Sennoside A protects mitochondrial structure and function to improve high-fat diet-induced hepatic steatosis by targeting VDAC1

Le, Jiamei; Jia, Weiping; Sun, Yongning

doi:10.1016/j.bbrc.2018.04.108

Cited by 21 publications

(19 citation statements)

References 28 publications

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“…Recently, it has been recognized that impaired hepatic mitochondrial function plays a key role in the progression of hepatocyte death [45]. Chronic lipid accumulation shifts the mitochondrial metabolism to beta-oxidation, and contributes to the overproduction of ROS and mitochondrial metabolism dysfunction [46]. In our study, we found that HFD treatment indeed induced the mitochondrial dysfunction, as revealed by oxidative stress, cyt-c release, ATP metabolism disorder, and caspase-9-involved mitochondrial apoptosis pathway activation.…”

Section: Discussionsupporting

confidence: 62%

Mst1 inhibition attenuates non-alcoholic fatty liver disease via reversing Parkin-related mitophagy

et al. 2019

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Obesity-related non-alcoholic fatty liver disease (NAFLD) is connected with mitochondrial stress and hepatocyte apoptosis. Parkin-related mitophagy sustains mitochondrial homeostasis and hepatocyte viability. However, the contribution and regulatory mechanisms of Parkin-related mitophagy in NAFLD are incompletely understood. Macrophage stimulating 1 (Mst1) is a novel mitophagy upstream regulator which excerbates heart and cancer apoptosisn via repressing mitophagy activity. The aim of our study is to explore whether Mst1 contributes to NAFLD via disrupting Parkin-related mitophagy. A NAFLD model was generated in wild-type (WT) mice and Mst1 knockout (Mst1-KO) mice using high-fat diet (HFD). Cell experiments were conducted via palmitic acid (PA) treatment in the primary hepatocytes. The results in our study demonstrated that Mst1 was significantly upregulated in HFD-treated livers. Genetic ablation of Mst1 attenuated HFD-mediated hepatic injury and sustained hepatocyte viability. Functional studies illustrated that Mst1 knockdown reversed Parkin-related mitophagy and the latter protected mitochondria and hepatocytes against HFD challenge. Besides, we further figured out that Mst1 modulated Parkin expression via the AMPK pathway; blockade of AMPK repressed Parkin-related mitophagy and recalled hepatocytes mitochondrial apoptosis. Altogether, our data identified that NAFLD was closely associated with the defective Parkin-related mitophagy due to Mst1 upregulation. This finding may pave the road to new therapeutic modalities for the treatment of fatty liver disease.

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Section: Discussionsupporting

confidence: 62%

Mst1 inhibition attenuates non-alcoholic fatty liver disease via reversing Parkin-related mitophagy

et al. 2019

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“…12 Also, SA improved hepatic steatosis with a beneficial effect on mitochondrial structure and function. 13 These studies demonstrate that SA may control obesity by means of the restoration of GLP-1 level in the obese mice. However, the mechanism of SA activity remains to be characterized in the regulation of GLP-1.…”

Section: Introductionmentioning

confidence: 79%

<p>Sennoside A Induces GLP-1 Secretion Through Activation of the ERK1/2 Pathway in L-Cells</p>

Ma¹,

Cao²,

Ye³

et al. 2020

DMSO

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Purpose: Glucagon-like peptide-1 (GLP-1) is secreted from the intestinal L-cells to stimulate insulin secretion in the blood glucose control. Our previous study indicates that Sennoside A (SA) can increase the plasma GLP-1 level in a mouse model of type 2 diabetes. However, the mechanism of SA activity remains largely unknown. This issue was explored in this study. Materials and Methods: C57BL/6 mice were randomly divided into four groups: a control group without drug treatment, and the other groups with different SA dosages, respectively. Blood glucose was assayed by oral glucose tolerance test (OGTT). Plasma GLP-1 and insulin were investigated. Colon tissues were collected for mRNA or Western blot analysis. Immunofluorescence staining assays were performed to evaluate the number of β-cells and L-cells. In NCI-H716 cells, extracellular signal-regulated kinase 1/2 (ERK1/2) inhibitors were employed to investigate the SA-induced GLP-1 secretion mechanism. Results: In this work, the SA was found to improve OGTT in mice. Plasma GLP-1 and insulin were markedly elevated by SA at the dosage of 45 mg/kg/day. Meanwhile, the increased phosphorylation status of EKR1/2 and prohormone convertase 1/3 (PC1/3) proteins were observed in the colon of SA-treated mice. The number of L-cells exhibited no change in each group. In the NCI-H716 cells, GLP-1 secretion induced by SA was blocked by the ERK1/2 inhibitor. Conclusion: The present study provides a direct evidence for the interaction between SA and L cells for induction of GLP-1 secretion. These data suggest that GLP-1 secretion induced by SA is dependent on the ERK1/2 signaling pathway. Therefore, the SA is a new drug candidate for the type 2 diabetes treatment by induction of GLP-1 secretion.

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“…This implied that the SE had more toxicity to the liver than the SS. Coincidentally, sennoside A, which are the main components of sennosides, was reported to protect mitochondrial function and structure to improve hepatic steatosis by inhibiting the mitochondrial respiratory chain complex I and the voltage-dependent anion channel 1 (VDAC1) [ 47 ]. We presume that the Aqp9 up-regulated by the SS and SA might function to protect the liver against the influence/cytotoxicity induced by the SE.…”

Section: Discussionmentioning

confidence: 99%

Aquaporins Alteration Profiles Revealed Different Actions of Senna, Sennosides, and Sennoside A in Diarrhea-Rats

Cao

et al. 2018

IJMS

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Senna and its main components sennosides are well-known effective laxative drugs and are used in the treatment of intestinal constipation in the world. Their potential side effects have attracted more attention in clinics but have little scientific justification. In this study, senna extract (SE), sennosides (SS), and sennoside A (SA) were prepared and used to generate diarrhea rats. The diarrhea rats were investigated with behaviors, clinical signs, organ index, pathological examination, and gene expression on multiple aquaporins (Aqps) including Aqp1, Aqp2, Aqp3, Aqp4, Aqp5, Aqp6, Aqp7, Aqp8, Aqp9, and Aqp11. Using qRT-PCR, the Aqp expression profiles were constructed for six organs including colon, kidney, liver, spleen, lung, and stomach. The Aqp alteration profiles were characterized and was performed with Principle Component Analysis (PCA). The SE treatments on the rats resulted in a significant body weight loss (p < 0.001), significant increases (p < 0.001) on the kidney index (27.72%) and liver index (42.55%), and distinguished changes with up-regulation on Aqps expressions in the kidneys and livers. The SS treatments showed prominent laxative actions and down regulation on Aqps expression in the colons. The study results indicated that the SE had more influence/toxicity on the kidneys and livers. The SS showed more powerful actions on the colons. We suggest that the caution should be particularly exercised in the patients with kidney and liver diseases when chronic using senna-based products.

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Sennoside A protects mitochondrial structure and function to improve high-fat diet-induced hepatic steatosis by targeting VDAC1

Cited by 21 publications

References 28 publications

Mst1 inhibition attenuates non-alcoholic fatty liver disease via reversing Parkin-related mitophagy

Mst1 inhibition attenuates non-alcoholic fatty liver disease via reversing Parkin-related mitophagy

<p>Sennoside A Induces GLP-1 Secretion Through Activation of the ERK1/2 Pathway in L-Cells</p>

Aquaporins Alteration Profiles Revealed Different Actions of Senna, Sennosides, and Sennoside A in Diarrhea-Rats

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