scholarly journals An AMPK–caspase-6 axis controls liver damage in nonalcoholic steatohepatitis

Science ◽  
2020 ◽  
Vol 367 (6478) ◽  
pp. 652-660 ◽  
Author(s):  
Peng Zhao ◽  
Xiaoli Sun ◽  
Cynthia Chaggan ◽  
Zhongji Liao ◽  
Kai in Wong ◽  
...  
Keyword(s):  
Liver Damage ◽  
Nonalcoholic Steatohepatitis ◽  
Adenosine Monophosphate ◽  
Cytochrome C Release ◽  
Energy Sensor ◽  
Ampk Activity ◽  
Caspase 6 ◽  
Amp Activated Protein Kinase ◽  
Hepatocyte Death ◽  
Liver Cell Death

Liver cell death has an essential role in nonalcoholic steatohepatitis (NASH). The activity of the energy sensor adenosine monophosphate (AMP)–activated protein kinase (AMPK) is repressed in NASH. Liver-specific AMPK knockout aggravated liver damage in mouse NASH models. AMPK phosphorylated proapoptotic caspase-6 protein to inhibit its activation, keeping hepatocyte apoptosis in check. Suppression of AMPK activity relieved this inhibition, rendering caspase-6 activated in human and mouse NASH. AMPK activation or caspase-6 inhibition, even after the onset of NASH, improved liver damage and fibrosis. Once phosphorylation was decreased, caspase-6 was activated by caspase-3 or -7. Active caspase-6 cleaved Bid to induce cytochrome c release, generating a feedforward loop that leads to hepatocyte death. Thus, the AMPK–caspase-6 axis regulates liver damage in NASH, implicating AMPK and caspase-6 as therapeutic targets.

scholarly journals Herba houttuyniae Extract Benefits Hyperlipidemic Mice via Activation of the AMPK/PGC-1α/Nrf2 Cascade

Nutrients ◽  
2020 ◽  
Vol 12 (1) ◽  
pp. 164
Author(s):  
Ke Cao ◽  
Weiqiang Lv ◽  
Xuyun Liu ◽  
Yingying Fan ◽  
Kexin Wang ◽  
...  
Keyword(s):  
Adenosine Monophosphate ◽  
Poloxamer 407 ◽  
Peroxisome Proliferator ◽  
Related Factor ◽  
Protective Effects ◽  
Peroxisome Proliferator Activated Receptor ◽  
Beneficial Effects ◽  
Ampk Activity ◽  
Amp Activated Protein Kinase ◽  
Complex Activities

Hyperlipidemia is associated with metabolic disorders, but the detailed mechanisms and related interventions remain largely unclear. As a functional food in Asian diets, Herba houttuyniae has been reported to have beneficial effects on health. The present research was to investigate the protective effects of Herba houttuyniae aqueous extract (HAE) on hyperlipidemia-induced liver and heart impairments and its potential mechanisms. Male C57BL/6J mice were administered with 200 or 400 mg/kg/day HAE for 9 days, followed by intraperitoneal injection with 0.5 g/kg poloxamer 407 to induce acute hyperlipidemia. HAE treatment significantly attenuated excessive serum lipids and tissue damage markers, prevented hepatic lipid deposition, improved cardiac remodeling, and ameliorated hepatic and cardiac oxidative stress induced by hyperlipidemia. More importantly, NF-E2 related factor (Nrf2)-mediated antioxidant and peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α)-mediated mitochondrial biogenesis pathways as well as mitochondrial complex activities were downregulated in the hyperlipidemic mouse livers and hearts, which may be attributable to the loss of adenosine monophosphate (AMP)-activated protein kinase (AMPK) activity: all of these changes were reversed by HAE supplementation. Our findings link the AMPK/PGC-1α/Nrf2 cascade to hyperlipidemia-induced liver and heart impairments and demonstrate the protective effect of HAE as an AMPK activator in the prevention of hyperlipidemia-related diseases.

scholarly journals Study of the AMP-activated protein kinase role in energy metabolism changes during the postmortem aging of yak longissimus lumborum

2019 ◽  
Author(s):  
Yayuan Yang ◽  
Ling Han ◽  
Qunli Yu ◽  
Yongfang Gao ◽  
Rende Song
Keyword(s):  
Energy Metabolism ◽  
Protein Kinase ◽  
Opposite Effect ◽  
Ph Value ◽  
Physiological Mechanism ◽  
Adenosine Monophosphate ◽  
Postmortem Aging ◽  
Longissimus Lumborum ◽  
Ampk Activity ◽  
Amp Activated Protein Kinase

AbstractTo explore the postmortem physiological mechanism of muscle, activity of adenosine monophosphate activated protein kinase (AMPK) as well as its role in energy metabolism of postmortem yaks were studied. In this experiment, we injected 5-amino-1-beta-d-furanonyl imidazole-4-formamide (AICAR), a specific activator of AMPK, and the specific AMPK inhibitor STO-609, to observe the changes in glycolysis, energy metabolism, AMPK activity and AMPK gene expression (PRKA1 and PRKA2) in postmortem yaks during maturation. The results showed that AICAR could increase the expression of the PRKKA1 and PRKAA2 genes, activate AMPK and increase its activity. The effects of AICAR include a lower concentration of ATP, an increase in AMP production, an acceleration of glycolysis, an increase in the lactic acid concentration, and a decrease in the pH value. In contrast, STO-609 had the opposite effect. Under hypoxic adaptation, the activity of the meat AMPK increased, which accelerated glycolysis and metabolism, and more effectively regulated energy production.

Metformin and phenformin activate AMP-activated protein kinase in the heart by increasing cytosolic AMP concentration

2007 ◽  
Vol 293 (1) ◽  
pp. H457-H466 ◽  
Author(s):  
Li Zhang ◽  
Huamei He ◽  
James A. Balschi
Keyword(s):  
Protein Kinase ◽  
Isolated Heart ◽  
Acetyl Coa Carboxylase ◽  
Acetyl Coa ◽  
Cellular Energy ◽  
Rat Hearts ◽  
Energy Sensor ◽  
Ampk Activity ◽  
Amp Activated Protein Kinase ◽  
Krebs Henseleit Buffer

AMP-activated protein kinase (AMPK) acts as a cellular energy sensor: it responds to an increase in AMP concentration ([AMP]) or the AMP-to-ATP ratio (AMP/ATP). Metformin and phenformin, which are biguanides, have been reported to increase AMPK activity without increasing AMP/ATP. This study tests the hypothesis that these biguanides increase AMPK activity in the heart by increasing cytosolic [AMP]. Groups of isolated rat hearts ( n = 5–7 each) were perfused with Krebs-Henseleit buffer with or without 0.2 mM phenformin or 10 mM metformin, and 31P-NMR-measured phosphocreatine, ATP, and intracellular pH were used to calculate cytosolic [AMP]. At various times, hearts were freeze-clamped and assayed for AMPK activity, phosphorylation of Thr172 on AMPK-α, and phosphorylation of Ser79 on acetyl-CoA carboxylase, an AMPK target. In hearts treated with phenformin for 18 min and then perfused for 20 min with Krebs-Henseleit buffer, [AMP] began to increase at 26 min and AMPK activity was elevated at 36 min. In hearts treated with metformin, [AMP] was increased at 50 min and AMPK activity, phosphorylated AMPK, and phosphorylated acetyl-CoA carboxylase were elevated at 61 min. In metformin-treated hearts, HPLC-measured total AMP content and total AMP/ATP did not increase. In summary, phenformin and metformin increase AMPK activity and phosphorylation in the isolated heart. The increase in AMPK activity was always preceded by and correlated with increased cytosolic [AMP]. Total AMP content and total AMP/ATP did not change. Cytosolic [AMP] reported metabolically active AMP, which triggered increased AMPK activity, but measures of total AMP did not.

scholarly journals Hypothalamic AMPK as a Regulator of Energy Homeostasis

2016 ◽  
Vol 2016 ◽  
pp. 1-12 ◽  
Author(s):  
My Khanh Q. Huynh ◽  
Ann W. Kinyua ◽  
Dong Joo Yang ◽  
Ki Woo Kim
Keyword(s):  
Energy Balance ◽  
Energy Homeostasis ◽  
Energy State ◽  
Glucose Production ◽  
Energy Output ◽  
Energy Sensor ◽  
Increase Energy Intake ◽  
Ampk Activity ◽  
Underlying Mechanisms ◽  
Amp Activated Protein Kinase

Activated in energy depletion conditions, AMP-activated protein kinase (AMPK) acts as a cellular energy sensor and regulator in both central nervous system and peripheral organs. Hypothalamic AMPK restores energy balance by promoting feeding behavior to increase energy intake, increasing glucose production, and reducing thermogenesis to decrease energy output. Besides energy state, many hormones have been shown to act in concert with AMPK to mediate their anorexigenic and orexigenic central effects as well as thermogenic influences. Here we explore the factors that affect hypothalamic AMPK activity and give the underlying mechanisms for the role of central AMPK in energy homeostasis together with the physiological effects of hypothalamic AMPK on energy balance restoration.

scholarly journals Study of the AMP-activated Protein Kinase Role in Energy Metabolism Changes during the Postmortem Aging of Yak Longissimus dorsal

Animals ◽  
2020 ◽  
Vol 10 (3) ◽  
pp. 427
Author(s):  
Yayuan Yang ◽  
Ling Han ◽  
Qunli Yu ◽  
Yongfang Gao ◽  
Rende Song
Keyword(s):  
Energy Metabolism ◽  
Protein Kinase ◽  
Opposite Effect ◽  
Ph Value ◽  
Physiological Mechanism ◽  
Adenosine Monophosphate ◽  
Theoretical System ◽  
Postmortem Aging ◽  
Ampk Activity ◽  
Amp Activated Protein Kinase

To explore the postmortem physiological mechanism of muscle, activity of adenosine monophosphate activated protein kinase (AMPK) as well as its role in energy metabolism of postmortem yaks were studied. In this experiment, we injected 5-amino-1-beta-d-furanonyl imidazole-4-formamide (AICAR), a specific activator of AMPK, and STO-609 to observe the changes in glycolysis, energy metabolism, AMPK activity, and AMPK gene expression (PRKA1 and PRKA2) in postmortem yaks during maturation. The results showed that AICAR could increase the expression of the PRKKA1 and PRKAA2 genes, activate AMPK and increase its activity. The effects of AICAR include a lower concentration of ATP, an increase in AMP production, an acceleration of glycolysis, an increase in the lactic acid concentration, and a decrease in the pH value. In contrast, STO-609 had the opposite effect. Under hypoxic adaptation, the activity of the meat AMPK increased, which accelerated glycolysis and metabolism and more effectively regulated energy metabolism. Therefore, this study lays the foundation for establishing a theoretical system of energy metabolism in postmortem yak meat.

scholarly journals Suppression of Kaposi's Sarcoma-Associated Herpesvirus Infection and Replication by 5′-AMP-Activated Protein Kinase

2016 ◽  
Vol 90 (14) ◽  
pp. 6515-6525 ◽  
Author(s):  
Fan Cheng ◽  
Meilan He ◽  
Jae U. Jung ◽  
Chun Lu ◽  
Shou-Jiang Gao
Keyword(s):  
Protein Kinase ◽  
Kaposi's Sarcoma ◽  
Kaposi’S Sarcoma ◽  
Lytic Replication ◽  
Energy Sensor ◽  
Ampk Activity ◽  
Kaposi's Sarcoma Associated Herpesvirus ◽  
Kaposi’S Sarcoma Associated Herpesvirus ◽  
Amp Activated Protein Kinase ◽  
Lytic Genes

ABSTRACTThe host intracellular antiviral restriction factors inhibit viral infection and replication. The 5′-AMP-activated protein kinase (AMPK) is a cellular energy sensor regulating metabolic homeostasis. Activated AMPK inhibits the replication of numerous RNA viruses but enhances the entry of vaccinia virus. However, the role of AMPK in herpesvirus infection is unclear. In this study, we showed that the constitutive AMPK activity restricted Kaposi's sarcoma-associated herpesvirus (KSHV) lytic replication in primary human umbilical vein endothelial cells while KSHV infection did not markedly affect the endogenous AMPK activity. Knockdown of the AMPKα1 considerably enhanced the expression of viral lytic genes and the production of infectious virions, while overexpression of a constitutively active AMPK had the opposite effects. Accordingly, an AMPK inhibitor, compound C, augmented viral lytic gene expressions and virion productions but an AMPK agonist, 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR), suppressed both. Furthermore, a common diabetes drug, metformin, which carries an AMPK-agonistic activity, drastically inhibited the expression of viral lytic genes and the production of infectious virions, suggesting the use of metformin as a therapeutic agent for KSHV infection and replication. Together, these results identify the host AMPK as a KSHV restriction factor that can serve as a potential therapeutic target.IMPORTANCEHost cells encode specific proteins to restrict viral infection and replication. Kaposi's sarcoma-associated herpesvirus (KSHV) is a human tumor virus associated with several cancers. In this study, we have identified 5′-AMP-activated protein kinase (AMPK), a cellular energy sensor, as a restriction factor of KSHV lytic replication during primary infection. Activation of AMPK suppresses, while inhibition of AMPK enhances, KSHV lytic replication by regulating the expression of viral genes. AICAR and metformin, both of which are AMPK agonists currently used in clinics for the treatment of conditions associated with metabolic disorders, inhibit KSHV lytic replication. Thus, our work has identified AMPK as a potential therapeutic target and AICAR and metformin as potential therapeutic agents for KSHV-associated cancers.

scholarly journals IKK promotes cytokine-induced and cancer-associated AMPK activity and attenuates phenformin-induced cell death in LKB1-deficient cells

2018 ◽  
Vol 11 (538) ◽  
pp. eaan5850 ◽  
Author(s):  
Ricardo J. Antonia ◽  
Albert S. Baldwin
Keyword(s):  
Cell Types ◽  
Response To Treatment ◽  
Important Target ◽  
Ampk Phosphorylation ◽  
Energy Stress ◽  
Iκb Kinase ◽  
Energy Sensor ◽  
Tnf Α ◽  
Ampk Activity ◽  
Amp Activated Protein Kinase

The 5′ AMP-activated protein kinase (AMPK) is an energy sensor that is activated upon phosphorylation of Thr172 in its activation loop by the kinase LKB1, CAMKK2, or TAK1. TAK1-dependent AMPK phosphorylation of Thr172 is less well characterized than phosphorylation of this site by LKB1 or CAMKK2. An important target of TAK1 is IκB kinase (IKK), which controls the activation of the transcription factor NF-κB. We tested the hypothesis that IKK acted downstream of TAK1 to activate AMPK by phosphorylating Thr172. IKK was required for the phosphorylation of Thr172 in AMPK in response to treatment with the inflammatory cytokine IL-1β or TNF-α or upon TAK1 overexpression. In addition, IKK regulated basal AMPK Thr172 phosphorylation in several cancer cell types independently of TAK1, indicating that other modes of IKK activation could stimulate AMPK. We found that IKK directly phosphorylated AMPK at Thr172 independently of the tumor suppressor LKB1 or energy stress. Accordingly, in LKB1-deficient cells, IKK inhibition reduced AMPK Thr172 phosphorylation in response to the mitochondrial inhibitor phenformin. This response led to enhanced apoptosis and suggests that IKK inhibition in combination with phenformin could be used clinically to treat patients with LKB1-deficient cancers.

scholarly journals AMP-activated protein kinase: a therapeutic target in intestinal diseases

Open Biology ◽  
2017 ◽  
Vol 7 (8) ◽  
pp. 170104 ◽  
Author(s):  
Xiaofei Sun ◽  
Mei-Jun Zhu
Keyword(s):  
Protein Kinase ◽  
Therapeutic Target ◽  
Inflammatory Diseases ◽  
Adenosine Monophosphate ◽  
Aetiological Factor ◽  
Ampk Activation ◽  
Intestinal Health ◽  
Intestinal Diseases ◽  
Energy Sensor ◽  
Amp Activated Protein Kinase

Adenosine monophosphate (AMP)-activated protein kinase (AMPK), a highly conserved energy sensor, has a crucial role in cardiovascular, neurodegenerative and inflammatory diseases, as well as in cancer and metabolic disorders. Accumulating studies have demonstrated that AMPK activation enhances paracellular junctions, nutrient transporters, autophagy and apoptosis, and suppresses inflammation and carcinogenesis in the intestine, indicating an essential role of AMPK in intestinal health. AMPK inactivation is an aetiological factor in intestinal dysfunctions. This review summarizes the favourable outcomes of AMPK activation on intestinal health, and discusses AMPK as a potential therapeutic target for intestinal diseases.

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