scholarly journals The Upstream Pathway of mTOR-Mediated Autophagy in Liver Diseases

Cells ◽  
2019 ◽  
Vol 8 (12) ◽  
pp. 1597 ◽  
Author(s):  
Haojie Wang ◽  
Yumei Liu ◽  
Dongmei Wang ◽  
Yaolu Xu ◽  
Ruiqi Dong ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Signaling Pathway ◽  
Liver Diseases ◽  
Ischemia Reperfusion ◽  
Adenosine Monophosphate ◽  
Hepatic Ischemia ◽  
Alcoholic Fatty Liver ◽  
Ampk Signaling ◽  
Stress States ◽  
Phosphoinositide 3 Kinase

Autophagy, originally found in liver experiments, is a cellular process that degrades damaged organelle or protein aggregation. This process frees cells from various stress states is a cell survival mechanism under stress stimulation. It is now known that dysregulation of autophagy can cause many liver diseases. Therefore, how to properly regulate autophagy is the key to the treatment of liver injury. mechanistic target of rapamycin (mTOR)is the core hub regulating autophagy, which is subject to different upstream signaling pathways to regulate autophagy. This review summarizes three upstream pathways of mTOR: the phosphoinositide 3-kinase (PI3K)/protein kinase (AKT) signaling pathway, the adenosine monophosphate-activated protein kinase (AMPK) signaling pathway, and the rat sarcoma (Ras)/rapidly accelerated fibrosarcoma (Raf)/mitogen-extracellular activated protein kinase kinase (MEK)/ extracellular-signal-regulated kinase (ERK) signaling pathway, specifically explored their role in liver fibrosis, hepatitis B, non-alcoholic fatty liver, liver cancer, hepatic ischemia reperfusion and other liver diseases through the regulation of mTOR-mediated autophagy. Moreover, we also analyzed the crosstalk between these three pathways, aiming to find new targets for the treatment of human liver disease based on autophagy.

scholarly journals L-theanine Prevents Progression of Nonalcoholichepatic Steatosis by Regulating Hepatocyte Lipid Metabolic Pathways via the CaMKKβ-AMPK Signaling Pathway

2021 ◽  
Author(s):  
Juanjuan Liang ◽  
Lili Gu ◽  
Xianli Liu ◽  
Xintong Yan ◽  
Xiaowen Bi ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Protein Kinase ◽  
Signaling Pathway ◽  
Hepatic Steatosis ◽  
Metabolic Pathways ◽  
Alcoholic Fatty Liver ◽  
Ampk Signaling ◽  
Nonalcoholic Hepatic Steatosis

Abstract Background: L-theanine, a non-protein amino acid found principally in the green tea, has been previously shown to possess potent anti-obesity property and hepatoprotective effect. Herein, we investigated the effects of L-theanine on alleviating nonalcoholic hepatic steatosis in vitro and in vivo, and explored the underlying molecular mechanism. Methods: In vitro, HepG2 and AML12 cells were treated with 500 μM oleic acid (OA) or treated with OA accompanied by L-theanine. In vivo, C57BL/6J mice were fed with normal control diet (NCD), high‐fat diet (HFD), or HFD along with L-theanine for 16 weeks. The levels of TG, accumulation of lipid droplets and the expression of genes related to hepatocyte lipid metabolic pathways were detected in vitro and in vivo.Results: Our data indicated that, in vivo, L-theanine significantly reduced body weight, hepatic steatosis, serum levels of alanine transaminase (ALT), aspartate transaminase (AST), TG and LDL cholesterol (LDL-C) in HFD-induced Non-alcoholic fatty liver disease (NAFLD) mice. In vitro, L-theanine also significantly alleviated OA induced hepatocytes steatosis. Mechanic studies showed that L-theanine significantly inhibited the nucleus translocation of sterol regulatory element binding protein 1c (SREBP-1c) through AMPK-mTOR signaling pathway, thereby contributing to the reduction of fatty acid synthesis. We also identified that L-theanine enhanced fatty acid β-oxidation by increasing the expression of peroxisome proliferator–activated receptor α (PPARα) and carnitine palmitoyltransferase-1 A (CPT1A) through AMP-activated protein kinase (AMPK). Furthermore, our study indicated that L-theanine can active AMPK via its upstream kinase Calmodulin-dependent protein kinase kinase-β (CaMKKβ). Conclusions: Taken together, our findings suggest that L-theanine alleviates nonalcoholic hepatic steatosis by regulating hepatocyte lipid metabolic pathways via the CaMKKβ-AMPK signaling pathway.

scholarly journals Effects of dietary corticosterone on the central adenosine monophosphate-activated protein kinase (AMPK) signaling pathway in broiler chickens

2020 ◽  
Vol 98 (7) ◽  
Author(s):  
Xiyi Hu ◽  
Yuanli Cai ◽  
Linglian Kong ◽  
Hai Lin ◽  
Zhigang Song ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Signaling Pathway ◽  
Broiler Chickens ◽  
Fatty Acid Synthase ◽  
Average Daily Gain ◽  
Mammalian Target Of Rapamycin ◽  
Adenosine Monophosphate ◽  
Ampk Signaling ◽  
Protein Levels ◽  
Liver Kinase B1

Abstract Glucocorticoids (GCs) induce the activation of the central adenosine 5′-monophosphate-activated protein kinase (AMPK) signaling pathway in birds. In this study, we aimed to investigate the effects of corticosterone (CORT) supplemented in diet on the central AMPK signaling pathway in broilers. The average daily gain was reduced by CORT treatment, and the average daily feed intake remained unchanged. Plasma glucose, triglyceride, total cholesterol, and CORT contents were increased by CORT administration. In addition, CORT treatment decreased the relative weights of heart, spleen, and bursa and increased the relative weights of liver and abdominal fat. The glycogen contents in the liver and breast muscle were higher in the chicks treated with CORT. CORT treatment upregulated the gene expression of mammalian target of rapamycin, glucocorticoid receptor, AMPKα2, neuropeptide Y(NPY), liver kinase B1 (LKB1), AMPKα1, and fatty acid synthase in the hypothalamus. Moreover, CORT treatment increased the protein levels of acetyl-coenzyme A carboxylase (ACC) phosphorylation and total AMPK and phosphorylated AMPK in the hypothalamus. Hence, CORT administration in the diet activated the LKB1-AMPK-NPY/ACC signaling pathway in the hypothalamus of broiler.

scholarly journals Role and Mechanisms of Mitophagy in Liver Diseases

Cells ◽  
2020 ◽  
Vol 9 (4) ◽  
pp. 837 ◽  
Author(s):  
Xiaowen Ma ◽  
Tara McKeen ◽  
Jianhua Zhang ◽  
Wen-Xing Ding
Keyword(s):  
Liver Disease ◽  
Liver Diseases ◽  
Ischemia Reperfusion Injury ◽  
Mitochondrial Dynamics ◽  
Ischemia Reperfusion ◽  
Vital Role ◽  
Drug Induced ◽  
Hepatic Ischemia ◽  
Alcoholic Fatty Liver ◽  
Molecular Events

The mitochondrion is an organelle that plays a vital role in the regulation of hepatic cellular redox, lipid metabolism, and cell death. Mitochondrial dysfunction is associated with both acute and chronic liver diseases with emerging evidence indicating that mitophagy, a selective form of autophagy for damaged/excessive mitochondria, plays a key role in the liver’s physiology and pathophysiology. This review will focus on mitochondrial dynamics, mitophagy regulation, and their roles in various liver diseases (alcoholic liver disease, non-alcoholic fatty liver disease, drug-induced liver injury, hepatic ischemia-reperfusion injury, viral hepatitis, and cancer) with the hope that a better understanding of the molecular events and signaling pathways in mitophagy regulation will help identify promising targets for the future treatment of liver diseases.

scholarly journals Mitochondrial-Derived Peptide MOTS-c Attenuates Vascular Calcification and Secondary Myocardial Remodeling via Adenosine Monophosphate-Activated Protein Kinase Signaling Pathway

2019 ◽  
Vol 10 (1) ◽  
pp. 42-50 ◽  
Author(s):  
Ming Wei ◽  
Lu Gan ◽  
Zheng Liu ◽  
Li Liu ◽  
Jin-Rui Chang ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Signaling Pathway ◽  
Vascular Calcification ◽  
Vitamin D3 ◽  
Adenosine Monophosphate ◽  
Ampk Signaling ◽  
Disease Entities ◽  
Endothelin B ◽  
Protein Kinase Signaling

Introduction: Vascular calcification (VC) is a complex, regulated process involved in many disease entities. So far, there are no treatments to reverse it. Exploring novel strategies to prevent VC is important and necessary for VC-related disease intervention. Objective: In this study, we evaluated whether MOTS-c, a novel mitochondria-related 16-aa peptide, can reduce vitamin D3 and nicotine-induced VC in rats. Methods: Vitamin D3 plus nicotine-treated rats were injected with MOTS-c at a dose of 5 mg/kg once a day for 4 weeks. Blood pressure, heart rate, and body weight were measured, and echocardiography was performed. The expression of phosphorylated adenosine monophosphate-activated protein kinase (AMPK) and the angiotensin II type 1 (AT-1) and endothelin B (ET-B) receptors was determined by Western blot analysis. Results: Our results showed that MOTS-c treatment significantly attenuated VC. Furthermore, we found that the level of phosphorylated AMPK was increased and the expression levels of the AT-1 and ET-B receptors were decreased after MOTS-c treatment. Conclusions: Our findings provide evidence that MOTS-c may act as an inhibitor of VC by activating the AMPK signaling pathway and suppressing the expression of the AT-1 and ET-B receptors.

scholarly journals The cGAS-STING Pathway: Novel Perspectives in Liver Diseases

2021 ◽  
Vol 12 ◽  
Author(s):  
Dongwei Xu ◽  
Yizhu Tian ◽  
Qiang Xia ◽  
Bibo Ke
Keyword(s):  
Liver Disease ◽  
Cyclic Gmp ◽  
Liver Diseases ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Innate Immune ◽  
Microbial Pathogens ◽  
Hepatic Ischemia ◽  
Sting Pathway

Liver diseases represent a major global health burden accounting for approximately 2 million deaths per year worldwide. The liver functions as a primary immune organ that is largely enriched with various innate immune cells, including macrophages, dendritic cells, neutrophils, NK cells, and NKT cells. Activation of these cells orchestrates the innate immune response and initiates liver inflammation in response to the danger signal from pathogens or injured cells and tissues. The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway is a crucial signaling cascade of the innate immune system activated by cytosol DNA. Recognizing DNA as an immune-stimulatory molecule is an evolutionarily preserved mechanism in initiating rapid innate immune responses against microbial pathogens. The cGAS is a cytosolic DNA sensor eliciting robust immunity via the production of cyclic GMP-AMPs that bind and activate STING. Although the cGAS-STING pathway has been previously considered to have essential roles in innate immunity and host defense, recent advances have extended the role of the cGAS-STING pathway to liver diseases. Emerging evidence indicates that overactivation of cGAS-STING may contribute to the development of liver disorders, implying that the cGAS-STING pathway is a promising therapeutic target. Here, we review and discuss the role of the cGAS-STING DNA-sensing signaling pathway in a variety of liver diseases, including viral hepatitis, nonalcoholic fatty liver disease (NAFLD), alcoholic liver disease (ALD), primary hepatocellular cancer (HCC), and hepatic ischemia-reperfusion injury (IRI), with highlights on currently available therapeutic options.

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