Exenatide Activates the APPL1-AMPK-PPAR<i>α</i>Axis to Prevent Diabetic Cardiomyocyte Apoptosis

Lei, Xiaotian; Wu, Qinan; XiaGuang, Gan; Deng, Wuquan; Chen, Bing; Liang, Ziwen

doi:10.1155/2016/4219735

Cited by 19 publications

(19 citation statements)

References 36 publications

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“…Increased ROS production and reduced antioxidant levels in diabetes have been widely documented in previous reports (Fiordaliso et al., 2004; Houstis et al., 2006). Earlier studies showed that CMs incubated with GLP‐1 or its analogs remained viable and lowered ROS levels and apoptosis rates in both diabetic and nondiabetic models (Inoue et al., 2015; Raab, Vuguin, Stoffers & Simmons, 2009; XiaoTian et al., 2016). Nevertheless, these reports failed to address the possible mechanisms responsible for these effects.…”

Section: Discussionmentioning

confidence: 99%

Glucagon‐like peptide‐1 ameliorates cardiac lipotoxicity in diabetic cardiomyopathy via the PPARα pathway

Wang

et al. 2018

Aging Cell

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SummaryLipotoxicity cardiomyopathy is the result of excessive accumulation and oxidation of toxic lipids in the heart. It is a major threat to patients with diabetes. Glucagon‐like peptide‐1 (GLP‐1) has aroused considerable interest as a novel therapeutic target for diabetes mellitus because it stimulates insulin secretion. Here, we investigated the effects and mechanisms of the GLP‐1 analog exendin‐4 and the dipeptidyl peptidase‐4 inhibitor saxagliptin on cardiac lipid metabolism in diabetic mice (DM). The increased myocardial lipid accumulation, oxidative stress, apoptosis, and cardiac remodeling and dysfunction induced in DM by low streptozotocin doses and high‐fat diets were significantly reversed by exendin‐4 and saxagliptin treatments for 8 weeks. We found that exendin‐4 inhibited abnormal activation of the (PPARα)‐CD36 pathway by stimulating protein kinase A (PKA) but suppressing the Rho‐associated protein kinase (ROCK) pathway in DM hearts, palmitic acid (PA)‐treated rat h9c2 cardiomyocytes (CMs), and isolated adult mouse CMs. Cardioprotection in DM mediated by exendin‐4 was abolished by combination therapy with the PPARα agonist wy‐14643 but mimicked by PPARα gene deficiency. Therefore, the PPARα pathway accounted for the effects of exendin‐4. This conclusion was confirmed in cardiac‐restricted overexpression of PPARα mediated by adeno‐associated virus serotype‐9 containing a cardiac troponin T promoter. Our results provide the first direct evidence that GLP‐1 protects cardiac function by inhibiting the ROCK/PPARα pathway, thereby ameliorating lipotoxicity in diabetic cardiomyopathy.

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Section: Discussionmentioning

confidence: 99%

Glucagon‐like peptide‐1 ameliorates cardiac lipotoxicity in diabetic cardiomyopathy via the PPARα pathway

Wang

et al. 2018

Aging Cell

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“…Through the recruitment of adaptor protein APPL1 by AdipoRs activation, adiponectin signaling regulates a series of signaling pathways [ 47 ]. AMP-activated protein kinase (AMPK), peroxisome proliferator-activated receptor-α (PPARα), IkB kinase (IKK)/NF-κB/PTEN, IRS1/2–Akt, and Ras-ERK1/2 signaling are examples of downstream adiponectin signaling [ 48 , 49 , 50 , 51 , 52 ]. Adiponectin receptors are found to be expressed throughout the whole brain.…”

Section: Adiponectin As a Modulator Of Metabolic Disordermentioning

confidence: 99%

Adiponectin: The Potential Regulator and Therapeutic Target of Obesity and Alzheimer’s Disease

Kim

Barua

Jeong

et al. 2020

IJMS

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Animal and human mechanistic studies have consistently shown an association between obesity and Alzheimer’s disease (AD). AD, a degenerative brain disease, is the most common cause of dementia and is characterized by the presence of extracellular amyloid beta (Aβ) plaques and intracellular neurofibrillary tangles disposition. Some studies have recently demonstrated that Aβ and tau cannot fully explain the pathophysiological development of AD and that metabolic disease factors, such as insulin, adiponectin, and antioxidants, are important for the sporadic onset of nongenetic AD. Obesity prevention and treatment can be an efficacious and safe approach to AD prevention. Adiponectin is a benign adipokine that sensitizes the insulin receptor signaling pathway and suppresses inflammation. It has been shown to be inversely correlated with adipose tissue dysfunction and may enhance the risk of AD because a range of neuroprotection adiponectin mechanisms is related to AD pathology alleviation. In this study, we summarize the recent progress that addresses the beneficial effects and potential mechanisms of adiponectin in AD. Furthermore, we review recent studies on the diverse medications of adiponectin that could possibly be related to AD treatment, with a focus on their association with adiponectin. A better understanding of the neuroprotection roles of adiponectin will help clarify the precise underlying mechanism of AD development and progression.

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“…The experiment was performed as described previously [ 15 , 17 ]. Deparaffinized sections were incubated with a Par-4 (dilution 1 : 200; Santa Cruz Biotechnology, USA) or TERT (dilution 1 : 200; Santa Cruz Biotechnology, USA) primary antibody overnight at 4°C.…”

Section: Methodsmentioning

confidence: 99%

“…TUNEL staining to detect the apoptosis rate and corresponding calculations were performed as previously described [ 15 , 17 ].…”

Section: Methodsmentioning

confidence: 99%

TERT and Akt Are Involved in the Par-4-Dependent Apoptosis of Islet β Cells in Type 2 Diabetes

Liu

Lei

et al. 2018

Journal of Diabetes Research

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Islet β cell apoptosis plays an important role in type 2 diabetes. We previously reported that Par-4-mediated islet β cell apoptosis is induced by high-glucose/fatty acid levels. In the present study, we show that Par-4, which is induced by high-glucose/fatty acid levels, interacts with and inhibits TERT in the cytoplasm and then translocates to the nucleus. Par-4 also inhibited Akt phosphorylation, leading to islet β cell apoptosis. We inhibited Par-4 in islet β cells under high-glucose/fatty acid conditions and knocked out Par-4 in diabetic mice, which led to the up-regulation of TERT and an improvement in the apoptosis rate. We inhibited Akt phosphorylation in islet β cells and diabetic mice, which led to aggressive apoptosis. In addition, the biological film interference technique revealed that Par-4 bound to TERT via its NLS and leucine zipper domains. Our research suggests that Par-4 activation and binding to TERT are key steps required for inducing the apoptosis of islet β cells under high-glucose/fatty acid conditions. Inhibiting Akt phosphorylation aggravated apoptosis by activating Par-4 and inhibiting TERT, and Par-4 inhibition may be an attractive target for the treatment of islet β cell apoptosis.

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Exenatide Activates the APPL1-AMPK-PPARαAxis to Prevent Diabetic Cardiomyocyte Apoptosis

Cited by 19 publications

References 36 publications

Glucagon‐like peptide‐1 ameliorates cardiac lipotoxicity in diabetic cardiomyopathy via the PPARα pathway

Glucagon‐like peptide‐1 ameliorates cardiac lipotoxicity in diabetic cardiomyopathy via the PPARα pathway

Adiponectin: The Potential Regulator and Therapeutic Target of Obesity and Alzheimer’s Disease

TERT and Akt Are Involved in the Par-4-Dependent Apoptosis of Islet β Cells in Type 2 Diabetes

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