Browsing by Subject "metabolism"

Now showing 1 - 9 of 9
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    3'UTR shortening of HAS2 promotes hyaluronan hyper-synthesis and bioenergetic dysfunction in pulmonary hypertension.
    (Matrix biology : journal of the International Society for Matrix Biology, 2022-06-04) Tseng, Victor; Collum, Scott D; Allawzi, Ayed; Crotty, Kathryn; Yeligar, Samantha; Trammell, Aaron; Ryan Smith, M; Kang, Bum-Yong; Sutliff, Roy L; Ingram, Jennifer L; Jyothula, Soma SSK; Thandavarayan, Rajarajan A; Huang, Howard J; Nozik, Eva S; Wagner, Eric J; Michael Hart, C; Karmouty-Quintana, Harry
    Pulmonary hypertension (PH) comprises a diverse group of disorders that share a common pathway of pulmonary vascular remodeling leading to right ventricular failure. Development of anti-remodeling strategies is an emerging frontier in PH therapeutics that requires a greater understanding of the interactions between vascular wall cells and their extracellular matrices. The ubiquitous matrix glycan, hyaluronan (HA), is markedly elevated in lungs from patients and experimental models with PH. Herein, we identified HA synthase-2 (HAS2) in the pulmonary artery smooth muscle cell (PASMC) layer as a predominant locus of HA dysregulation. HA upregulation involves depletion of NUDT21, a master regulator of alternative polyadenylation, resulting in 3'UTR shortening and hyper-expression of HAS2. The ensuing increase of HAS2 and hyper-synthesis of HA promoted bioenergetic dysfunction of PASMC characterized by impaired mitochondrial oxidative capacity and a glycolytic shift. The resulting HA accumulation stimulated pro-remodeling phenotypes such as cell proliferation, migration, apoptosis-resistance, and stimulated pulmonary artery contractility. Transgenic mice, mimicking HAS2 hyper-synthesis in smooth muscle cells, developed spontaneous PH, whereas targeted deletion of HAS2 prevented experimental PH. Pharmacological blockade of HAS2 restored normal bioenergetics in PASMC, ameliorated cell remodeling phenotypes, and reversed experimental PH in vivo. In summary, our results uncover a novel mechanism of HA hyper-synthesis and downstream effects on pulmonary vascular cell metabolism and remodeling.
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    Combined Inflammation and Metabolism Biomarker Indices of Robust and Impaired Physical Function in Older Adults.
    (Journal of the American Geriatrics Society, 2018-05-08) Zuo, Xintong; Luciano, Alison; Pieper, Carl F; Bain, James R; Kraus, Virginia B; Kraus, William E; Morey, Miriam C; Cohen, Harvey J
    To determine whether combinations of inflammatory markers are related to physical function.secondary analysis of baseline of three observational studies of community-dwelling older adults MEASUREMENTS: The baseline data from 3 cohorts of older adults with different health and disease status were employed. Twenty markers of inflammation and metabolism were individually assessed for correlation with usual gait speed and were separated into robust and impairment quartiles. For the robustness and impairment indices, individual markers were selected using step-wise regression over bootstrapping iterations, and regression coefficients were estimated for the markers individually and collectively as an additive score.We developed a robustness index involving 6 markers and an impairment index involving 8 markers corresponding positively and negatively with gait speed. Two markers, glycine and tumor necrosis factor receptor 1 (TNFR1), appeared only in the robustness index, and TNFR2; regulated on activation, normal T-cell expressed and secreted; the amino acid factor; and matrix metallopeptidase 3; appeared only in the impairment index.Indices of biomarkers were associated with robust and impaired physical performance but differ, in composition suggesting potential biological differences that may contribute to robustness and impairment.
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    Genomic deletion of GIT2 induces a premature age-related thymic dysfunction and systemic immune system disruption.
    (Aging (Albany NY), 2017-03-04) Siddiqui, Sana; Lustig, Ana; Carter, Arnell; Sankar, Mathavi; Daimon, Caitlin M; Premont, Richard T; Etienne, Harmonie; van Gastel, Jaana; Azmi, Abdelkrim; Janssens, Jonathan; Becker, Kevin G; Zhang, Yongqing; Wood, William; Lehrmann, Elin; Martin, James G; Martin, Bronwen; Taub, Dennis D; Maudsley, Stuart
    Recent research has proposed that GIT2 (G protein-coupled receptor kinase interacting protein 2) acts as an integrator of the aging process through regulation of 'neurometabolic' integrity. One of the commonly accepted hallmarks of the aging process is thymic involution. At a relatively young age, 12 months old, GIT2(-/-) mice present a prematurely distorted thymic structure and dysfunction compared to age-matched 12 month-old wild-type control (C57BL/6) mice. Disruption of thymic structure in GIT2(-/-) (GIT2KO) mice was associated with a significant reduction in the expression of the cortical thymic marker, Troma-I (cytokeratin 8). Double positive (CD4(+)CD8(+)) and single positive CD4(+) T cells were also markedly reduced in 12 month-old GIT2KO mice compared to age-matched control wild-type mice. Coincident with this premature thymic disruption in GIT2KO mice was the unique generation of a novel cervical 'organ', i.e. 'parathymic lobes'. These novel organs did not exhibit classical peripheral lymph node-like characteristics but expressed high levels of T cell progenitors that were reflexively reduced in GIT2KO thymi. Using signaling pathway analysis of GIT2KO thymus and parathymic lobe transcriptomic data we found that the molecular signaling functions lost in the dysfunctional GIT2KO thymus were selectively reinstated in the novel parathymic lobe - suggestive of a compensatory effect for the premature thymic disruption. Broader inspection of high-dimensionality transcriptomic data from GIT2KO lymph nodes, spleen, thymus and parathymic lobes revealed a systemic alteration of multiple proteins (Dbp, Tef, Per1, Per2, Fbxl3, Ddit4, Sin3a) involved in the multidimensional control of cell cycle clock regulation, cell senescence, cellular metabolism and DNA damage. Altered cell clock regulation across both immune and non-immune tissues therefore may be responsible for the premature 'aging' phenotype of GIT2KO mice.
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    GIT2 Acts as a Systems-Level Coordinator of Neurometabolic Activity and Pathophysiological Aging.
    (Front Endocrinol (Lausanne), 2015) Martin, Bronwen; Chadwick, Wayne; Janssens, Jonathan; Premont, Richard T; Schmalzigaug, Robert; Becker, Kevin G; Lehrmann, Elin; Wood, William H; Zhang, Yongqing; Siddiqui, Sana; Park, Sung-Soo; Cong, Wei-Na; Daimon, Caitlin M; Maudsley, Stuart
    Aging represents one of the most complicated and highly integrated somatic processes. Healthy aging is suggested to rely upon the coherent regulation of hormonal and neuronal communication between the central nervous system and peripheral tissues. The hypothalamus is one of the main structures in the body responsible for sustaining an efficient interaction between energy balance and neurological activity and therefore likely coordinates multiple systems in the aging process. We previously identified, in hypothalamic and peripheral tissues, the G protein-coupled receptor kinase interacting protein 2 (GIT2) as a stress response and aging regulator. As metabolic status profoundly affects aging trajectories, we investigated the role of GIT2 in regulating metabolic activity. We found that genomic deletion of GIT2 alters hypothalamic transcriptomic signatures related to diabetes and metabolic pathways. Deletion of GIT2 reduced whole animal respiratory exchange ratios away from those related to primary glucose usage for energy homeostasis. GIT2 knockout (GIT2KO) mice demonstrated lower insulin secretion levels, disruption of pancreatic islet beta cell mass, elevated plasma glucose, and insulin resistance. High-dimensionality transcriptomic signatures from islets isolated from GIT2KO mice indicated a disruption of beta cell development. Additionally, GIT2 expression was prematurely elevated in pancreatic and hypothalamic tissues from diabetic-state mice (db/db), compared to age-matched wild type (WT) controls, further supporting the role of GIT2 in metabolic regulation and aging. We also found that the physical interaction of pancreatic GIT2 with the insulin receptor and insulin receptor substrate 2 was diminished in db/db mice compared to WT mice. Therefore, GIT2 appears to exert a multidimensional "keystone" role in regulating the aging process by coordinating somatic responses to energy deficits.
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    Metabolic Changes with Base-Loading in CKD.
    (Clinical journal of the American Society of Nephrology : CJASN, 2018-06-22) Scialla, Julia J; Scialla, Julia J; Brown, Landon; Gurley, Susan; Corcoran, David L; Bain, James R; Muehlbauer, Michael J; O'Neal, Sara K; M O'Connell, Thomas; Wolf, Myles; Melamed, Michal L; Hostetter, Thomas H; Abramowitz, Matthew K
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    Metabolomic Profiling Identifies Novel Circulating Biomarkers of Mitochondrial Dysfunction Differentially Elevated in Heart Failure With Preserved Versus Reduced Ejection Fraction: Evidence for Shared Metabolic Impairments in Clinical Heart Failure.
    (J Am Heart Assoc, 2016-07-29) Hunter, Wynn G; Kelly, Jacob P; McGarrah, Robert W; Khouri, Michel G; Craig, Damian; Haynes, Carol; Ilkayeva, Olga; Stevens, Robert D; Bain, James R; Muehlbauer, Michael J; Newgard, Christopher B; Felker, G Michael; Hernandez, Adrian F; Velazquez, Eric J; Kraus, William E; Shah, Svati H
    BACKGROUND: Metabolic impairment is an important contributor to heart failure (HF) pathogenesis and progression. Dysregulated metabolic pathways remain poorly characterized in patients with HF and preserved ejection fraction (HFpEF). We sought to determine metabolic abnormalities in HFpEF and identify pathways differentially altered in HFpEF versus HF with reduced ejection fraction (HFrEF). METHODS AND RESULTS: We identified HFpEF cases, HFrEF controls, and no-HF controls from the CATHGEN study of sequential patients undergoing cardiac catheterization. HFpEF cases (N=282) were defined by left ventricular ejection fraction (LVEF) ≥45%, diastolic dysfunction grade ≥1, and history of HF; HFrEF controls (N=279) were defined similarly, except for having LVEF <45%. No-HF controls (N=191) had LVEF ≥45%, normal diastolic function, and no HF diagnosis. Targeted mass spectrometry and enzymatic assays were used to quantify 63 metabolites in fasting plasma. Principal components analysis reduced the 63 metabolites to uncorrelated factors, which were compared across groups using ANCOVA. In basic and fully adjusted models, long-chain acylcarnitine factor levels differed significantly across groups (P<0.0001) and were greater in HFrEF than HFpEF (P=0.0004), both of which were greater than no-HF controls. We confirmed these findings in sensitivity analyses using stricter inclusion criteria, alternative LVEF thresholds, and adjustment for insulin resistance. CONCLUSIONS: We identified novel circulating metabolites reflecting impaired or dysregulated fatty acid oxidation that are independently associated with HF and differentially elevated in HFpEF and HFrEF. These results elucidate a specific metabolic pathway in HF and suggest a shared metabolic mechanism in HF along the LVEF spectrum.
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    Progress and challenges in the biology of FNDC5 and irisin.
    (Endocrine reviews, 2021-01-25) Maak, Steffen; Norheim, Frode; Drevon, Christian A; Erickson, Harold P
    In 2002, a transmembrane protein now known as FNDC5 was discovered and shown to be expressed in skeletal muscle, heart and brain. It was virtually ignored for 10 years, until a study in 2012 proposed that, in response to exercise, the ectodomain of skeletal muscle FNDC5 was cleaved,traveled to white adipose tissue and induced browning. The wasted energy of this browning raised the possibility that this myokine, named irisin, might mediate some beneficial effects of exercise. Since then, more than 1,000 papers have been published exploring the roles of irisin. A major interest has been on adipose tissue and metabolism, following up the major proposal from 2012. Many studies correlating plasma irisin levels with physiological conditions are questioned for use of flawed assays for irisin concentration. However, experiments altering irisin levels by injecting recombinant irisin or by gene knockout are more promising. Recent discoveries have suggested potential roles of irisin to bone remodeling and to brain, with effects potentially related to Alzheimer's disease. We also discuss some discrepancies between research groups and mechanisms that need to be determined. Some important questions raised in the initial discovery of irisin like the role of the mutant start codon of human FNDC5, the mechanism of ectodomain cleavage remain to be answered. Apart from these specific questions, a promising new tool has been developed - mice with a global or tissue-specific knockout of FNDC5. In this review, we critically examine the current knowledge and delineate potential solutions to resolve existing ambiguities.
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    Regulation of Adaptive Immune Cells by Sirtuins
    (Frontiers in Endocrinology, 2019-07-11) Warren, Jonathan L; MacIver, Nancie J
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    Type-2 diabetes, pancreatic amylin and neuronal metabolic remodeling in Alzheimer's Disease.
    (Mol Nutr Food Res, 2023-01-28) Leibold, Noah; Bain, James R; Despa, Florin
    Type-2 diabetes raises the risk for Alzheimer's disease (AD)-type dementia and the conversion from mild cognitive impairment to dementia, yet mechanisms connecting type-2 diabetes to AD remain largely unknown. Amylin, a pancreatic β-cell hormone co-secreted with insulin, participates in the central regulation of satiation, but also forms pancreatic amyloid in persons with type-2 diabetes and synergistically interacts with brain amyloid β (Aβ) pathology, in both sporadic and familial Alzheimer's disease (AD). Growing evidence from studies of tumor growth, together with early observations in skeletal muscle, indicate amylin as a potential trigger of cellular metabolic reprogramming. Because the blood, cerebrospinal fluid, and brain parenchyma in humans with AD have increased concentrations of amylin, amylin-mediated pathological processes in the brain may involve neuronal metabolic remodeling. We summarize recent progress in understanding the link between prediabetic hypersecretion of amylin and risk of neuronal metabolic remodeling and AD and suggest nutritional and medical effects of food constituents that might prevent and/or ameliorate amylin-mediated neuronal metabolic remodeling. This article is protected by copyright. All rights reserved.