatment of liver fibrosis.

Apigenin role against thioacetamide-triggered liver fibrosis: Deciphering the PPARγ/TGF-β1/NF-κB and the HIF/FAK/AKT pathways

“…GraphPad Prism software (version 9, USA) was employed to perform the statistical analysis and to establish the represented graphs. The significance level was set to (P ≤ 0.05) for all statistical tests (23).…”

Nrf2/HO‐1, NF‐κB and PI3K/Akt signalling pathways decipher the therapeutic mechanism of pitavastatin in early phase liver fibrosis in rats

“…It was employed in the present study as it is associated with lower mortality rates than other models. ALT and AST are cytoplasmic in origin, and elevated serum levels, as shown in the TAA group, reflect cell membrane destruction and hepatocyte death 32,37–41 . Our results indicated that, unlike all other statins, Pit undergoes minimal hepatic metabolism 42 and does not cause any elevation in aminotransferase levels.…”

“…origin, and elevated serum levels, as shown in the TAA group, reflect cell membrane destruction and hepatocyte death. 32,[37][38][39][40][41] Our results indicated that, unlike all other statins, Pit undergoes minimal hepatic metabolism 42 and does not cause any elevation in aminotransferase levels. Infect, Pit is a highly lipophilic agent that undergoes glucuronic acid conjugation, and a recent meta-analysis study demonstrated that only hydrophilic statins result in the risk of aminotransferase elevation.…”

“…GraphPad Prism software (version 9, CA, USA) was employed to perform the statistical analysis and establish the represented graphs. The significance level was set to p < 0.05 for all statistical tests 32 …”

Empagliflozin attenuates liver fibrosis in high‐fat diet/streptozotocin‐induced mice by modulating gut microbiota

“…Here, we discovered that empagliflozin attenuated the liver fibrosis induced by HFD/STZ, which is consistent with the reports in previous studies. 9,18 Combined with the promoting effect of intestinal flora on liver fibrosis 19 and the alleviating effect of empagliflozin on liver fibrosis, 20 we further explored the potential mechanism and revealed that empagliflozin altered the intestinal flora of liver fibrosis. More importantly, further data revealed that Lactobacillus, Ruminococcus and Adlercreutzia might be the vital microbiota for empagliflozin to improve liver fibrosis in HFD/STZ-induced mice.…”