AMP ‐activated protein kinase: a key regulator of energy balance with many roles in human disease
Open accessAbstract
The AMP-activated protein kinase (AMPK) is a sensor of cellular energy status that regulates cellular and whole-body energy balance. A recently reported crystal structure has illuminated the complex regulatory mechanisms by which AMP and ADP cause activation of AMPK, involving phosphorylation by the upstream kinase LKB1. Once activated by falling cellular energy status, AMPK activates catabolic pathways that generate ATP whilst inhibiting anabolic pathways and other cellular processes that consume ATP. A role of AMPK is implicated in many human diseases. Mutations in the γ2 subunit cause heart disease due to excessive glycogen storage in cardiac myocytes, leading to ventricular pre-excitation. AMPK-activating drugs reverse many of the metabolic defects associated with insulin resistance, and recent findings suggest that the insulin-sensitizing effects of the widely used antidiabetic drug metformin are mediated by AMPK. The upstream kinase LKB1 is a tumour suppressor, and AMPK may exert many of its antitumour effects. AMPK activation promotes the oxidative metabolism typical of quiescent cells, rather than the aerobic glycolysis observed in tumour cells and cells involved in inflammation, explaining in part why AMPK activators have both antitumour and anti-inflammatory effects. Salicylate (the major in vivo metabolite of aspirin) activates AMPK, and this could be responsible for at least some of the anticancer and anti-inflammatory effects of aspirin. In addition to metformin and salicylates, novel drugs that modulate AMPK are likely to enter clinical trials soon. Finally, AMPK may be involved in viral infection: downregulation of AMPK during hepatitis C virus infection appears to be essential for efficient viral replication.
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AMPK is an intracellular energy sensor and a key factor regulating glucose and lipid metabolism.
“The serine kinase adenosine 5’-monophosphate-activated protein kinase is an intracellular energy sensor that is a key factor that plays a role in regulating glucose and lipid metabolism [10].”
From Regulatory Efficacy of the Polyunsaturated Fatty Acids from Microalgae Spirulina platensis on Lipid Metabolism and Gut Microbiota in High-Fat Diet Rats (2018) · cites this paper as [10]
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Inhibition by AICA Riboside of Gluconeogenesis in Isolated Rat Hepatocytes
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Phosphorylation by Akt within the ST loop of AMPK-α1 down-regulates its activation in tumour cells
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AMPK Promotes p53 Acetylation via Phosphorylation and Inactivation of SIRT1 in Liver Cancer Cells
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Complementary regulation of TBC1D1 and AS160 by growth factors, insulin and AMPK activators
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Structural insight into the autoinhibition mechanism of AMP-activated protein kinase
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Involvement of Organic Cation Transporter 1 in the Lactic Acidosis Caused by Metformin
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Gastrointestinal hamartomatous polyposis in Lkb1 heterozygous knockout mice.
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Structural Basis for Glycogen Recognition by AMP-Activated Protein Kinase
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The AMP-activated protein kinase: a multisubstrate regulator of lipid metabolism
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Pehmøller, C., Treebak, J. T., Birk, J. B., Chen, S., MacKintosh, C., Hardie, D. G., Richter, E. A., & Wojtaszewski, J. F. P. (2009) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00115.2009 · Cited by 171 · see citing works
Chen, S., Wasserman, D. H., MacKintosh, C., & Sakamoto, K. (2011) · Cell Metabolism · doi:10.1016/j.cmet.2010.12.005 · Cited by 161 · see citing works
Burwinkel, B., Scott, J. W., Bührer, C., van Landeghem, F. K. H., Cox, G. F., Wilson, C. J., Hardie, D. G., & Kilimann, M. W. (2005) · The American Journal of Human Genetics · doi:10.1086/430840 · Cited by 152 · see citing works
Mankouri, J., Tedbury, P. R., Gretton, S., Hughes, M. E., Griffin, S. D. C., Dallas, M. L., Green, K. A., Hardie, D. G., Peers, C., & Harris, M. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0912426107 · Cited by 150 · see citing works
Sidhu, J. S., Rajawat, Y. S., Rami, T. G., Gollob, M. H., Wang, Z., Yuan, R., Marian, A. J., DeMayo, F. J., Weilbaecher, D., Taffet, G. E., et al. (2004) · Circulation · doi:10.1161/01.cir.0000151291.32974.d5 · Cited by 145 · see citing works
Fogarty, S., Hawley, S. A., Green, K. A., Saner, N., Mustard, K. J., & Hardie, D. G. (2009) · Biochemical Journal · doi:10.1042/bj20091372 · Cited by 140 · see citing works
Hepatocellular carcinoma caused by loss of heterozygosity in Lkb1 gene knockout mice.
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Effect of metformin on glucose metabolism in the splanchnic bed
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LKB1/STK11 Inactivation Leads to Expansion of a Prometastatic Tumor Subpopulation in Melanoma
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AMP-Activated Protein Kinase Induces p53 by Phosphorylating MDMX and Inhibiting Its Activity
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Conserved regulatory elements in AMPK
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AMPK: mediating the metabolic effects of salicylate-based drugs?
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Viruses and the fuel sensor: the emerging link between AMPK and virus replication
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Systemic pan-AMPK activator MK-8722 improves glucose homeostasis but induces cardiac hypertrophy
Myers, R. W., Guan, H.-P., Ehrhart, J., Petrov, A., Prahalada, S., Tozzo, E., Yang, X., Kurtz, M. M., Trujillo, M., Gonzalez Trotter, D., et al. (2017) · Science · doi:10.1126/science.aah5582 · Cited by 346 · see citing works
HIF-1-Independent Mechanisms Regulating Metabolic Adaptation in Hypoxic Cancer Cells
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Unravelling the mechanisms regulating muscle mitochondrial biogenesis
Hood, D. A., Tryon, L. D., Carter, H. N., Kim, Y., & Chen, C. C. W. (2016) · Biochemical Journal · doi:10.1042/bcj20160009 · Cited by 159 · see citing works
Li, T.-T., Liu, Y.-Y., Wan, X.-Z., Huang, Z.-R., Liu, B., & Zhao, C. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19103075 · Cited by 103 · see citing works
Discovery of MK-8722: A systemic, direct pan-activator of amp-activated protein kinase
Feng, D., Biftu, T., Romero, F. A., Kekec, A., Dropinski, J., Kassick, A., Xu, S., Kurtz, M. M., Gollapudi, A., Shao, Q., et al. (2018) · ACS Medicinal Chemistry Letters · doi:10.1021/acsmedchemlett.7b00417 · Cited by 64 · see citing works
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Khaliq, M., Noor, Z., Moazzam, M., Saeed, F., Tul-Zohra, K., Tariq, E., Muhammad Shahbaz, H., & Khaliq, K. (2026) · Annals of Medicine · doi:10.1080/07853890.2026.2637282 · Cited by 4 · see citing works
“One of the most important regulators of energy balance in the body is an enzyme known as AMP-activated protein kinase (AMPK) [154].”
- Authors
- Grahame Hardie, D.
- Affiliations
- Division of Cell Signalling and Immunology College of Life Sciences University of Dundee Scotland UK
- Venue
- Journal of Internal Medicine
- Publisher
- Wiley
- Published
- 2014-05-27
- Volume
- 276
- Issue
- 6
- Pages
- 543-559
- ISSN
- 0954-6820 (ISSN-L)
- 1365-2796
- PMC
- PMC5705060
- OpenAlex
- W1979000812
- Cited by
- 285
- References
- 121
- Citations by year
- 2026: 24 · 2025: 18 · 2024: 22 · 2023: 18 · 2022: 16 · 2021: 26 · 2020: 26 · 2019: 18 · 2018: 25 · 2017: 27 · 2016: 34 · 2015: 28 · 2014: 3
- FWCI
- 2.89
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- public-domain
- onlinelibrary.wiley.com/termsAndConditions#vor (vor)
- Locations
- Journal of Internal Medicine (publishedVersion, public-domain)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Discovery Research Portal (University of Dundee) (acceptedVersion, other-oa)
- Funders
- Wellcome Trust (097726)
- Cancer Research UK (C37030/A15101)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biochemical and Molecular Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Keywords
- AMPK, energy balance, LKB1, AMPK activators, metformin, insulin resistance, heart disease, glycogen storage, tumor suppression, oxidative metabolism, aerobic glycolysis, anti-inflammatory activity, aspirin, salicylates, hepatitis C virus, viral replication
- MeSH terms
- Adenine Nucleotides, Cardiomyopathy, Hypertrophic, Diabetes Mellitus, Type 2, Energy Metabolism, Humans, Inflammation, Mutation, Neoplasms, Virus Diseases, Calcium Channels, Molecular Structure, AMP-Activated Protein Kinases
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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