Opinion: alternative views of AMP-activated protein kinase
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AMP-Activated Protein Kinase
Adenosine monophosphate
Abstract AMP-activated protein kinase (AMPK) is a central kinase involved in energy homeostasis. Increased intracellular adenosine monophosphate (AMP) levels result in AMPK activation through the binding of AMP to the γ-subunit of AMPK. Recently, we reported that AMP-induced AMPK activation is impaired in the kidneys in chronic kidney disease (CKD) despite an increase in the AMP/ATP ratio. However, the mechanisms by which AMP sensing is disrupted in CKD are unclear. In this study, we identified mechanisms of energy homeostasis in which Unc-51-like kinase 1 (ULK1)-dependent phosphorylation of AMPKγ1 at Ser260/Thr262 promotes AMP sensitivity of AMPK. AMPK activation by AMP was impaired in Ulk1 −/− mice despite an increased AMP/ATP ratio. We also demonstrated that MK8722, an allosteric AMPK activator, activates AMPK in the kidneys of a CKD mouse model via a pathway that is independent of AMP sensing. MK8722 treatment significantly attenuates the deterioration of renal function in CKD and is a potential therapeutic option in CKD therapeutics.
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5'-Adenosine monophosphate-activated protein kinase (AMPK) is a potential therapeutic target for various medical conditions. We here identify a small-molecule compound (RX-375) that activates AMPK and inhibits fatty acid synthesis in cultured human hepatocytes. RX-375 does not bind to AMPK but interacts with prohibitins (PHB1 and PHB2), which were found to form a complex with AMPK. RX-375 induced dissociation of this complex, and PHBs knockdown resulted in AMPK activation, in the cultured cells. Administration of RX-375 to obese mice activated AMPK and ameliorated steatosis in the liver. High-throughput screening based on disruption of the AMPK-PHB interaction identified a second small-molecule compound that activates AMPK, confirming the importance of this interaction in the regulation of AMPK. Our results thus indicate that PHBs are previously unrecognized negative regulators of AMPK, and that compounds that prevent the AMPK-PHB interaction constitute a class of AMPK activator.
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Adenosine 5′-monophosphate activated protein kinase (AMPK) is a master sensor of cellular energy status that plays a key role in the regulation of whole-body energy homeostasis. AMPK is a serine/threonine kinase that is activated by upstream kinases LKB1, CaMKKβ, and Tak1, among others. AMPK exists as αβγ trimeric complexes that are allosterically regulated by AMP, ADP, and ATP. Dysregulation of AMPK has been implicated in a number of metabolic diseases including type 2 diabetes mellitus and obesity. Recent studies have associated roles of AMPK with the development of cancer and neurological disorders, making it a potential therapeutic target to treat human diseases. This review focuses on the structure and function of AMPK, its role in human diseases, and its direct substrates and provides a brief synopsis of key AMPK modulators and their relevance in human diseases.
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5′-adenosine monophosphate (AMP)-activated protein kinase (AMPK) is an enzyme that regulates cellular energy homeostasis, glucose, fatty acid uptake, and oxidation at low cellular ATP levels. AMPK plays an important role in several molecular mechanisms and physiological conditions. It has been shown that AMPK can be dysregulated in different chronic diseases, such as inflammation, diabetes, obesity, and cancer. Due to its fundamental role in physiological and pathological cellular processes, AMPK is considered one of the most important targets for treating different diseases. Over decades, different AMPK targeting compounds have been discovered, starting from those that activate AMPK indirectly by altering intracellular AMP:ATP ratio to compounds that activate AMPK directly by binding to its activation sites. However, indirect altering of intracellular AMP:ATP ratio influences different cellular processes and induces side effects. Direct AMPK activators showed more promising results in eliminating side effects as well as the possibility to engineer drugs for specific AMPK isoforms activation. In this review, we discuss AMPK targeting drugs, especially concentrating on those compounds that activate AMPK by mimicking AMP. These compounds are poorly described in the literature and still, a lot of questions remain unanswered about the exact mechanism of AMP regulation. Future investigation of the mechanism of AMP binding will make it possible to develop new compounds that, in combination with others, can activate AMPK in a synergistic manner.
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背景 Metformin 与 type-2 糖尿病在病人的治疗成为了一块奠基石。积累的证据建议 metformin 支持指导心血管的效果。如果 metformin 在主要 cardiomyocytes 上有有益的效果，试图调查的现在的学习由 H2O2 损坏了，并且表明 metformin.Methods Cardiomyocytes 的行动的潜在的机制面对 100 umol/L 被孵化。为 12 个小时的 H2O2。Cardiomyocytes 是有在不同集中和时间并且与 aminoimidazole carboxamide ribonucleotide (AICAR )(500 umol/L ) 的 metformin 的 pretreated，腺苷 monophophate (安培) 激活为 60 的收缩筋在 H2O2 的增加前纪录的蛋白质 kinase (AMPK ) 。另外的房间是有复合 C 的 preincubated (一个 AMPK 对手， 20 umol/L ) 为 4 个小时。房间的生存能力和 apoptosis 被分析。AMPK， endothelial 氮的氧化物 synthase (eNOS ) ，和转变生长因素(TGF )-1 用 immunblotting.Results Metformin 被分析细胞生存能力和稀释氧化导致压力的 apoptosis 上的 H2O2 的影响上的有的对抗效果。Metformin 也增加了 AMPK 和 eNOS 的 phosphorylation，并且减少了 TGF-1，基本成纤维细胞生长因素(bFGF ) ，和肿瘤坏死因素(TNF )-.Conclusions Metformin 的表示在 cardiomyocytes 上有有益的效果，并且这效果包含 AMPK-eNOS 小径的激活。Metformin 可能为心疾病的处理是潜在地有益的。
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The generally accepted mechanism of metformin’s effect is stimulation of adenosine monophosphate (AMP)-activated protein kinase (AMPK). AMPK is directly activated by an increase in AMP:ATP ratio in metabolic stress conditions including hypoxia and glucose deprivation. Lately, many novel pathways, besides AMPK induction, have been revealed, which can explain some of metformin’s beneficial effects. It may help to identify new targets for treatment of diabetes and metabolic syndrome. Moreover, metformin is now attracting the attention of researchers in fields other than diabetes, as it has been shown to have anti-cancer, immunoregulatory and anti-aging effects. The aim of this review is to describe the potential anti-cancer and anti-aging properties of metformin and discuss the possible underlying mechanisms.
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5'-adenosine monophosphate-activated protein kinase (AMPK) is an enzyme activated when cellular energy status is threatened. AMPK activates energy-providing processes, while energy-consuming processes are inhibited. AMPK is also involved in regulation of gene expression and in appetite control. Pharmacological activation of AMPK in animal models of the metabolic syndrome leads to marked amelioration of symptoms. Some antidiabetic drugs activate AMPK, and activation also occurs during physical exercise. It is likely that part of the effect of physical activity in preventing the development of diseases related to a sedentary lifestyle is due to activation of AMPK.
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A possible molecular mechanism of action for a metabolite of aspirin is described.
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Salicylate, a plant product, has been in medicinal use since ancient times. More recently, it has been replaced by synthetic derivatives such as aspirin and salsalate, both of which are rapidly broken down to salicylate in vivo. At concentrations reached in plasma after administration of salsalate or of aspirin at high doses, salicylate activates adenosine monophosphate-activated protein kinase (AMPK), a central regulator of cell growth and metabolism. Salicylate binds at the same site as the synthetic activator A-769662 to cause allosteric activation and inhibition of dephosphorylation of the activating phosphorylation site, threonine-172. In AMPK knockout mice, effects of salicylate to increase fat utilization and to lower plasma fatty acids in vivo were lost. Our results suggest that AMPK activation could explain some beneficial effects of salsalate and aspirin in humans.
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