AICAR is the short form for 5-aminoimidazole-4-carboxamide 1-D-ribofuranoside.
Alternative names: AICA-Riboside, AICA-Ribonucleotide, Acadesine, 5- aminoimidazole-4-carboxamide (AICA)-riboside.
What is AICAR?
AICAR is an analog of AMP, that activates the AMP-Depending Protein Kinase, up to here AMPK. To understand the main role of AICAR, is necessary to see where AMPK occur and the activation and inhibition effects it provokes.
AMP-Depending Protein Kinase
AMPK is a Serine-Threonine Protein Kinases which is consider as a sensor of cell energy. Nevertheless recently other non-metabolic effects have been discover, keep reading for more details:
AMPK is an heterotrimeric complex compose of a catalytic Î±-subunit and two different regulatory subunits Î² and Î³.
AMPK enable the phosphorilation of enzymes, transcription factors, coactivators or corepressors, most of them involved in ATP-supply process.
1)Under hypoxia, ischemia, heat shock or low-food conditions, the levels of ATP decrease but it is balanced with a high level of 5'-AMP. 5'-AMP interacts with the regulatory subunit Î³ of AMPK, that is essential to initiate AMPK activation.
2.1)LKB1,a primary upstream kinase of AMPK, in complex with the pseudokinase STRAD and the scaffolding protein MO25, phosphorylates AMPK, on Thr 172 at Î±-loop and, activating AMPK.
2.2) AMPK can be also activated directly through CAMKK2 (Calcium/ Calmodulin- Dependent Protein Kinase Kinase 2) on Thr 172 at Î±-loop, which detects an increase in intracellular calcium (Ca2+) level as a result of hormone's stimulation like adopnectin or leptin.
As we said the beggining of this blog, AMPK is mostly involve in energy homeostasis regulation. Besides activating catabolic proces and inhibiting anabolic process, it also affects other process as anti-inflammatory or supressing apoptosis.
STOP ENERGY-CONSUMING PATHWAYS
When intracellular ATP concentration decrease, AMPK will phosohorilate SREPB. SREBP is a transcription factor, shorted from sterol regulatory element-binding protein. It is synthesized as precursor, it stays attached at nuclear membrane, waiting for cell-nutritional status. SREBP will stay at the nuclear membrane, if there is enought energy for the cell metabolism, but if there is low energy conditions SREBP will cleavage and enter in the nucleus activating lipogenesis genes, such as HMG-CoA-synthase and ACC or FAS. AMPK will phosphorilate SREBP avoiding the entrance into the nucleus, thus stopping the transcriptional activation of the lipogenesis genes:
-ACC 1 and FAS are enzymes from fatty acid synthese pathway. ACC (Acetyl CoA Carboxylase) is the first enzyme of long-chain fatty acid synthese, it forms the Malonyl-CoA from Acetyl-CoA, ATP and HCO3 -.There are two isoforms ACC 1 and ACC 2. The distribution of the isoforms is not homogenous. ACC 1 is expressed in lipogenetic tissues such as liver and adipose tissue. Its synthesis is regulated by SREBP, and its activity is regulated by phosphorilations and allosteric stimulation. On this tissues, AMPK phosphorilates ACC 1 inhibiting the enzyme, thus the consume of energy by the liposynthesis process is stopped. ACC 2 is explained below. Fatty Acid Synthase (FAS), is a complexe with seven differents active sites. It carry on the final steps for Fatty Acid synthesis. Both enzymes, ACC and FAS will be suppress by low energy levels, saving it for energy supply.
-HMG-CoA-reductase, is the major point of regulation at steroids and cholesterols syntheses. SREBP will not active HMG-CoA-reductase transcription if the energy supply levels are low due to AMPK fosforilation. As ACC and FAS inhibition, HMG-Coa-reductase phosphorilation, save energy for catabolic process.
2) CARBOHYDRATE METABOLISM: Stop Glycogenesis, at skeleton muscles and liver 3
While fasting, the little glucose available should be keep for energy supply intead of being storage as glycogen. The glycogen-synthesis pathway (glycogenesis) will be inhibit by the AMPK phosphorilation of Glycogen Synthase (GS) at the Serine 7 at the site 2, due to decreasing the affinity of GS for UDP-Glucose. Thus the glucose will be available to be degrade at the glycolysis.
Hepatic glyconeogenesis, an anabolic pathway for convert not carbohydrate into glucose, will be inhibited under low ATP conditions. Under this situation, TORC2 will be phosphorilated at the Ser 171 by AMPK, this phosphorilation will induce 14-3-3 to sequester TORC2. TORC2-14-3-3 stayed at the citoplasma, it cannot enter in the nucleous and activate the gluconeogenesis genes transcription.
4) CARBOHYDRATE METABOLISM: Decrease of Glucose Uptake, at adipose tissue
5) PROTEIN METABOLISM: Stop Protein Synthesis, at liver and heart 6
By scarcy enegy conditions, AMPK also affects protein metabolism by phosphorilation of EF2k, eukaryotic translation elongation factor 2-kinase. EF2 is a GTP-binding factor family which is indispensable for protein synthesis. It promotes the GTP-dependent translocation of the nascent protein chain from the A-site to the P-site of the ribosome. When EF2 is phosphorilated by EF2k, EF2 is inactivated, and thus there is no protein synthesis.
6) Cell Growth 7
If there is not enough energy source for maintance cell energy necessity, makes sense that cell growth will be stop. Cell growth is related with protein synthesis, this pathway include the interaction of different proteins: TSC2, RHEBand MTOR. It is an enzymatic cascade that under low energy situation will be inactivated after AMPK phosphorilation of TSC2 and RAPTOR, ending with inactivation of mTOR responsible for protein translation, ribosome biogenesis and other cell growth route.
7) Cell Cyclus 8
Cell cyclus will be stop is the energy source is not enough. P53, became a very important molecule in the recent years. It is known for the importance as guardian of the genome and its mutation is present in most of the human cancers. It encodes a tumor suppressor protein which will activate the transcription of p21. P21 is a cyclin-dependent kinas- inhibitor-protein, which impair G1/S-Cdk and S-Cdk activation, stopping cell cycle at G1/S-phase. Usually p53 is blocked by a ubiquitin-protein-like ligase (mdm2) and follow to proteosoma degragation. But if AMPK activates it by phosphorilation, p53 is not going to be degradated so it will enable p21 synthesis and the block of cell cyclus.
ACTIVATE ENERGY-SUPPLY PATHWAYS
1) CARBOHYDRATE METABOLISM: Increase of Glucose uptake, at skeleton muscle and heart 9
The effect of insulin by reducing free-circulating glucose level, is due to the recruitment of GLUT 4 receptors to cell membrane, which are storage at the citoplasma forming microvesicles. After the insuline signal, GLUT 4 receptors will move from citoplasma to cell membrane (not to T-tubulus) increasing glucose uptake and thus glucose cell available. AMPK has same effect than insulin, it increase GLUT 4 receptors at cell membrane, it makes that by inactivation of vesicle-inhibitor TBC1D1, which reduce GLUT 4 translocation. Several experiement demostrate that insulin and AMPK-activator (AICAR), share part of the pathway of GLUT 4 recruitment.
2) CARBOHYDRATE METABOLISM: Increase stimulation of glycolysis, at heart and skeleton muscles 10
Short energy supply situations provokes an activation of glycolysis, PFKFB3 (6-phosphofructo-2 kinase / Fructose 2,6 bi phosphatase) is a complex of two enzymes with opposite function. It controls the balance between Fructose-6-phosphate (F-6-P) and Fructose-2,6-biphospahate (F-2,6-biP). F-2,6-biP, is considered a potent regulator of glycolysis by allosteric activation of the glycolyses enzyme, Phosphofructosekinasa 1 (PFK-1) and inactivation of gluconeogenesis, Fructobiphosphatase 1 (FBPase). Low ATP level will induce AMPK phosohorilation of PFKFB3, what induce F-2,6-biP synthesis and thus glycolysis increase.
3) LIPOLYSIS METABOLISM: Stimulation of mitochondria synthesis, at skeleton muscles 11
The mitochondria genesis activation is mediated by CREB which activate the expression of PGC-1 (Peroxisome proliferator-activated receptor gamma coactivator 1-alpha) responsible for mitochondria synthesis. AMPK will stimulate this pathway in order to support the increase of Î²-FA-oxidation by low energy situations.
Under low energy situation, AMPK will phosphorilate ACC 2, Acetyl CoA Carboxylase 2. ACC 2 is insert at the mitochondria out membrane,no free imn citoplasma like ACC 1. It it occurs in heart and skeleton muscle cells. ACC 2, Acetil CoA Carboxilase, is the first enzyme of the Liposynthesis, (that we refer above at Stop Energy-consuming pathways). Its product, Malonyl-Coa, suppress the CPT 1(Carnitine palmitoyl 1), which enables the entry of FA into the mitochondria to start the Î²-oxidation. But the inhibition of ACC 2 after AMPK phosphorilation, provokes the stimualtio of Î²-oxidation, by decreasing Malonyl CoA levels.
Lipolysis is a process to provide energy from adipose tissue to the other organs. ATGL (Adipose Triglyceride Lipase) is the enzyme in charge for the first step of FA mobilization from the adipose tissue, it will be activated after AMPK phosphorilation. The free FA will be oxidated in to the Î²-FA-oxidation, increasing the energy supply. Other enzyme involve at the increasing lipolysis process is HSL, hormone-sensitive lipase. It is involve at the degradation triacylglycerols, diacylglycerols, monoacylglycerols, and cholesteryl esters. But HSL is inactivated by AMPK phosphorilation in order to control TG breakdown, not to degradate faster TG than FA oxidation, because that will follow to a energy-consuming futile cycle where the excess of FA waiting for being oxidate will sterified into TG back.
6) PROTEIN METABOLISM: Autophagy Inducer 17
If the low energy condition get further, cell will be force to trigger the autophagy process AMPK will activate ULK-1 (Unc-51-Like Kinase 1) which acts upstream of PIK3C3(Phosphatidylinositol 3-Kinase, Catalytic Subunit Type 3) to regulate the formation of autophagophores, the precursors of autophagosomes.
7) Appetitive inducer, hypothalamus neurons
AMPK will stimulate appetitive and thus food intake, by stimulation of glucose depending neurons in the paraventricular nuclei of hypothalamus.
NOT METABOLISM PROCESS
1) Anti-inflammatory 18
AMPK is involve in anti-inflammatory process. AMPK will phosphorilate NF-KÎ² (nuclear factor kappa-light-chain-enhancer of activated B cells) inactivating its function as pro-inflamatory genes stimulator. The not activation of genes as TNF-1 (Tumor necrosis factor alpha), ICAM-1 (Intercellular Adhesion Molecule 1) and MCP-1 (monocyte chemotactic protein 1) produce decrease of cell-infiltration by maintance of vascular impermeability and also decrease of CD-14 (monocyte differentiation antigen CD 14) what provokes a decrease in endotoxin suspectibility.
2) Vasorelaxation 19
Also AMPK mediated aorta vasorelaxation has been analysed by low energy conditions. The experimentes shown that AMPK activation induce eNOS (endothelial Nitric Oxidase Synthase) phosphorilation.
3) Apoptosis-supressor 20
Recently there are some experiments that show a posible relation between AICAR anti-oxidative effect with AMPKanti-palmitate-induce-apoptotic effect. AMPK will block the generation of ROS by increasing Palmitate, stopping as well, p38 activation and further on, supressing apoptosis. Until now that has been tested in aortic endothelial bovine cells. 21
4) Regulator Neuronal Excitability 21
Another application of AMPK, as decreasing-neurons-excitability as threatment against neuropathic pain. After peripheral nerve injury, the affected nerves develop a hyperexcitability due to dysregulation of translation regulation. The reorganization of translation machinery after lesion, follow into an increase of nascent protein synthesis and hence an augmented neuron activity. The role of AMPK at this chronic pain state is by inhibition of nascent protein synthesis at injured nerves, EIf4F complex formation and Na+-channel excitability of sensory neurons.