α‑lipoic acid protects against carbon tetrachloride‑induced liver cirrhosis through the suppression of the TGF‑β/Smad3 pathway and autophagy

Abstract

α-lipoic acid (ALA) is a naturally occurring antioxidant with protective effects against various hepatic injuries. The aim of the present study was to investigate the mechanisms by which ALA protects the liver from carbon tetrachloride (CCl4)-induced liver cirrhosis. The widely used liver cirrhosis rat model was established via an intraperitoneal injection of 2 mg/kg 50% CCl4, three times/week for 8 weeks. Simultaneously, 50 or 100 mg/kg ALA was orally administrated to the rats every day for 8 weeks. The activity of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) was detected in the serum. The pathological liver injuries were analyzed using hematoxylin and eosin and Masson's trichrome staining. The principal factors involved in the transforming growth factor-β (TGF-β)/mothers against decapentaplegic homolog 9 (Smad3) and protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathways and in autophagy were examined using reverse transcription-quantitative polymerase chain reaction or western blot analysis. The results demonstrated that the administration of ALA alleviated CCl4-induced liver injury, as demonstrated by decreased ALT and AST activity, improved pathological injuries and reduced collagen deposition. The CCl4-induced increase in TGF-β and phosphorylated-Smad3 expression levels was additionally inhibited by treatment with ALA. Furthermore, the administration of ALA reversed the CCl4-induced upregulation of light chain 3II and Beclin-1, and downregulation of p62. The CCl4-induced suppression of the AKT/mTOR pathway was additionally restored following treatment with ALA. In combination, the results of the present study demonstrated that ALA was able to protect CCl4-induced liver cirrhosis, an effect that may be associated with inactivation of the TGF-β/Smad3 pathway and suppression of autophagy.

Natural Sulfur-Containing Compounds: An Alternative Therapeutic Strategy against Liver Fibrosis

“…Furthermore, the treatment with ALA of rats with hepatic fibrosis resulted in a reduction in the activity of aspartate transaminase (AST) and alanine transaminase (ALT), improveed hepatic injury by decreasing the deposition of collagen fibers, and restoreed the Akt/mammalian target of rapamycin (mTOR) pathway. All this is possible thanks to its ability to inhibit the TGF-β/Smad3 pathway with consequent suppression of autophagy [65]. In addition, clinical trials consisting in ALA supplementation in patients with NAFLD have reported a modulation of some of the oxidative stress related parameters, including serum malondialdehyde levels and total antioxidant status, as well as a modification of the adipokine profile, known to play a key role in the progression of NAFLD [66,67].…”

α-Lipoik asit ve N-asetilsisteinin sıçan karaciğerinde dietilnitrozamin ve yüksek yağlı diyetin neden olduğu oksidatif stres ve preneoplastik lezyonlar üzerine etkisi

“…In our study, we aimed to investigate the effects of ALA and NAC and their combination on DEN-initiated HFDpromoted hepatic lesions. ALA is an antioxidant with protective effects against various hepatic injuries [13,14]. ALA supplementation was reported to reduce lipid accumulation, inflammation, and oxidative stress in the liver of MCD-and HFD-fed mice [13].…”

“…In our study, HFD composition [24] and the used doses of DEN [25], ALA [13,14] and NAC [19,20] were selected with respect to previous studies.…”

“…As an antioxidant ALA is competent to scavenge reactive oxygen species (ROS), regenerate various antioxidants such as glutathione (GSH), and vitamins E, C, and possess metal chelating activity [12]. Additionally, ALA treatment was noticed to be protective in oxidative stress-induced pathologies including liver damage [12][13][14]. On the other hand, ALA was found to suppress tumor growth in mice treated with Ehrlich carcinoma cells and improve prooxidant-antioxidant balance in the liver [15].…”

Hepatic morphological alterations in lopinavir/ ritonavir–intoxicated rats were abrogated by melatonin and α lipoic acidElias

“…15 It has abrogated xenobioticinduced fibrosis, necrosis, and steatosis in rats. [16][17][18] In the light of the aforementioned information, the present study examined the protective effects of MT and ALA against LPV/r-induced hepatic alterations in rats.…”