Dataset Information

Cyanidin-3-O-glucoside improves non-alcoholic fatty liver disease by promoting PINK1-mediated mitophagy in mice.

ABSTRACT:

Background and purpose

Identifying safe and effective compounds that target to mitophagy to eliminate impaired mitochondria may be an attractive therapeutic strategy for non-alcoholic fatty liver disease. Here, we investigated the effects of cyanidin-3-O-glucoside (C3G) on non-alcoholic fatty liver disease (NAFLD) and the underlying mechanism.

Experimental approach

Non-alcoholic fatty liver disease was induced by a high-fat diet for 16 weeks. C3G was administered during the last 4 weeks. In vivo, recombinant adenoviruses and AAV8 were used for overexpression and knockdown of PTEN-induced kinase 1 (PINK1), respectively. AML-12 and HepG2 cells were used for the mechanism study.

Key results

C3G administration suppressed hepatic oxidative stress, NLR family pyrin domain containing 3 (NLRP3) inflammasome activation and steatosis and improved systemic glucose metabolism in mice with NAFLD. These effects of C3G were also observed in palmitic acid-treated AML-12 cells and hepatocytes from NAFLD patients. Mechanistic investigations revealed that C3G increased PINK1/Parkin expression and mitochondrial localization and promoted PINK1-mediated mitophagy to clear damaged mitochondria. Knockdown of hepatic PINK1 abolished the mitophagy-inducing effect of C3G, which blunted the beneficial effects of C3G on oxidative stress, NLRP3 inflammasome activation, hepatic steatosis and glucose metabolism.

Conclusion and implications

These results demonstrate that PINK1-mediated mitophagy plays an essential role in the ability of C3G to alleviate NAFLD and suggest that C3G may be a potential drug candidate for NAFLD treatment.

SUBMITTER: Li X

PROVIDER: S-EPMC7348088 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Cyanidin-3-O-glucoside improves non-alcoholic fatty liver disease by promoting PINK1-mediated mitophagy in mice.

Li Xinwei X Shi Zhen Z Zhu Yiwei Y Shen Taiyu T Wang Heyuan H Shui Guanghou G Loor Juan J JJ Fang Zhiyuan Z Chen Meng M Wang Xinghui X Peng Zhicheng Z Song Yuxiang Y Wang Zhe Z Du Xiliang X Liu Guowen G

British journal of pharmacology 20200614 15

<h4>Background and purpose</h4>Identifying safe and effective compounds that target to mitophagy to eliminate impaired mitochondria may be an attractive therapeutic strategy for non-alcoholic fatty liver disease. Here, we investigated the effects of cyanidin-3-O-glucoside (C3G) on non-alcoholic fatty liver disease (NAFLD) and the underlying mechanism.<h4>Experimental approach</h4>Non-alcoholic fatty liver disease was induced by a high-fat diet for 16 weeks. C3G was administered during the last 4 ...[more]

PMID: 32343398

Similar Datasets

Project description:Most studies regarding the beneficial effect of sulforaphane (SFN) on non-alcoholic fatty liver disease (NAFLD) have focused on nuclear factor E2-related factor 2 (Nrf2). But the molecular mechanisms underlying the beneficial effect of SFN in the treatment of NAFLD remain controversial. Fibroblast growth factor (FGF) 21 is a member of the FGF family expressed mainly in liver but also in adipose tissue, muscle and pancreas, which functions as an endocrine factor and has been considered as a promising therapeutic candidate for the treatment of NAFLD. In the present study we investigated whether FGF21 was involved in the therapeutic effect of SFN against NAFLD. C57BL/6J mice were fed a high-fat diet (HFD) for 12 weeks to generate NAFLD and continued on the HFD for additional 6 weeks with or without SFN treatment. We showed that administration of SFN (0.56 g/kg) significantly ameliorated hepatic steatosis and inflammation in NAFLD mice, along with the improved glucose tolerance and insulin sensitivity, through suppressing the expression of proteins responsible for hepatic lipogenesis, while enhancing proteins for hepatic lipolysis and fatty acids oxidation. SFN administration significantly increased hepatic expression of FGFR1 and fibroblast growth factor 21 (FGF21) in NAFLD mice, along with decreased phosphorylation of p38 MAPK (the downstream of FGF21). HepG2 cells were treated in vitro with FFAs (palmitic acid and oleic acid) followed by different concentrations of SFN. We showed that the effects of SFN on FGF21 and FGFR1 protein expression were replicated in FFAs-treated HepG2 cells. Moreover, the increased FGFR1 protein occurred earlier than increased FGF21 protein. Interestingly, the rapid effect of SFN on FGFR1 protein was not regulated by the FGFR1 gene transcription. Knockdown of FGFR1 and p38 genes weakened SFN-reduced lipid deposition in FFAs-treated HepG2 cells. SFN administration in combination with rmFGF21 (1.5 mg/kg, i.p., every other day) for 3 weeks further suppressed hepatic steatosis in NAFLD mice. In conclusion, SFN ameliorates lipid metabolism disorders in NAFLD mice by upregulating FGF21/FGFR1 pathway. Our results verify that SFN may become a promising intervention to treat or relieve NAFLD.

Project description:Introduction: Non-alcoholic fatty liver disease (NAFLD) is one of the metabolic disorders related to the pathophysiology of type 2 diabetes mellitus (T2DM). Therapeutic strategies are focused on the improvement of energy balance and lifestyle modification. Additionally, the derivative of the bioactive fungal metabolite is of interest to provide health benefits, especially in obese and pre-diabetic conditions. In our screening of anti-diabetic compounds from fungal metabolites and semisynthetic derivatives, a depsidone derivative, namely pyridylnidulin (PN), showed potent glucose uptake-inducing activity. The present study aimed to investigate the liver lipid metabolism and anti-diabetic properties of PN in diet-induced obesity mice. Methods: Male C57BL/6 mice were induced obesity and pre-diabetic conditions by dietary intervention with a high-fat diet (HFD) for 6 weeks. These obese mice were orally administered with PN (40 or 120 mg/kg), metformin (150 mg/kg), or vehicle for 4 weeks. Glucose tolerance, plasma adipocytokines, hepatic gene and protein expressions were assessed after treatment. Results: Improved glucose tolerance and reduced fasting blood glucose levels were found in the PN and metformin-treated mice. Additionally, hepatic triglyceride levels were consistent with the histopathological steatosis score regarding hepatocellular hypertrophy in the PN and metformin groups. The levels of plasma adipocytokines such as tumor necrosis factor-α (TNF-α) and monocyte chemoattractant protein-1 (MCP-1) were reduced in the PN (120 mg/kg) and metformin-treated mice. In addition, hepatic gene expression involved in lipid metabolism, including lipogenic enzymes was significantly reduced in the PN (120 mg/kg) and metformin-treated mice. The increased protein expression levels of phosphorylated AMP-activated protein kinase (p-AMPK) was also found in PN and metformin-treated mice. Discussion: Considering the increased p-AMPK protein expression levels in PN and metformin-treated mice were revealed as the underlying mechanisms to improve metabolic parameters. These results suggested that PN provided the health benefit to slow the progression of NAFLD and T2DM in obese and pre-diabetic conditions.

Dataset Information

Cyanidin-3-O-glucoside improves non-alcoholic fatty liver disease by promoting PINK1-mediated mitophagy in mice.

Background and purpose

Experimental approach

Key results

Conclusion and implications

Publications

Cyanidin-3-O-glucoside improves non-alcoholic fatty liver disease by promoting PINK1-mediated mitophagy in mice.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets