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Isosteviol Protects Free Fatty Acid- and High Fat Diet-Induced Hepatic Injury via Modulating PKC-?/p66Shc/ROS and Endoplasmic Reticulum Stress Pathways.

ABSTRACT: Aims: Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver diseases. However, there are no approved pharmacotherapies for the treatment of NAFLD other than managing life style and controlling diets. Extensive studies have demonstrated that multiple mechanisms are involved in free fatty acid (FFA)- and high fat diet (HFD)-induced hepatic injury, including mitochondrial dysfunction, activation of oxidative stress and endoplasmic reticulum (ER) stress, and lysosome dysfunction. A previous study reported that Isosteviol (ISV), a derivative of stevioside, prevents HFD-induced hepatic injury. However, the underlying mechanisms remain unclear. Results: In this study, we examined the potential cellular/molecular mechanisms underlying ISV-mediated protective effect against FFA-/HFD-induced hepatic lipotoxicity by using both in vitro primary rat hepatocytes and the in vivo rat NAFLD model. The results indicated that ISV inhibits FFA-/HFD-induced hepatic injury via reducing oxidative and ER stress. Specifically, ISV inhibited the expression, activation, and mitochondrial translocation of Src-homology-2-domain-containing transforming protein 1 (p66Shc), an adapter protein that mediates oxidative stress-induced injury and is a substrate of protein kinase C-? (PKC-?), via inhibition of PKC-? activity. However, ISV had no effect on the expression and activity of peptidyl-prolyl cis-trans isomerase and serine/threonine protein phosphatase 2A, isomerase and phosphorylase of p66Shc. In addition, ISV also inhibited FFA-induced ER stress and decreased ER-mitochondrial interaction. Innovation and Conclusion: We first identified that ISV prevents FFA-/HFD-induced hepatic injury through modulating PKC-?/p66Shc/oxidative and ER stress pathways. ISV represents a promising therapeutic agent for NAFLD in the future. Antioxid. Redox Signal. 30, 1949-1968.

SUBMITTER: Yi H

PROVIDER: S-EPMC6486675 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Isosteviol Protects Free Fatty Acid- and High Fat Diet-Induced Hepatic Injury via Modulating PKC-β/p66Shc/ROS and Endoplasmic Reticulum Stress Pathways.

Yi Hongwei H Xu Deyi D Wu Xudong X Xu Fang F Lin Lin L Zhou Huiping H

Antioxidants & redox signaling 20190128 17

Aims: Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver diseases. However, there are no approved pharmacotherapies for the treatment of NAFLD other than managing life style and controlling diets. Extensive studies have demonstrated that multiple mechanisms are involved in free fatty acid (FFA)- and high fat diet (HFD)-induced hepatic injury, including mitochondrial dysfunction, activation of oxidative stress and endoplasmic reticulum (ER) stress, an ...[more]

PMID: 30484323

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Project description:The aim of the present study was to explore the effect of exogenous hydrogen sulphide (H2S) on endoplasmic reticulum (ER) stress (ERS) in a rat model of hepatic ischemia/reperfusion (I/R) injury. A total of 48 Sprague-Dawley rats were randomly divided into four groups (n=12/group) as follows: Sham, I/R, I/R preceded by NaHS (I/R-NaHS) and I/R preceded by L-C-propargylglycine (PAG), a H2S inhibitor (I/R-PAG). With the exception of the sham group, the rats in the other groups were subjected to 30 min hepatic warm ischemia followed by reperfusion for 6 or 12 h. Hepatic function was evaluated by serum concentrations of alanine aminotransferase (ALT). Apoptosis of hepatic cells was assessed by TUNEL staining and measurement of caspase-12 expression. The expression levels of ERS-associated proteins and mRNAs of pancreatic ER eukaryotic translation initiation factor-2a kinase (PERK), activating transcription factor-6 (ATF6), glucose-regulated protein (GRP) 78, TNF-receptor-associated factor (TRAF)-2, C/EBP homologous protein (CHOP) and caspase-12 were also measured by western blotting and reverse transcription-quantitative PCR. The serum concentrations of ALT in the I/R and I/R-PAG groups were found to be significantly higher compared with those in the sham and I/R-NaHS groups after 6 h of reperfusion; in addition, the ALT level returned to normal in the I/R group, while it increased further in the I/R-PAG group after 12 h of reperfusion. A higher cell apoptosis rate was observed in the I/R and I/R-PAG groups and the highest cell apoptosis rate was observed in the I/R-PAG group; correspondingly, the expression of caspase-12 was increased in the I/R and I/R-PAG groups. H2S appeared to significantly attenuate hepatic I/R-induced ERS response, as indicated by the decreased expression of ATF6, PERK, GRP78, TRAF2 and CHOP. Endogenous H2S may serve a hepatoprotective function after I/R, and inhibition of endogenous H2S results in aggravation of I/R damage. Exogenous H2S was shown to inhibit ERS-related gene expression, leading to suppression of inflammatory reaction and improvement of I/R damage. Therefore, exogenous H2S has therapeutic potential to alleviate hepatic I/R injury.

Dataset Information

Isosteviol Protects Free Fatty Acid- and High Fat Diet-Induced Hepatic Injury via Modulating PKC-?/p66Shc/ROS and Endoplasmic Reticulum Stress Pathways.

Publications

Isosteviol Protects Free Fatty Acid- and High Fat Diet-Induced Hepatic Injury <i>via</i> Modulating PKC-β/p66Shc/ROS and Endoplasmic Reticulum Stress Pathways.

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