Abstract
This study investigated the antioxidative effect of S-propargyl-cysteine (SPRC) on nonalcoholic fatty liver (NAFLD) by treating mice fed a methionine and choline deficient (MCD) diet with SPRC for four weeks. We found that SPRC significantly reduced hepatic reactive oxygen species (ROS) and methane dicarboxylic aldehyde (MDA) levels. Moreover, SPRC also increased the superoxide dismutase (SOD) activity. By Western blot, we found that this protective effect of SPRC was importantly attributed to the regulated hepatic antioxidant-related proteins, including protein kinase B (Akt), heme oxygenase-1 (HO-1), nuclear factor erythroid 2-related factor 2 (Nrf2), and cystathionine γ-lyase (CSE, an enzyme that synthesizes hydrogen sulfide). Next, we examined the detailed molecular mechanism of the SPRC protective effect using oleic acid- (OA-) induced HepG2 cells. The results showed that SPRC significantly decreased intracellular ROS and MDA levels in OA-induced HepG2 cells by upregulating the phosphorylation of Akt, the expression of HO-1 and CSE, and the translocation of Nrf2. SPRC-induced HO-1 expression and Nrf2 translocation were abolished by the phosphoinositide 3-kinase (PI3K) inhibitor LY294002. Moreover, the antioxidative effect of SPRC was abolished by CSE inhibitor DL-propargylglycine (PAG) and HO-1 siRNA. Therefore, these results proved that SPRC produced an antioxidative effect on NAFLD through the PI3K/Akt/Nrf2/HO-1 signaling pathway.
Highlights
Nonalcoholic fatty liver disease (NAFLD) that is currently one of the most common chronic liver diseases is considered to be closely associated with central obesity, dyslipidemia, hypertension, hyperglycemia, and other metabolic disorders [1]
Groups treated with SPRC (40 mg/kg/d) significantly regained the weight at the 1st week, and the SPRC (20, 40 mg/kg/d) groups alleviated the weight loss at the 3rd week compared to the methionine and choline deficient (MCD) control group
The data showed that PAG reversed the effect on the weight loss only at the 1st week compared to SPRC 40 mg/kg/d group
Summary
Nonalcoholic fatty liver disease (NAFLD) that is currently one of the most common chronic liver diseases is considered to be closely associated with central obesity, dyslipidemia, hypertension, hyperglycemia, and other metabolic disorders [1]. HO-1 is the most important rate-limiting enzyme in heme catabolism and can strongly protect the liver from oxidative damage and cell death [5, 6]. Previous studies indicated that the expression of HO-1 in the liver was generally regulated by the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) [7]. Recent studies indicated a close link between phosphoinositol 3-kinase (PI3K/Akt) and Nrf activation [8, 9]. We hypothesize that the phosphorylation of Akt, translocation of Nrf, and subsequent modulation of HO-1 expression were considered as the Oxidative Medicine and Cellular Longevity important molecular targets for therapeutic intervention for NAFLD [10]
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