MAPK signalling in cellular metabolism: stress or wellness?

Mitogen-activated protein kinase (MAPK) signalling occurs in response to almost any change in the extracellular or intracellular milieu that affects the metabolism of the cell, organ or the entire organism. MAPK-dependent signal transduction is required for physiological metabolic adaptation, but inappropriate MAPK signalling contributes to the development of several interdependent pathological traits, collectively known as metabolic syndrome. Metabolic syndrome leads to life-threatening clinical consequences, such as type 2 diabetes. This Review provides an overview of the MAPK-signalling mechanisms that underly basic cellular metabolism, discussing their link to disease.     

Coordinated activation of metabolic pathways for antioxidants and defence compounds by jasmonates and their roles in stress tolerance in Arabidopsis

Jasmonic acid (JA) and methyl jasmonate (MeJA), collectively termed jasmonates, are ubiquitous plant signalling compounds. Several types of stress conditions, such as wounding and pathogen infection, cause endogenous JA accumulation and the expression of jasmonate-responsive genes. Although jasmonates are important signalling components for the stress response in plants, the mechanism by which jasmonate signalling contributes to stress tolerance has not been clearly defined. A comprehensive analysis of jasmonate-regulated metabolic pathways in Arabidopsis was performed using cDNA macroarrays containing 13516 expressed sequence tags (ESTs) covering 8384 loci. The results showed that jasmonates activate the coordinated gene expression of factors involved in nine metabolic pathways belonging to two functionally related groups: (i) ascorbate and glutathione metabolic pathways, which are important in defence responses to oxidative stress, and (ii) biosynthesis of indole glucosinolate, which is a defence compound occurring in the Brassicaceae family. We confirmed that JA induces the accumulation of ascorbate, glutathione and cysteine and increases the activity of dehydroascorbate reductase, an enzyme in the ascorbate recycling pathway. These antioxidant metabolic pathways are known to be activated under oxidative stress conditions. Ozone (O3) exposure, a representative oxidative stress, is known to cause activation of antioxidant metabolism. We showed that O3 exposure caused the induction of several genes involved in antioxidant metabolism in the wild type. However, in jasmonate-deficient Arabidopsis 12-oxophytodienoate reductase 3 (opr3) mutants, the induction of antioxidant genes was abolished. Compared with the wild type, opr3 mutants were more sensitive to O3 exposure. These results suggest that the coordinated activation of the metabolic pathways mediated by jasmonates provides resistance to environmental stresses.     

PPARA/RXRA signalling regulates the fate of hepatic non-esterified fatty acids in a sheep model of maternal undernutrition

Maternal undernutrition during late gestation accelerates body fat mobilization to provide more energy for foetal growth and development, which unbalances metabolic homeostasis and results in serious lipid metabolism disorder. However, detailed regulatory mechanisms are poorly understood. Here, a sheep model was used to explore the regulatory role of PPARA/RXRA signalling in hepatic lipid metabolism in undernutrition based on RNA sequencing and cell experiments. KOG function classification showed that lipid transport and metabolism was markedly altered in an undernourished model. In detail, when compared with the controls, fatty acid transport and oxidation and triglyceride metabolism were up-regulated in an undernourished model, while fatty acid synthesis, steroid synthesis, and phospholipid metabolism were down-regulated. Kyoto Encyclopaedia of Genes and Genomes (KEGG) pathway analysis demonstrated that PPARA/RXRA signalling pathway was altered. Moreover, PPARA signalling associated genes were positively correlated with hepatic non-esterified fatty acid (NEFA) levels, while retinol metabolism associated genes were negatively correlated with blood beta-hydroxybutyric acid (BHBA) levels. Results of primary hepatocytes showed that NEFAs could activate PPARA signalling and facilitate fatty acid oxidation (FAO) and ketogenesis, while BHBA could inhibit RXRA signalling and repress FAO and ketogenesis. Excessively accumulated NEFAs in hepatocytes promoted triglyceride synthesis. Furthermore, activation of PPARA/RXRA signalling by WY14643 and 9-cis-retinoic acid could enhance FAO and ketogenesis and reduce NEFAs accumulation and esterification. Our findings elucidate the regulatory mechanisms of NEFAs and BHBA on lipid metabolism as well as the potential role of the PPARA/RXRA signalling pathway in hepatic lipid metabolism, which may contribute to exploring new strategies to maintain lipid metabolic homeostasis in human beings.     

The TOR signalling network from yeast to man

The target of rapamycin, TOR, is an essential ser/thr protein kinase that functions in two distinct multiprotein complexes, TOR complex 1 and 2. The structure and functions of these complexes have been conserved from yeast to man. TOR complex 1 is inhibited by rapamycin and is thought to couple growth cues to cellular metabolism; TOR complex 2 is not inhibited by rapamycin and appears to regulate spatial aspects of growth such as cell polarity. Work done in a variety of model systems, continues to contribute to our current understanding of this TOR signalling network. Recent studies in flies and mammalian tissue culture cells have elucidated many signalling components upstream of TOR complex 1. These studies also suggest that aberrant mammalian TOR complex 1 signalling contributes to a number of pathologies ranging from metabolic diseases to hyperproliferative disorders and cancers. Consequently the efficacies of rapamycin and related compounds in treating such diseases are being evaluated in clinical trials.     

内质网应激与肝细胞脂类代谢

肝细胞担负大量的代谢功能,包括脂肪酸的合成与类固醇的代谢。内质网应激反应（ERstressresponse）作为内质网中特殊的机制用以保证内质网内部的稳态和功能正常。有研究指出内质网应激诱导的信号通路及其通路上的关键蛋白参与肝细胞的脂类代谢过程。本文主要讨论内质网应激反应影响肝细胞脂类代谢的机制,以及内质网应激与脂类代谢紊乱疾病的相关性。     

Oxyl radicals, redox-sensitive signalling cascades and antioxidants

Oxidative stress is an increase in the reduction potential or a large decrease in the reducing capacity of the cellular redox couples. A particularly destructive aspect of oxidative stress is the production of reactive oxygen species (ROS), which include free radicals and peroxides. Some of the less reactive of these species can be converted by oxidoreduction reactions with transition metals into more aggressive radical species that can cause extensive cellular damage. In animals, ROS may influence cell proliferation, cell death (either apoptosis or necrosis) and the expression of genes, and may be involved in the activation of several signalling pathways, activating cell signalling cascades, such as those involving mitogen-activated protein kinases. Most of these oxygen-derived species are produced at a low level by normal aerobic metabolism and the damage they cause to cells is constantly repaired. The cellular redox environment is preserved by enzymes and antioxidants that maintain the reduced state through a constant input of metabolic energy. This review summarizes current studies that have been regarding the production of ROS and the general redox-sensitive targets of cell signalling cascades.     

PKB and the mitochondria: AKTing on apoptosis

Cellular homeostasis depends upon the strict regulation of responses to external stimuli, such as signalling cascades triggered by nutrients and growth factors, and upon cellular metabolism. One of the major molecules coordinating complex signalling pathways is protein kinase B (PKB), a serine/threonine kinase also known as Akt. The number of substrates known to be phosphorylated by PKB and its interacting partners, as well as our broad understanding of how PKB is implicated in responses to growth factors, metabolic pathways, proliferation, and cell death via apoptosis is constantly increasing. Activated by the insulin/growth factor-phosphatidylinositol 3-kinase (PI3K) cascade, PKB triggers events that promote cell survival and prevent apoptosis. It is also now widely accepted that mitochondria are not just suppliers of ATP, but that they participate in regulatory and signalling events, responding to multiple physiological inputs and genetic stresses, and regulate both cell proliferation and death. Thus, mitochondria are recognized as important players in apoptotic events and it is logical to predict some form of interplay with PKB. In this review, we will summarize mechanisms by which PKB mediates its anti-apoptotic activities in cells and survey recent developments in understanding mitochondrial dynamics and their role during apoptosis.     

Glucose induces an autocrine activation of the Wnt/beta-catenin pathway in macrophage cell lines

The canonical Wnt signalling pathway acts by slowing the rate of ubiquitin-mediated beta-catenin degradation. This results in the accumulation and subsequent nuclear translocation of beta-catenin, which induces the expression of a number of genes involved in growth, differentiation and metabolism. The mechanisms regulating the Wnt signalling pathway in the physiological context is still not fully understood. In the present study we provide evidence that changes in glucose levels within the physiological range can acutely regulate the levels of beta-catenin in two macrophage cell lines (J774.2 and RAW264.7 cells). In particular we find that glucose induces these effects by promoting an autocrine activation of Wnt signalling that is mediated by the hexosamine pathway and changes in N-linked glycosylation of proteins. These studies reveal that the Wnt/beta-catenin system is a glucose-responsive signalling system and as such is likely to play a role in pathways involved in sensing changes in metabolic status.     

Effect of diazepam treatment on metabolic indices in trained and untrained rats

Exercise training, like diazepam, is commonly employed as a means of reducing anxiety. Both diazepam and exercise training have been shown to modify carbohydrate and lipid metabolism as well as influence calcium metabolism in skeletal muscle. As receptor binding and thereby efficacy of diazepam has been demonstrated to be modulated by the lipid environment of the receptor, and changes in calcium levels can affect a number of intracellular signalling pathways, we sought to determine if the interaction of both chronic diazepam and exercise training would modify selected metabolic indices in an animal model. For this purpose, muscle and liver glycogen, blood glucose and plasma free fatty acids (FFA) were measured in sedentary, exercise trained and exercise trained, acutely exhausted animals. Alterations in lipid and carbohydrate metabolism were observed in all experimental groups. Diazepam treatment alone exerts metabolic consequences, such as elevated muscle glycogen and plasma FFA and depressed blood glucose levels, which are similar to those observed with exercise training. When animals are acutely exercised to exhaustion, however, differences appear, including a reduced rise in plasma FFA, which suggests that long-term diazepam treatment does influence exercise metabolism, possibly as a result of effects on the sympatho-adrenal system.     

Methionine supplementation stimulates mitochondrial respiration

Mitochondria play essential metabolic functions in eukaryotes. Although their major role is the generation of energy in the form of ATP, they are also involved in maintenance of cellular redox state, conversion and biosynthesis of metabolites and signal transduction. Most mitochondrial functions are conserved in eukaryotic systems and mitochondrial dysfunctions trigger several human diseases.By using multi-omics approach, we investigate the effect of methionine supplementation on yeast cellular metabolism, considering its role in the regulation of key cellular processes. Methionine supplementation induces an up-regulation of proteins related to mitochondrial functions such as TCA cycle, electron transport chain and respiration, combined with an enhancement of mitochondrial pyruvate uptake and TCA cycle activity. This metabolic signature is more noticeable in cells lacking Snf1/AMPK, the conserved signalling regulator of energy homeostasis. Remarkably, snf1Δ cells strongly depend on mitochondrial respiration and suppression of pyruvate transport is detrimental for this mutant in methionine condition, indicating that respiration mostly relies on pyruvate flux into mitochondrial pathways.These data provide new insights into the regulation of mitochondrial metabolism and extends our understanding on the role of methionine in regulating energy signalling pathways.     

Regulatory network of tetrapyrrole biosynthesis – studies of intracellular signalling involved in metabolic and developmental control of plastids

Plant tetrapyrrole metabolism is located in two different organelles and distributes end products into the whole cell. A complex regulatory network is involved to prevent metabolic imbalance and inefficient allocation of intermediates as well as to correlate the metabolic activities with organelle development. This review presents new findings about the control of tetrapyrrole biosynthesis and addresses the question of which regulatory principles are involved in controlling the expression of the participating enzymes and the metabolic flow in the entire pathway. It is suggested that functional organelles are required for nuclear gene expression and that metabolic signals participate in a signalling cascade transferring information from plastids to the nucleus. Recent reports about plastid-localised control mechanisms for plant tetrapyrrole metabolism are summarised and compared with results obtained in experiments on nucleus-plastid communication.     

Aspects of astrocyte energy metabolism,amino acid neurotransmitter homoeostasis and metabolic compartmentation

Astrocytes are key players in brain function; they are intimately involved in neuronal signalling processes and their metabolism is tightly coupled to that of neurons. In the present review, we will be concerned with a discussion of aspects of astrocyte metabolism, including energy-generating pathways and amino acid homoeostasis. A discussion of the impact that uptake of neurotransmitter glutamate may have on these pathways is included along with a section on metabolic compartmentation.