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      AMP-activated protein kinase: a target for drugs both ancient and modern

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      Author(s): 1 , * , 1 , 1
      Publication date PMC-release:
      Journal: Chemistry & biology

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          Abstract

          The AMP-activated protein kinase (AMPK) is a sensor of cellular energy status. It is activated, by a mechanism requiring the tumor suppressor LKB1, by metabolic stresses that increase cellular ADP:ATP and/or AMP:ATP ratios. Once activated, it switches on catabolic pathways that generate ATP, while switching off biosynthetic pathways and cell cycle progress. These effects suggest that AMPK activators might be useful for treatment and/or prevention of type 2 diabetes and cancer. Indeed, AMPK is activated by the drugs metformin and salicylate, the latter being the major breakdown product of aspirin. Metformin is widely used to treat diabetes, while there is epidemiological evidence that both metformin and aspirin provide protection against cancer. We review the mechanisms of AMPK activation by these and other drugs, and by natural products derived from traditional herbal medicines.

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          AMP-activated protein kinase (AMPK) action in skeletal muscle via direct phosphorylation of PGC-1alpha.

          Sibylle Jager, Christoph Handschin, Julie St-Pierre … (2007)
          Activation of AMP-activated kinase (AMPK) in skeletal muscle increases glucose uptake, fatty acid oxidation, and mitochondrial biogenesis by increasing gene expression in these pathways. However, the transcriptional components that are directly targeted by AMPK are still elusive. The peroxisome-proliferator-activated receptor gamma coactivator 1alpha (PGC-1alpha) has emerged as a master regulator of mitochondrial biogenesis; furthermore, it has been shown that PGC-1alpha gene expression is induced by exercise and by chemical activation of AMPK in skeletal muscle. Using primary muscle cells and mice deficient in PGC-1alpha, we found that the effects of AMPK on gene expression of glucose transporter 4, mitochondrial genes, and PGC-1alpha itself are almost entirely dependent on the function of PGC-1alpha protein. Furthermore, AMPK phosphorylates PGC-1alpha directly both in vitro and in cells. These direct phosphorylations of the PGC-1alpha protein at threonine-177 and serine-538 are required for the PGC-1alpha-dependent induction of the PGC-1alpha promoter. These data indicate that AMPK phosphorylation of PGC-1alpha initiates many of the important gene regulatory functions of AMPK in skeletal muscle.
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            AMP-activated/SNF1 protein kinases: conserved guardians of cellular energy.

            D Hardie (2007)
            The SNF1/AMP-activated protein kinase (AMPK) family maintains the balance between ATP production and consumption in all eukaryotic cells. The kinases are heterotrimers that comprise a catalytic subunit and regulatory subunits that sense cellular energy levels. When energy status is compromised, the system activates catabolic pathways and switches off protein, carbohydrate and lipid biosynthesis, as well as cell growth and proliferation. Surprisingly, recent results indicate that the AMPK system is also important in functions that go beyond the regulation of energy homeostasis, such as the maintenance of cell polarity in epithelial cells.
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              Fat mobilization in adipose tissue is promoted by adipose triglyceride lipase.

              Robert Zimmermann, Juliane G. Strauss, Guenter Haemmerle … (2004)
              Mobilization of fatty acids from triglyceride stores in adipose tissue requires lipolytic enzymes. Dysfunctional lipolysis affects energy homeostasis and may contribute to the pathogenesis of obesity and insulin resistance. Until now, hormone-sensitive lipase (HSL) was the only enzyme known to hydrolyze triglycerides in mammalian adipose tissue. Here, we report that a second enzyme, adipose triglyceride lipase (ATGL), catalyzes the initial step in triglyceride hydrolysis. It is interesting that ATGL contains a "patatin domain" common to plant acyl-hydrolases. ATGL is highly expressed in adipose tissue of mice and humans. It exhibits high substrate specificity for triacylglycerol and is associated with lipid droplets. Inhibition of ATGL markedly decreases total adipose acyl-hydrolase activity. Thus, ATGL and HSL coordinately catabolize stored triglycerides in adipose tissue of mammals.
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                Author and article information

                Journal
                Journal ID (nlm-journal-id): 9500160
                Journal ID (pubmed-jr-id): 20384
                Journal ID (nlm-ta): Chem Biol
                Journal ID (iso-abbrev): Chem. Biol.
                Title: Chemistry & biology
                ISSN (Print): 1074-5521
                ISSN (Electronic): 1879-1301
                Publication date Nihms-submitted: 4 December 2017
                Publication date (Print): 26 October 2012
                Publication date PMC-release: 08 December 2017
                Volume: 19
                Issue: 10
                Pages: 1222-1236
                Affiliations
                [1 ]Division of Cell Signalling & Immunology, College of Life Sciences, University of Dundee, Dundee, DD1 5EH, Scotland, UK
                Author notes
                Article
                Manuscript ID: EMS75238
                DOI: 10.1016/j.chembiol.2012.08.019
                PMC ID: 5722193
                PubMed ID: 23102217
                SO-VID: 8cfb4424-c011-4f96-abcd-f995f7cc0601
                License:

                This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/

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                Subject: Article

                ScienceOpen disciplines: Biochemistry
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                ScienceOpen disciplines: Biochemistry

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