Alpha-lipoic acid improves high-fat diet-induced hepatic steatosis by modulating the transcription factors SREBP-1, FoxO1 and Nrf2 via the SIRT1/LKB1/AMPK pathway

Abstract

Understanding the mechanism by which alpha-lipoic acid supplementation has a protective effect upon nonalcoholic fatty liver disease in vivo and in vitro may lead to targets for preventing hepatic steatosis. Male C57BL/6J mice were fed a normal diet, high-fat diet or high-fat diet supplemented with alpha-lipoic acid for 24 weeks. HepG2 cells were incubated with normal medium, palmitate or alpha-lipoic acid. The lipid-lowering effects were measured. The protein expression and distribution were analyzed by Western blot, immunoprecipitation and immunofluorescence, respectively. We found that alpha-lipoic acid enhanced sirtuin 1 deacetylase activity through liver kinase B1 and stimulated AMP-activated protein kinase. By activating the sirtuin 1/liver kinase B1/AMP-activated protein kinase pathway, the translocation of sterol regulatory element-binding protein-1 into the nucleus and forkhead box O1 into the cytoplasm was prevented. Alpha-lipoic acid increased adipose triacylglycerol lipase expression and decreased fatty acid synthase abundance. In in vivo and in vitro studies, alpha-lipoic acid also increased nuclear NF-E2-related factor 2 levels and downstream target amounts via the sirtuin 1 pathway. Alpha-lipoic acid eventually reduced intrahepatic and serum triglyceride content. The protective effects of alpha-lipoic acid on hepatic steatosis appear to be associated with the transcription factors sterol regulatory element-binding protein-1, forkhead box O1 and NF-E2-related factor 2.

(S)YS-51, a novel isoquinoline alkaloid, attenuates obesity-associated non-alcoholic fatty liver disease in mice by suppressing lipogenesis, inflammation and coagulation

“…Indeed, (S)YS-51 increased SIRT1 mRNA and protein expression in the livers of HFD mice. It has been shown that SIRT1 is activated by an increased NAD + /NADH ratio and then deacetylates by liver kinase B1 (LKB1) which follows phosphorylation of AMPK (Ruderman et al, 2010;Yang et al, 2014). In agreement with these reports, (S)YS-51 increased the NAD + /NADH ratio and phosphorylation of LKB1, which resulted in an increase of phosphorylation of AMPK in the livers of HFD mice in a dose of 10 mg/kg.…”

Improved Glycemic Control and Vascular Function in Overweight and Obese Subjects by Glyoxalase 1 Inducer Formulation

“…Herein we found that tRES also induces expression of Glo1 with high E max . Our recent studies (7,8) and those of others (31) suggest that this is achieved by preventing nuclear acetylation and inactivation of Nrf2 via increasing in situ activity of sirtuin-1. At low tRES concentrations, this occurs through inhibition of cAMP phosphodiesterases, activation of AMPK, and increased NAD + .…”

“…2B), which is likely due to inhibitory nuclear acetylation of Nrf2 blocking a high E max . Combination with tRES and HESP provides for faster nuclear translocation and decreased inactivation of Nrf2 (7,8,31). Use of HESP rather than related dietary glycoside hesperidin found in citrus fruits (34) is likely crucial: HESP has ;70-fold greater potency in Nrf2 activation and higher bioavailability than hesperidin (35).…”

Resveratrol protects mice from paraquat-induced lung injury: The important role of SIRT1 and NRF2 antioxidant pathways

“…Kawai et al (7) demonstrated that SIRT1-mediated deacetylation of the NRF2 protein terminated the transcription of antioxidant genes in vitro. However, other studies have demonstrated that SIRT1 overexpression significantly promoted the nuclear accumulation, DNA binding and transcriptional activity of NRF2 and NRF2-mediated gene expression (8,9,23). In the current study, an increase in the SIRT1 expression levels by Res was associated with a high level of NRF2.…”