Levels Of Physiology Research Articles

Sustainable harvest: managing plasticity for resilient crops.

Maintaining crop production to feed a growing world population is a major challenge for this period of rapid global climate change. No consistent conceptual or experimental framework for crop plants integrates information at the levels of genome regulation, metabolism, physiology and response to growing environment. An important role for plasticity in plants is assisting in homeostasis in response to variable environmental conditions. Here, we outline how plant plasticity is facilitated by epigenetic processes that modulate chromatin through dynamic changes in DNA methylation, histone variants, small RNAs and transposable elements. We present examples of plant plasticity in the context of epigenetic regulation of developmental phases and transitions and map these onto the key stages of crop establishment, growth, floral initiation, pollination, seed set and maturation of harvestable product. In particular, we consider how feedback loops of environmental signals and plant nutrition affect plant ontogeny. Recent advances in understanding epigenetic processes enable us to take a fresh look at the crosstalk between regulatory systems that confer plasticity in the context of crop development. We propose that these insights into genotype × environment (G × E) interaction should underpin development of new crop management strategies, both in terms of information-led agronomy and in recognizing the role of epigenetic variation in crop breeding.

Allogeneic Splenocyte Transfer and Lipopolysaccharide Inhalations Induce Differential T Cell Expansion and Lung Injury: A Novel Model of Pulmonary Graft-versus-Host Disease

BackgroundPulmonary GVHD (pGVHD) is an important complication of hematopoietic cell transplant (HCT) and is thought to be a consequence of the HCT conditioning regimen, allogeneic donor cells, and posttransplant lung exposures. We have previously demonstrated that serial inhaled lipopolysaccharide (LPS) exposures potentiate the development of pGVHD after murine allogeneic HCT. In the current study we hypothesized that allogeneic lymphocytes and environmental exposures alone, in the absence of a pre-conditioning regimen, would cause features of pGVHD and would lead to a different T cell expansion pattern compared to syngeneic cells.MethodsRecipient Rag1−/− mice received a transfer of allogeneic (Allo) or syngeneic (Syn) spleen cells. After 1 week of immune reconstitution, mice received 5 daily inhaled LPS exposures and were sacrificed 72 hours after the last LPS exposure. Lung physiology, histology, and protein levels in bronchoalveolar lavage (BAL) were assessed. Lung cells were analyzed by flow cytometry.ResultsBoth Allo and Syn mice that undergo LPS exposures (AlloLPS and SynLPS) have prominent lymphocytic inflammation in their lungs, resembling pGVHD pathology, not seen in LPS-unexposed or non-transplanted controls. Compared to SynLPS, however, AlloLPS have significantly increased levels of BAL protein and enhancement of airway hyperreactivity, consistent with more severe lung injury. This injury in AlloLPS mice is associated with an increase in CD8 T cells and effector CD4 T cells, as well as a decrease in regulatory to effector CD4 T cell ratio. Additionally, cytokine analysis is consistent with a preferential Th1 differentiation and upregulation of pulmonary CCL5 and granzyme B.ConclusionsAllogeneic lymphocyte transfer into lymphocyte-deficient mice, followed by LPS exposures, causes features of pGVHD and lung injury in the absence of a pre-conditioning HCT regimen. This lung disease associated with an expansion of allogeneic effector T cells provides a novel model to dissect mechanisms of pGVHD independent of conditioning.

Potential for increased photosynthetic performance and crop productivity in response to climate change: role of CBFs and gibberellic acid.

We propose that targeting the enhanced photosynthetic performance associated with the cold acclimation of winter cultivars of rye (Secale cereale L.), wheat (Triticum aestivum L.), and Brassica napus L. may provide a novel approach to improve crop productivity under abiotic as well as biotic stress conditions. In support of this hypothesis, we provide the physiological, biochemical, and molecular evidence that the dwarf phenotype induced by cold acclimation is coupled to significant enhancement in photosynthetic performance, resistance to photoinhibition, and a decreased dependence on photoprotection through non-photochemical quenching which result in enhanced biomass production and ultimately increased seed yield. These system-wide changes at the levels of phenotype, physiology, and biochemistry appear to be governed by the family of C-repeat/dehydration-responsive family of transcription factors (CBF/DREB1). We relate this phenomenon to the semi-dwarf, gibberellic acid insensitive (GAI), cereal varieties developed during the “green revolution” of the early 1960s and 1970s. We suggest that genetic manipulation of the family of C-repeat/dehydration-responsive element binding transcription factors (CBF/DREB1) may provide a novel approach for the maintenance and perhaps even the enhancement of plant productivity under conditions of sub-optimal growth conditions predicted for our future climate.

Paradoxes in cell‐based transcriptomic and systematic research data in aging and obesity studies and the attempt of bridging (1180.1)

Transcriptomic studies unmask important molecular information at cellular levels, which may meet paradoxes in interpretation in whole body settings when hyper‐/atrophy or hyper‐/hypoplasia occurs (FASEB J 2007, 21:A1352). In an obesity study, microarray assay revealed an unaltered expression of adiponectin gene in obese adipocytes, paradoxically to the reduced plasma adiponectin (‐27%, p<0.01). After normalized with total DNA and tissue weight, we observed reduced adiponectin mRNA at the tissue level (‐26%, p<0.01), consistent with the plasma changes under the physiological control. In an aging study, Chuk (NF‐κB activator) was down‐regulated (‐20%, P<0.01), inhibitor Ikbkb gene up‐regulated (+20%, p=0.02) & NF‐κB gene (Rela) unchanged at a hepatocyte level in the enlarged, inflammatory liver, but these genes were all up‐regulated at the tissue level (+40% → +100%; p<0.02). But NF‐κB activity was not changed in the whole liver. Gstk1 & Gstk7 genes were unchanged with aging per cell, but up‐regulated at the level of whole liver (p<0.01). In contrast, GSH‐Px activity was reduced in the aged liver (p<0.01). Our studies indicate that bridging the cell‐based trancriptomic data to systems physiology levels is necessary for understanding the whole body physiological and pathological regulations, including feedback compensatory regulations and decompensation, of different biological pathways.

A method for bridging cell‐based transcriptomic and systematic data in obesity and aging studies (1180.2)

We have reported the challenges of directly interpreting transcriptomic data at systems physiology levels, when hyper‐/hypotrophy or hyper‐/hypoplasia occurs (FASEB J 2007, 21:A1352). We found (1) some gene expressions were under whole body physiological controls; (2) some reflected compensatory feedback control or decompensation at organ levels. Transgenic manipulations on a gene or genes often follow the transcriptomic studies, but may lead to non‐physiological phenotypes and non‐pathophysiological interruption of the gene regulations and the cascade of signal transduction. Here we report a method to bridge the cellular transcriptomic data and tissue/systems physiology. In obesity studies with cell hypertrophy and hyperplasia and enlarged liver and adipose tissue masses, the collected tissues were weighted in whole and in small divided pieces before freezing immediately for DNA, protein and activity tests or after being socked in RANlater for gene expression test. The total DNA and RNA concentrations were measured as the indicators of cell number, assuming that total DNA is constant per cell at normal or disease conditions. Such middle information allowed us to convert the cellular transcriptomic data under the conditions with changes in cell size and number and tissue mass to a tissue/organ level and to interpret the outcomes under the regulations of systems physiology and pathology.

Endogenous Glucocorticoids and Bone.

While the adverse effects of glucocorticoids on bone are well described, positive effects of glucocorticoids on the differentiation of osteoblasts are also observed. These paradoxical effects of glucocorticoids are dose dependent. At both physiologicaland supraphysiological levels of glucocorticoids, osteoblasts and osteocytes are the major glucocorticoid target cells. However, the response of the osteoblasts to each of these is quite distinct. At physiology levels, glucocorticoids direct mesenchymal progenitor cells to differentiate towards osteoblasts and thus increase bone formation in a positive way. In contrast with ageing, the excess production of glucocorticoids, at both systemic and intracellular levels, appear to impact on osteoblast and osteocytes in a negative way in a similar fashion to that seen with therapeutic glucocorticoids. This review will focus on therole of glucocorticoids in normal bone physiology, with particular emphasis on the mechanism by which endogenous glucocorticoids impact on bone and its constituent cells.

Inorganic Pyrophosphatase Defects Lead to Cell Cycle Arrest and Autophagic Cell Death through NAD+ Depletion in Fermenting Yeast

Inorganic pyrophosphatases are required for anabolism to take place in all living organisms. Defects in genes encoding these hydrolytic enzymes are considered inviable, although their exact nature has not been studied at the cellular and molecular physiology levels. Using a conditional mutant in IPP1, the Saccharomyces cerevisiae gene encoding the cytosolic soluble pyrophosphatase, we show that respiring cells arrest in S phase upon Ipp1p deficiency, but they remain viable and resume growth if accumulated pyrophosphate is removed. However, fermenting cells arrest in G1/G0 phase and suffer massive vacuolization and eventual cell death by autophagy. Impaired NAD(+) metabolism is a major determinant of cell death in this scenario because demise can be avoided under conditions favoring accumulation of the oxidized pyridine coenzyme. These results posit that the mechanisms related to excess pyrophosphate toxicity in eukaryotes are dependent on the energy metabolism of the cell.

Effect of a probiotic preparation (VSL#3) in critically ill patients: A randomized, double-blind, placebo-controlled trial (Pilot Study)

Objective : Reactive oxygen species (ROS) are a major contributing factor in diseases pathophysiology in critically ill patients. Oxidative stress usually occurs in critical illnesses, specifically during sepsis, and organ dysfunction. The anti-oxidative properties of probiotics may serve as a defense in intestine and overcome various oxidative stresses. The aim of this trial was to determine the effect of probiotics on inflammation, antioxidant capacity and lipid peroxidation in critically ill patients. Methodology : Forty patients admitted to the intensive care unit were enrolled in this double-blind, randomized controlled trial. They were randomized to receive placebo or probiotic for 7 days. Serum levels of Total Antioxidant Capacity (TAC), Malodialdehyde (MDA), C-Reactive Protein (CRP) and Acute Physiology and Chronic Health Evaluation (APACHE II) score were measured before initiation of the study and on the 7(th) day. There was a significant difference in CRP levels and APACHE II score between two groups at the end of the study (P= 0.003 and 0.001, respectively). There was not a significant difference in levels of TAC and MDA between two groups. Administration of probiotics to critically ill patients caused reduction in inflammation and improvement of clinical outcome. However, there were not significant changes in markers of oxidative stress.

TCF7L2 and Glucose Metabolism: Time to Look Beyond the Pancreas

Noncoding genetic variation in the locus encoding for the Wnt signaling effector TCF7L2 remains the strongest genetic determinant of type 2 diabetes (T2D) risk in humans. This association raises the hypothesis that disease variants alter the quantitative, spatial, and/or temporal expression patterns of this gene. Understanding the mechanisms by which TCF7L2 and Wnt signaling regulate glucose metabolism may reveal novel insights into the pathogenesis of T2D, as well as highlight cellular and genetic pathways amenable to becoming novel therapeutic targets. Therefore, a large body of work has emerged over the past 4 years describing previously unknown glucose metabolism roles of TCF7L2. Curiously, most of this work has focused on TCF7L2 actions in pancreatic β-cells, despite evidence that canonical Wnt signaling is not active in adult β-cells (1). The extensive evaluation of TCF7L2 actions or Wnt signaling effects in β-cells have resulted in contradictory findings at the molecular (2,3), cellular (1,4), and whole-animal physiology levels (5–7). Particularly difficult to reconcile is the incongruence of data showing that the presumed diabetogenic effects of TCF7L2 in β-cells, such as a blunted glucose-stimulated insulin secretion response, arises from reducing TCF7L2 expression (3,8). In contrast, evidence from human genetics and genomics studies suggests the risk alleles associated with T2D lead to increased expression of TCF7L2 (2,9–11), a notion recently confirmed by mouse models harboring germline null alleles …

Screening acute cytotoxicity biomarkers using a microalga as test organism

The present study checked the suitability of the integration of flow cytometry (FCM) as technique and a freshwater microalga (Chlamydomonas moewusii) as cell system model for ecotoxicological studies, looking for sensitive biomarkers of acute cytotoxicity of potential contaminants in aquatic systems. The detection of the potential acute toxicity of a pollutant is of interest because pulse discharges of contaminants to natural waters could lead to high concentrations of these substances that are only present for short periods of time but can affect aquatic organisms such as microalgae. Physiological alterations in C. moewusii cells were analysed after 1h of exposure to different concentrations of the herbicide paraquat. Cell viability was not affected, but the acute toxicity of paraquat was evident at other levels of cell physiology. Herbicide-treated cells showed lower autofluorescence and higher size and internal complexity, lower esterase activity and lower mitochondrial membrane potential. Paraquat induced the depolarisation of the plasma membrane and the increase of intracellular free calcium level and cytosolic pH in a concentration-dependent percentage of cells. All these effects can be related to the oxidative stress induced by the herbicide, as revealed the significantly increased intracellular levels of reactive oxygen species in cultures exposed to paraquat concentrations which induced the physiological alterations mentioned above. Excluding cell viability and mitochondrial membrane potential, these cytotoxicity endpoints could be considered sensitive biomarkers for the short-term exposure to pollutants such as herbicides.

Performance, Personality, and Energetics: Correlation, Causation, and Mechanism

The study of phenotypic evolution should be an integrative endeavor that combines different approaches and crosses disciplinary and phylogenetic boundaries to consider complex traits and organisms that historically have been studied in isolation from each other. Analyses of individual variation within populations can act to bridge studies focused at the levels of morphology, physiology, biochemistry, organismal performance, behavior, and life history. For example, the study of individual variation recently facilitated the integration of behavior into the concept of a pace-of-life syndrome and effectively linked the field of energetics with research on animal personality. Here, we illustrate how studies on the pace-of-life syndrome and the energetics of personality can be integrated within a physiology-performance-behavior-fitness paradigm that includes consideration of ecological context. We first introduce key concepts and definitions and then review the rapidly expanding literature on the links between energy metabolism and personality traits commonly studied in nonhuman animals (activity, exploration, boldness, aggressiveness, sociability). We highlight some empirical literature involving mammals and squamates that demonstrates how emerging fields can develop in rather disparate ways because of historical accidents and/or particularities of different kinds of organisms. We then briefly discuss potentially interesting avenues for future conceptual and empirical research in relation to motivation, intraindividual variation, and mechanisms underlying trait correlations. The integration of performance traits within the pace-of-life-syndrome concept has the potential to fill a logical gap between the context dependency of selection and how energetics and personality are expected to interrelate. Studies of how performance abilities and/or aspects of Darwinian fitness relate to both metabolic rate and personality traits are particularly lacking.

Evaluation of two dairy herd reproductive performance indicators that are adjusted for voluntary waiting period

BackgroundOverall reproductive performance of dairy herds is monitored by various indicators. Most of them do not consider all eligible animals and do not consider different management strategies at farm level. This problem can be alleviated by measuring the proportion of pregnant cows by specific intervals after their calving date or after a fixed time period, such as the voluntary waiting period. The aim of this study was to evaluate two reproductive performance indicators that consider the voluntary waiting period at the herd. The two indicators were: percentage of pregnant cows in the herd after the voluntary waiting period plus 30 days (PV30) and percentage of inseminated cows in the herd after the voluntary waiting period plus 30 days (IV30). We wanted to assess how PV30 and IV30 perform in a simulation of herds with different reproductive management and physiology and to compare them to indicators of reproductive performance that do not consider the herd voluntary waiting period.MethodsTo evaluate the reproductive indicators we used the SimHerd-program, a stochastic simulation model, and 18 scenarios were simulated. The scenarios were designed by altering the reproductive management efficiency and the status of reproductive physiology of the herd. Logistic regression models, together with receiver operating characteristics (ROC), were used to examine how well the reproductive performance indicators could discriminate between herds of different levels of reproductive management efficiency or reproductive physiology.ResultsThe logistic regression models with the ROC analysis showed that IV30 was the indicator that best discriminated between different levels of management efficiency followed by PV30, calving interval, 200-days not-in calf-rate (NotIC200), in calf rate at100-days (IC100) and a fertility index. For reproductive physiology the ROC analysis showed that the fertility index was the indicator that best discriminated between different levels, followed by PV30, NotIC200, IC100 and the calving interval. IV30 could not discriminate between the two levels.ConclusionPV30 is the single best performance indicator for estimating the level of both herd management efficiency and reproductive physiology followed by NotIC200 and IC100. This indicates that PV30 could be a potential candidate for inclusion in dairy herd improvement schemes.

An Omics Approach to Understand the Plant Abiotic Stress

Abiotic stress can lead to changes in development, productivity, and severe stress and may even threaten survival of plants. Several environmental stresses cause drastic changes in the growth, physiology, and metabolism of plants leading to the increased accumulation of secondary metabolites. As medicinal plants are important sources of drugs, steps are taken to understand the effect of stress on the physiology, biochemistry, genomic, proteomic, and metabolic levels. The molecular responses of plants to abiotic stress are often considered as a complex process. They are mainly based on the modulation of transcriptional activity of stress-related genes. Many genes have been induced under stress conditions. The products of stress-inducible genes protecting against these stresses includes the enzymes responsible for the synthesis of various osmoprotectants. Genetic engineering of tolerance to abiotic stresses help in molecular understanding of pathways induced in response to one or more of the abiotic stresses. Systems biology and virtual experiments allow visualizing and understanding how plants work to overcome abiotic stress. This review discusses the omic approach to understand the plant response to abiotic stress with special emphasis on medicinal plant.

Regulation of alpha-secretase ADAM10 expression and activity

The amyloid precursor protein (APP) has a pivotal role in pathogenesis of Alzheimer's disease (AD) via its beta- and gamma-secretase-derived cleavage products--the A-beta peptides. An alternative processing pathway provided by the alpha-secretase prevents formation of those toxic peptides and gives rise to the neurotrophic and neuroprotective cleavage product APPs-alpha. The molecular identity of the alpha-secretase has been confirmed recently, and there is consistency about ADAM10 being the most relevant and physiological enzyme of this class. It is not clear to what extent a deficiency in the catalytic activity of ADAM10 contributes to AD pathology and whether a decline occurs in aging humans. Nevertheless, ADAM10 has been suggested as a valuable target for prevention and/or for treatment of Alzheimer's disease. This review focuses on our knowledge about regulation of ADAM10 on different levels of cell physiology, such as transcription and translation, as well as protein-protein interactions and how this especially in the case of transcriptional regulation by retinoic acids might lead to the development of new therapeutic approaches.

Development of a source-to-outcome model for dietary exposures to insecticide residues: An example using chlorpyrifos

Probabilistic models of interindividual variation in exposure and response were linked to create a source-to-outcome population model. This model was used to investigate cholinesterase inhibition from dietary exposures to an insecticide (chlorpyrifos) in populations of adults and 3 year old children. A physiologically based pharmacokinetic and pharmacodynamic (PBPK/PD) model was used to calculate the variation in sensitivity occurring from interindividual variability in physiology, metabolism, and physical activity levels. A dietary intake model characterizes the variation in dietary insecticide exposures and variation in anthropometry in the populations. Published equations were used to describe the necessary physiology for each simulated individual based on the anthropometry from the dietary intake model. The model of the interindividual variation in response to chlorpyrifos was developed by performing a sensitivity analysis on the PBPK/PD model to determine the parameters that drive variation in pharmacodynamics outcomes (brain and red blood cell acetylcholinesterase inhibition). Distributions of interindividual variation were developed for parameters with the largest impact; the probabilistic model sampled from these distributions. The impact of age and interindividual variation on sensitivity at the doses that occur from dietary exposures, typically orders of magnitude lower than exposures assessed in toxicological studies, was assessed using the source-to-outcome model. The resulting simulations demonstrated that metabolic detoxification capacity was sufficient to prevent significant brain and red blood cell acetylcholinesterase inhibition, even in individuals with the lowest detoxification potential. Age-specific pharmacokinetic and pharmacodynamic parameters did not predict differences in susceptibility between adults and children. In the future, the approach of this case study could be used to assess the risks from low level exposures to other chemicals.

The genomic and physiological basis of life history variation in a butterfly metapopulation

Unravelling the mechanisms underlying variation in life history traits is of fundamental importance for our understanding of adaptation by natural selection. While progress has been made in mapping fitness-related phenotypes to genotypes, mainly in a handful of model organisms, functional genomic studies of life history adaptations are still in their infancy. In particular, despite a few notable exceptions, the genomic basis of life history variation in natural populations remains poorly understood. This is especially true for the genetic underpinnings of life history phenotypes subject to diversifying selection driven by ecological dynamics in patchy environments--as opposed to adaptations involving strong directional selection owing to major environmental changes, such as latitudinal gradients, extreme climatic events or transitions from salt to freshwater. In this issue of Molecular Ecology,Wheat et al. (2011) now make a significant leap forward by applying the tools of functional genomics to dispersal-related life history variation in a butterfly metapopulation. Using a combination of microarrays, quantitative PCR and physiological measurements, the authors uncover several metabolic and endocrine factors that likely contribute to the observed life history phenotypes. By identifying molecular candidate mechanisms of fitness variation maintained by dispersal dynamics in a heterogeneous environment,they also begin to address fascinating interactions between the levels of physiology, ecology and evolution.

Evening exposure to a light-emitting diodes (LED)-backlit computer screen affects circadian physiology and cognitive performance

Many people spend an increasing amount of time in front of computer screens equipped with light-emitting diodes (LED) with a short wavelength (blue range). Thus we investigated the repercussions on melatonin (a marker of the circadian clock), alertness, and cognitive performance levels in 13 young male volunteers under controlled laboratory conditions in a balanced crossover design. A 5-h evening exposure to a white LED-backlit screen with more than twice as much 464 nm light emission {irradiance of 0,241 Watt/(steradian × m(2)) [W/(sr × m(2))], 2.1 × 10(13) photons/(cm(2) × s), in the wavelength range of 454 and 474 nm} than a white non-LED-backlit screen [irradiance of 0,099 W/(sr × m(2)), 0.7 × 10(13) photons/(cm(2) × s), in the wavelength range of 454 and 474 nm] elicited a significant suppression of the evening rise in endogenous melatonin and subjective as well as objective sleepiness, as indexed by a reduced incidence of slow eye movements and EEG low-frequency activity (1-7 Hz) in frontal brain regions. Concomitantly, sustained attention, as determined by the GO/NOGO task; working memory/attention, as assessed by "explicit timing"; and declarative memory performance in a word-learning paradigm were significantly enhanced in the LED-backlit screen compared with the non-LED condition. Screen quality and visual comfort were rated the same in both screen conditions, whereas the non-LED screen tended to be considered brighter. Our data indicate that the spectral profile of light emitted by computer screens impacts on circadian physiology, alertness, and cognitive performance levels. The challenge will be to design a computer screen with a spectral profile that can be individually programmed to add timed, essential light information to the circadian system in humans.

Soluble CD40 ligand is not solely related to the presence and severity of sepsis

We read with interest the recently published paper by Lorente and colleagues reporting that levels of soluble CD40 ligand (CD40L) are increased in septic patients compared with healthy controls and that increased circulating CD40L levels may be an independent predic tor of mortality in patients with sepsis [1]. Th e relation ship between platelets and soluble CD40L seen in this study is consistent with previous data showing that soluble CD40L is mainly released from activated platelets and mediates neutrophil-induced lung injury in sepsis [2]. We believe that the functional role of soluble CD40L is complex, however, and not solely related to the presence of sepsis or its severity. Th is is indicated in the study by Lorente and colleagues, in which no associations were found between soluble levels of CD40L and Acute Physiology and Chronic Health Evaluation scores, Sequential Organ Failure Assessment scores, and TNF and IL-10 levels [1], which is in agreement with previous fi ndings [3,4]. Further, although the study was conducted in patients with sepsis, we suggest that soluble CD40L is a common denominator for patients with shock, rather than with sepsis per se. Th us, in a study of critically ill patients admitted to the intensive care unit with shock due to diff erent aetiologies, we found no diff erences in the levels of soluble CD40L between septic and nonseptic shock patients [4]. Th e relevance of soluble CD40L as a potential therapeutic target for sepsis therefore remains to be explored. We suggest that targeting CD40L in order to ameliorate pathological infl ammatory responses is not limited to septic patients but also includes nonseptic shock patients.

The origins and evolution of genetic disease risk in modern humans

Patterns and risks of human disease have evolved. In this article, I review evidence regarding the importance of recent adaptive evolution, positive selection, and genomic conflicts in shaping the genetic and phenotypic architectures of polygenic human diseases. Strong recent selection in human populations can create and maintain genetically based disease risk primarily through three processes: increased scope for dysregulation from recent human adaptations, divergent optima generated by intraspecific genomic conflicts, and transient or stable deleterious by-products of positive selection caused by antagonistic pleiotropy, ultimately due to trade-offs at the levels of molecular genetics, development, and physiology. Human disease due to these processes appears to be concentrated in three sets of phenotypes: cognition and emotion, reproductive traits, and life-history traits related to long life-span. Diverse, convergent lines of evidence suggest that a small set of tissues whose pleiotropic patterns of gene function and expression are under especially strong selection-brain, placenta, testis, prostate, breast, and ovary-has mediated a considerable proportion of disease risk in modern humans.

FATP2 is a hepatic fatty acid transporter and peroxisomal very long-chain acyl-CoA synthetase

Fatty acid transport protein (FATP)2, a member of the FATP family of fatty acid uptake mediators, has independently been identified as a hepatic peroxisomal very long-chain acyl-CoA synthetase (VLACS). Here we address whether FATP2 is 1) a peroxisomal enzyme, 2) a plasma membrane-associated long-chain fatty acid (LCFA) transporter, or 3) a multifunctional protein. We found that, in mouse livers, only a minor fraction of FATP2 localizes to peroxisomes, where it contributes to approximately half of the peroxisomal VLACS activity. However, total hepatic (V)LACS activity was not significantly affected by loss of FATP2, while LCFA uptake was reduced by 40%, indicating a more prominent role in hepatic LCFA uptake. This suggests FATP2 as a potential target for a therapeutic intervention of hepatosteatosis. Adeno-associated virus 8-based short hairpin RNA expression vectors were used to achieve liver-specific FATP2 knockdown, which significantly reduced hepatosteatosis in the face of continued high-fat feeding, concomitant with improvements in liver physiology, fasting glucose, and insulin levels. Based on our findings, we propose a model in which FATP2 is a multifunctional protein that shows subcellular localization-dependent activity and is a major contributor to peroxisomal (V)LACS activity and hepatic fatty acid uptake, suggesting FATP2 as a potential novel target for the treatment of nonalcoholic fatty liver disease.