GLP-1 analogue improves hepatic lipid accumulation by inducing autophagy via AMPK/mTOR pathway

He, Qin; Sha, Sha; Sun, Lei; Zhang, Jing; Dong, Ming

doi:10.1016/j.bbrc.2016.05.086

Cited by 116 publications

(83 citation statements)

References 27 publications

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“…It has been reported that cell autophagy could be regulated by AMPK-mTOR signaling pathway (24). Results of the present study showed that miR-138 could regulate Sirt1 to inhibit AMPK signaling pathway and promote mTOR phosphorylation.…”

Section: Resultsmentioning

confidence: 99%

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miR-138 suppresses the proliferation, metastasis and autophagy of non-small cell lung cancer by targeting Sirt1

Fang

Pan

et al. 2017

Oncology Reports

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The present study determined the role and mechanism of miR-138 in non-small cell lung cancer (NSCLC). In total, 45 freshly resected clinical NSCLC tissues were collected. The expression of miR-138 in tissues and cell lines were determined by real-time quantitative PCR. miR-138 mimics were transfected into A549 and Calu-3 cells in vitro, and then the effects of miR-138 on lung cancer cell proliferation, cell cycle, invasion and metastasis were investigated by CCK-8 assay, Transwell and flow cytometry, respectively. The protein expression of the potential target gene Sirt1 in lung cancer cells were determined by western blot analysis. Dual-Luciferase reporter assay was performed to further confirm whether Sirt1 was the target gene of miR-138. The expression of miR-138 was significantly lower in lung cancer tissues and was negatively correlated to the differentiation degree and lymph node metastasis of lung cancer. In vitro experiment results showed that miR-138 inhibited lung cancer cell proliferation, invasion and migration. It was verified that miR-138 could downregulate Sirt1 protein expression, inhibit epithelial-mesenchymal transition (EMT), decrease the activity of AMPK signaling pathway and elevate mTOR phosphorylation level. Dual-Luciferase reporter assay demonstrated that miR-138 could directly regulate Sirt1. Downregulation of Sirt1 alone can also cause the same molecular and biological function changes. Western blot analysis and confocal microscopy results indicated that overexpression of miR-138 or interference of Sirt1 expression could inhibit lung cancer cell autophagy activity possibly through AMPK-mTOR signaling pathway. miR-138 plays a tumor suppressor function in lung cancer. It may inhibit the proliferation, invasion and migration of lung cancer through downregulation of Sirt1 expression and activation of cell autophagy. The downregulation of miR-138 is closely related to the development of lung cancer.

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Section: Resultsmentioning

confidence: 99%

“…Convincing evidence showed that AMPK-mTOR pathway is important in regulating autophagy (25,47). Activation of AMPK is capable of inhibiting the phosphorylation of mTOR, and thus promotes cell autophagy (24,48). Autophagy is closely related to tumor metastasis, EMT, apoptosis and drug resistance (49–51).…”

Section: Discussionmentioning

confidence: 99%

miR-138 suppresses the proliferation, metastasis and autophagy of non-small cell lung cancer by targeting Sirt1

Fang

Pan

et al. 2017

Oncology Reports

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“…It has been shown that excessive lipid accumulation within hepatocytes is the main cause to hepatocyte injury characterized by increased ALT and AST concentrations (Magee et al, 2016). Previous studies showed that HFD induced hepatic lipid accumulation was associated with increased liver inflammation, elevated hepatic endoplasmic reticulum stress and activation relevant signaling pathways (Liu et al, 2014), in which the obese-related liver injury could be ameliorated by GLP-1 treatment or therapies using GLP-1 mimetic (Armstrong et al, 2016a,b; Bouchi et al, 2016; He et al, 2016; Valdecantos et al, 2016). …”

Section: Discussionmentioning

confidence: 99%

Novel GLP-1 Analog Supaglutide Reduces HFD-Induced Obesity Associated with Increased Ucp-1 in White Adipose Tissue in Mice

et al. 2017

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GLP-1, an important incretin hormone plays an important role in the regulation of glucose homeostasis. However, the therapeutic use of native GLP-1 is limited due to its short half-life. We recently developed a novel GLP-1 mimetics (supaglutide) by genetically engineering recombinant fusion protein production techniques. We demonstrated that this formulation possessed long-lasting GLP-1 actions and was effective in glycemic control in both type 1 and type 2 diabetes rodent models. Here, we investigated the effects of supaglutide in regulating energy homeostasis in obese mice. Mice were fed with high-fat diet (HFD) for 6 months to induce obesity and then subjected to supaglutide treatment (300 μg/kg, bi-weekly for 4 weeks), and placebo as control. Metabolic conditions were monitored and energy expenditure was assessed by indirect calorimetry (CLAMS). Cold tolerance test was performed to evaluate brown-adipose tissue (BAT) activities in response to cold challenge. Glucose tolerance and insulin resistance were evaluated by intraperitoneal glucose tolerance test and insulin tolerance tests. Liver and adipose tissues were collected for histology analysis. Expression of uncoupling protein 1(Ucp1) in adipose tissues was evaluated by Western blotting. We found that supaglutide treatment reduced body weight, which was associated with reduced food intake. Compared to the placebo control, supaglutide treatment improved lipid profile, i.e., significantly decreased circulating total cholesterol levels, declined serum triglyceride, and free fatty acid levels. Importantly, the intervention significantly reduced fatty liver, decreased liver triglyceride content, and concomitantly ameliorated liver injury exemplified by declined hepatic alanine aminotransferase (ALT) and aspartic transaminase (AST) content. Remarkably, supaglutide reduced hepatic lipid accumulation and altered morphometry in favor of small adipocytes in fat. This is consistent with the observation that supaglutide increased tolerance of the mice to cold environment associated with up-regulation of Ucp1 in the inguinal fat. Furthermore, supaglutide improved glucose tolerance, and insulin sensitivity in the obese mice suggesting improved glucose and energy homeostasis. Our findings suggest that supaglutide exerts beneficial effect on established obesity through reducing energy intake and is associated with brown remodeling of white adipose tissue.

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“…Recently, autophagic machinery is involved in the pathophysiology of type 2 diabetes mellitus (T2DM) disease, and it regulates normal function of pancreatic beta cells. On the other hand, enhanced autophagy acts as an important protective mechanism against to oxidative stress on insulin-target tissues such as liver, adipose tissue and skeletal muscle [14–19]. In this review, we outline the relationship among autophagy, pancreatic beta cells and T2DM.…”

Section: Introductionmentioning

confidence: 99%

Autophagy and its link to type II diabetes mellitus

Yang¹,

Lu²,

Kuo³

et al. 2017

BioMedicine

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Autophagy, a double-edged sword for cell survival, is the research object on 2016 Nobel Prize in Physiology or Medicine. Autophagy is a molecular mechanism for maintaining cellular physiology and promoting survival. Defects in autophagy lead to the etiology of many diseases, including diabetes mellitus (DM), cancer, neurodegeneration, infection disease and aging. DM is a metabolic and chronic disorder and has a higher prevalence in the world as well as in Taiwan. The character of diabetes mellitus is hyperglycemia resulting from defects in insulin secretion, insulin action, or both. Type 2 diabetes mellitus (T2DM) is characterized by insulin resistance and failure of producing insulin on pancreatic beta cells. In T2DM, autophagy is not only providing nutrients to maintain cellular energy during fasting, but also removes damaged organelles, lipids and miss-folded proteins. In addition, autophagy plays an important role in pancreatic beta cell dysfunction and insulin resistance. In this review, we summarize the roles of autophagy in T2DM.

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GLP-1 analogue improves hepatic lipid accumulation by inducing autophagy via AMPK/mTOR pathway

Cited by 116 publications

References 27 publications

miR-138 suppresses the proliferation, metastasis and autophagy of non-small cell lung cancer by targeting Sirt1

miR-138 suppresses the proliferation, metastasis and autophagy of non-small cell lung cancer by targeting Sirt1

Novel GLP-1 Analog Supaglutide Reduces HFD-Induced Obesity Associated with Increased Ucp-1 in White Adipose Tissue in Mice

Autophagy and its link to type II diabetes mellitus

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