腺苷酸活化蛋白激酶在糖脂代谢调控中的研究进展

AMP激活的蛋白激酶(AMP-activated protein kinase,AMPK)是一种异源三聚体复合物,作为机体能量平衡和糖脂代谢的重要激酶参与多种生理过程的调节。研究表明,炎症、糖尿病和癌症等多种慢性疾病也与AMPK功能和活性调节有密切关系。新近发现,糖尿病一线用药二甲双胍抑制肝糖产生改善病人高血糖的作用与AMPK激活有关,提示靶向AMPK可能是预防和治疗多种慢性疾病的有效策略之一。文中从AMPK的结构与活性、AMPK在糖代谢调控中的作用和AMPK在血脂代谢调控中的作用3个方面综述了AMPK研究的进展,旨在为糖脂代谢调控的基础和临床研究提供依据。     

人脂素基因LIPIN1在酵母中的异源表达及细胞功能分析

脂类代谢调控是维持生物体能量平衡的重要环节,脂类代谢调控的紊乱与肥胖症、糖尿病和高血压等疾病密切相关。脂素基因三LIPIN1是诱导脂肪细胞分化、调控脂类合成的关键基因．其编码的磷脂磷酸酶（phosphatidate phosphatase,PAP）在人体三酰甘油合成中起关键作用,是维持人体脂类平衡的重要保障。此外,该基因还作为重要的转录辅激活因子参与多种生长及营养代谢调控。多种生物中均有类似功能的基因被发现,暗示了其功能的多样性及物种间的保守性。该文利用酿酒酵母在脂类代谢研究中性状易于表征、同源基因剧刖功能明确的优势,通过同源重组技术构建脂素缺陷型酵母,探索脂素基因在维持酵母正常生长及脂类合成中的重要作用,并通过功能互补及生物信息学技术对比分析了人源LIPIN1基因与酵母PdH1基因编码蛋白在结构和功能上的保守性,为脂素基因LIPIN1的细胞功能研究提供基础数据。     

AMPK相关代谢机制在非创伤性股骨头坏死中的研究进展

腺苷酸活化的蛋白激酶(AMP-activated protein kinase, AMPK)作为"人体物质能量的调节器",在肥胖症、糖尿病、高脂血症等人体代谢性疾病中起着重要的调节作用。近年来研究表明AMPK信号通路对成骨成脂分化、破骨等人体骨稳态代谢微环境具有调控作用,而骨稳态代谢微环境的失衡失调是骨质疏松症、股骨头坏死等骨病发生的重要原因之一。本文主要通过对AMPK结构、功能及其在人体脂代谢、骨代谢中的作用机制进行探讨,探析其在骨病形成中的作用,并探析其在非创伤性股骨头坏死(non-traumatic osteonecrosis of the femoral head, NONFH)中的可能作用机制,从而为NONFH的研究及靶向治疗提供理论依据。     

AMPK在机体骨骼肌运动代谢适应方面的研究进展

腺苷酸活化蛋白激酶(AMP-activated protein kinase,AMPK)作为机体细胞的"能量感受器",可通过激活其下游靶蛋白调节组织细胞糖、脂代谢过程。运动适应涉及机体多个系统和器官,其中骨骼肌在机体对运动产生的代谢适应方面的作用最为明显。运动作为对机体的一个刺激可活化组织细胞AMPK,本文将针对AMPK在机体组织对运动产生代谢适应方面的最新研究进展加以综述,以期为阐明运动防治代谢性疾病的机制提供理论依据。     

LKB1-AMPKα-SIRT1信号通路在奶牛脂肪组织脂代谢中的调控作用

奶牛脂肪细胞体积和数目的不断增加会导致脂肪组织脂代谢的紊乱,引起一系列相关慢性疾病如Ⅱ型糖尿病、酮病、脂肪肝、高脂血症等的发生,LKB1-AMPKα-SIRT1信号通路在奶牛脂肪组织脂代谢中起着重要的调控作用。单磷酸腺苷活化蛋白激酶(AMPK)是比较保守的丝氨酸/苏氨酸激酶,在调节能量代谢中起着枢纽作用。肝激酶B1(LKB1)属于一种丝氨酸激酶,是AMPKα的上游激酶,可参与细胞内能量代谢等多种生物活动。沉默信息调节因子1(SIRT1)是一种NAD+依赖的组蛋白去乙酰化酶,可通过去乙酰化LKB1增加AMPKα的活性。就LKB1-AMPKα-SIRT1信号转导通路在奶牛脂肪组织脂代谢紊乱中的调控机制作一综述,旨在为下一步研究奶牛脂代谢相关信号通路调控机理提供依据。     

MicroRNAs与脂类代谢

本文综述了miRNAs在脂类代谢调控以及脂肪酸对miRNAs影响的研究进展.miRNA能够在转录后水平参与脂类代谢的多个层面,其中miR-122、miR-370、miR33等能够通过与靶基因(Cpt1α、ABCA1等)结合,直接或间接调节细胞内脂肪酸生成、脂肪酸氧化、甘油三酯合成、胆固醇流动及脂蛋白合成等多个路径.而饮食中的脂类,尤其是必需脂肪酸,能够通过对miRNAs表达的调节参与到包括癌症抵抗、炎症缓解等多个生物学进程中.     

AMPK在肿瘤发生发展中的研究现状

单磷酸腺苷激活的蛋白质激酶(AMP-activated protein kinase,AMPK)作为真核细胞内重要的能量感受器,是一种进化上高度保守的丝氨酸/苏氨酸蛋白质激酶,能够维持和调控细胞能量动态平衡,在糖脂代谢调控的生理状态以及癌症和糖尿病等病理状态中均发挥着不可或缺的作用。随着对AMPK调控网络研究的进一步深入,发现在不同肿瘤细胞及特定发展阶段中,AMPK可能通过不同的信号通路发挥其促进和抑制肿瘤发生发展的双重功能。深入理解AMPK复杂的调控网络与癌细胞不同代谢需求之间相互作用的方式具有重要指导意义。AMPK激活剂二甲双胍(metformin)作为经典的抗糖尿病药物如今备受肿瘤界关注,但其是否依赖于AMPK发挥作用仍存在很多争议,其能否用于临床肿瘤治疗还有待进一步研究讨论。本文通过对AMPK的功能结构及其与肿瘤生长(能量代谢、自噬、死亡方式)、肿瘤转移、血管生成之间的关系进行系统阐述,并着重讨论AMPK激活剂二甲双胍与肿瘤的相关研究,旨在为靶向AMPK抑制肿瘤发生发展提供理论基础。     

奶牛乳腺脂肪酸合成相关基因研究进展

数量和种类繁多的脂肪酸构成了牛奶中不同分子量和饱和度的甘油三酯,也是乳脂的主要成分.链长不同的脂肪酸来源也不尽相同,几乎所有的短链和中链脂肪酸都由乳腺内源合成,长链脂肪酸主要是由血液中转运而来,奶牛乳腺在转运和合成脂肪酸过程中起着重要作用.近年来,研究人员将传统营养与分子生物学研究相结合,发现了大量与乳脂合成相关基因,并揭示了其功能和相互之间的作用.就奶牛乳腺的脂肪酸摄取和转运,脂肪酸的内源合成,乳腺重要酶类,脂肪酸酯化和相关基因网络调控几方面对脂肪酸合成相关基因进行归类,对其研究进展进行介绍.     

NR4A1调控系统糖脂代谢的分子机制

系统性糖脂代谢紊乱是2型糖尿病、肥胖、非酒精性脂肪性肝病等代谢综合征的主要病理生理学改变。孤核受体家族成员NR4A1广泛表达于糖和脂质代谢旺盛的组织,例如:肝、脂肪和肌肉等组织,在不同组织或细胞中,NR4A1通过不同靶点,例如:AMPK、PPARγ、SREBP1c等参与机体糖脂代谢的调控。然而,NR4A1介导的系统糖脂代谢的调控机理目前仍存在很大争议,大部分研究认为NR4A1的表达具有降糖、降脂的作用,亦有研究认为NR4A1的表达促进脂肪生成。基于目前NR4A1参与机体糖脂代谢的研究,现对NR4A1在肝脏、脂肪和肌肉中参与葡萄糖和脂质代谢调控的分子机制进行总结。     

miRNA通过PPAR和AMPK/SREBPs信号通路调控脂质代谢

机体内脂质的稳态受到多条信号通路及其交错形成的复杂网络的调节,其中过氧化物酶体增殖物激活受体(peroxisome proliferator-activated receptor,PPAR)信号通路可促进脂质生成,而腺苷酸活化的蛋白激酶(AMP-activated protein kinase,AMPK)信号通路促进脂肪酸的分解。miRNA作为一种转录后调控因子,可以调控脂质合成、分解等过程,在脂质代谢异常相关的疾病中具有重要的调控地位。本文基于61个已被报道受miRNA调控的脂质代谢相关基因,绘制这些基因之间的互作网络,从PPAR以及AMPK/SREBPs(sterol regulatory element-binding proteins)信号途径的角度综述了miRNA对脂质代谢的调控作用。     

Role of AMP-activated protein kinase in the regulation of gene transcription

AMP-activated protein kinase (AMPK) is a regulator of cellular metabolism in response to changes in the energy status of the cells. AMPK was known to shut down energy-consuming pathways in response to a fall in the ATP/AMP ratio by phosphorylating key enzymes of intermediate metabolism. Here we will discuss the recent evidence implicating AMPK in the regulation of gene expression in mammals, mainly in the liver and in the pancreatic beta-cells.     

AMP-activated protein kinase: balancing the scales

AMP-activated protein kinase (AMPK) is the central component of a protein kinase cascade that plays a key role in the regulation of energy control. AMPK is activated in response to an increase in the ratio of AMP:ATP within the cell. Activation requires phosphorylation of threonine 172 within the catalytic subunit of AMPK by an upstream kinase. The identity of the upstream kinase in the cascade remained frustratingly elusive for many years, but was recently identified as LKB1, a kinase that is inactivated in a rare hereditary form of cancer called Peutz-Jeghers syndrome. Once activated, AMPK initiates a series of responses that are aimed at restoring the energy balance within the cell. ATP-consuming, anabolic pathways, such as fatty acid synthesis and protein synthesis are switched-off, whereas ATP-generating, catabolic pathways, such as fatty acid oxidation and glycolysis, are switched-on. More recent studies have indicated, that AMPK plays an important role in the regulation of whole body energy metabolism. The adipocyte-derived hormones, leptin and adiponectin, activate AMPK in peripheral tissues, including skeletal muscle and liver, increasing energy expenditure. In the hypothalamus, AMPK is inhibited by leptin and insulin, hormones which suppress feeding, whilst ghrelin, a hormone that increases food intake, activates AMPK. Furthermore, direct pharmacological activation of AMPK in the hypothalamus by 5-aminoimidazole-4-carboxamide ribose increases food intake in rats, demonstrating that AMPK plays a direct role in the regulation of feeding. Taken together these findings indicate that AMPK has a pivotal role in regulating pathways that control both energy expenditure and energy intake.     

AMPK: a nutrient and energy sensor that maintains energy homeostasis

AMP-activated protein kinase (AMPK) is a crucial cellular energy sensor. Once activated by falling energy status, it promotes ATP production by increasing the activity or expression of proteins involved in catabolism while conserving ATP by switching off biosynthetic pathways. AMPK also regulates metabolic energy balance at the whole-body level. For example, it mediates the effects of agents acting on the hypothalamus that promote feeding and entrains circadian rhythms of metabolism and feeding behaviour. Finally, recent studies reveal that AMPK conserves ATP levels through the regulation of processes other than metabolism, such as the cell cycle and neuronal membrane excitability.     

The Opposing Actions of Target of Rapamycin and AMP-Activated Protein Kinase in Cell Growth Control

Cell growth is a highly regulated, plastic process. Its control involves balancing positive regulation of anabolic processes with negative regulation of catabolic processes. Although target of rapamycin (TOR) is a major promoter of growth in response to nutrients and growth factors, AMP-activated protein kinase (AMPK) suppresses anabolic processes in response to energy stress. Both TOR and AMPK are conserved throughout eukaryotic evolution. Here, we review the fundamentally important roles of these two kinases in the regulation of cell growth with particular emphasis on their mutually antagonistic signaling.An efficient homeostatic response to maintain cellular energy despite a noncontinuous supply of nutrients is crucial for the survival of organisms. Cells have, therefore, evolved a host of molecular pathways to sense both intra- and extracellular nutrients and thereby quickly adapt their metabolism to changing conditions. The target of rapamycin (TOR) and AMP-activated protein kinase (AMPK) signaling pathways control growth and metabolism in a complementary manner with TOR promoting anabolic processes under nutrient- and energy-rich conditions, whereas AMPK promotes a catabolic response when cells are low on nutrients and energy. Both pathways are highly conserved from yeast to human. This review summarizes the cross talk between TOR and AMPK in different organisms.     

AMPK, an active player in the control of metabolism

Impairment in the regulation of energy homeostasis and imbalance between energy intake and energy expenditure lead to many metabolic disorders and diseases such as obesity and type 2 diabetes. AMP-activated protein kinase (AMPK) is considered as a "fuel-gauge" in the cell and plays a key role in the regulation of energy metabolism. Activated by an increase in the AMP/ATP ratio, AMPK switches on catabolic pathways such as fatty acid oxidation and switches off anabolic pathways such as lipogenesis or gluconeogenesis. Insulin-sensitizing adipokines (leptin and adiponectin) and anti-diabetic drugs (thiazolidinediones and biguanides) are acting in part through the activation of AMPK. More recent findings indicate that AMPK plays also a major role in the control of whole body energy homeostasis by integrating, at the hypothalamus level, nutrient and hormonal signals that regulate food intake and energy expenditure. AMPK provides therefore a potential target for the treatment of metabolic diseases such as obesity and type II diabetes.     

Dual regulation of the AMP-activated protein kinase provides a novel mechanism for the control of creatine kinase in skeletal muscle.

The AMP-activated protein kinase (AMPK) is activated by a fall in the ATP:AMP ratio within the cell in response to metabolic stresses. Once activated, it phosphorylates and inhibits key enzymes in energy-consuming biosynthetic pathways, thereby conserving cellular ATP. The creatine kinase-phosphocreatine system plays a key role in the control of ATP levels in tissues that have a high and rapidly fluctuating energy requirement. In this study, we provide direct evidence that these two energy-regulating systems are linked in skeletal muscle. We show that the AMPK inhibits creatine kinase by phosphorylation in vitro and in differentiated muscle cells. AMPK is itself regulated by a novel mechanism involving phosphocreatine, creatine and pH. Our findings provide an explanation for the high expression, yet apparently low activity, of AMPK in skeletal muscle, and reveal a potential mechanism for the co-ordinated regulation of energy metabolism in this tissue. Previous evidence suggests that AMPK activates fatty acid oxidation, which provides a source of ATP, following continued muscle contraction. The novel regulation of AMPK described here provides a mechanism by which energy supply can meet energy demand following the utilization of the immediate energy reserve provided by the creatine kinase-phosphocreatine system.     

AMPK/mTOR信号通路的研究进展

mTOR是细胞生长和增殖的中枢调控因子。mTOR形成2个不同的复合物mTORC1和mTORC2。mTORC1受多种信号调节,如生长因子、氨基酸和细胞能量,同时,mTORC1调节许多重要的细胞过程,包括翻译、转录和自噬。AMPK作为一种关键的生理能量传感器,是细胞和有机体能量平衡的主要调节因子,协调多种代谢途径,平衡能量的供应和需求,最终调节细胞和器官的生长。能量代谢平衡调控是由多个与之相关的信号通路所介导,其中AMPK/mTOR信号通路在细胞内共同构成一个合成代谢和分解代谢过程的开关。此外,AMPK/mTOR信号通路还是一个自噬的重要调控途径。本文着重于目前对AMPK和mTOR信号传导之间关系的了解,讨论了AMPK/mTOR在细胞和有机体能量稳态中的作用。     

AMP-activated protein kinase: an emerging drug target to regulate imbalances in lipid and carbohydrate metabolism to treat cardio-metabolic diseases: Thematic Review Series: New Lipid and Lipoprotein Targets for the Treatment of Cardiometabolic Diseases

The adenosine monophosphate-activated protein kinase (AMPK) is a metabolic sensor of energy metabolism at the cellular as well as whole-body level. It is activated by low energy status that triggers a switch from ATP-consuming anabolic pathways to ATP-producing catabolic pathways. AMPK is involved in a wide range of biological activities that normalizes lipid, glucose, and energy imbalances. These pathways are dysregulated in patients with metabolic syndrome (MetS), which represents a clustering of major cardiovascular risk factors including diabetes, lipid abnormalities, and energy imbalances. Clearly, there is an unmet medical need to find a molecule to treat alarming number of patients with MetS. AMPK, with multifaceted activities in various tissues, has emerged as an attractive drug target to manage lipid and glucose abnormalities and maintain energy homeostasis. A number of AMPK activators have been tested in preclinical models, but many of them have yet to reach to the clinic. This review focuses on the structure-function and role of AMPK in lipid, carbohydrate, and energy metabolism. The mode of action of AMPK activators, mechanism of anti-inflammatory activities, and preclinical and clinical findings as well as future prospects of AMPK as a drug target in treating cardio-metabolic disease are discussed.