Inborn errors of metabolism (IEMs) occur with high incidence in human populations. Especially prevalent among these are inborn deficiencies in fatty acid β-oxidation (FAO), which are clinically ...associated with developmental neuropsychiatric disorders, including autism. We now report that neural stem cell (NSC)-autonomous insufficiencies in the activity of TMLHE (an autism risk factor that supports long-chain FAO by catalyzing carnitine biosynthesis), of CPT1A (an enzyme required for long-chain FAO transport into mitochondria), or of fatty acid mobilization from lipid droplets reduced NSC pools in the mouse embryonic neocortex. Lineage tracing experiments demonstrated that reduced flux through the FAO pathway potentiated NSC symmetric differentiating divisions at the expense of self-renewing stem cell division modes. The collective data reveal a key role for FAO in controlling NSC-to-IPC transition in the mammalian embryonic brain and suggest NSC self renewal as a cellular mechanism underlying the association between IEMs and autism.
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•TMLHE controls the neural stem cell (NSC) pool in the embryonic mouse neocortex•CPT1A and fatty acid mobilization from lipid droplets regulate the NSC pool•TMLHE deficiencies lead to increased symmetric differentiating division of NSCs•NSC defects under TMLHE deficiencies can be rescued by exogenous carnitine
The mechanisms underlying the association between inborn errors of fatty acid metabolism and developmental brain disorders such as autism remain unclear. Xie et al. find that TMLHE, a carnitine biosynthesis enzyme, and carnitine-dependent long-chain fatty acid β-oxidation control the neural stem cell pool during neocortical development by maintaining self-renewing divisions.
Key tissues are dysfunctional in obesity, diabetes, cardiovascular disease, fatty liver and other metabolic diseases. Focus has centered on individual organs as though each was isolated. Attention ...has been paid to insulin resistance as the key relevant pathosis, particularly insulin receptor signaling. However, many tissues play important roles in synergistically regulating metabolic homeostasis and should be considered part of a network. Our approach identifies redox as an acute regulator of the greater metabolic network. Redox reactions involve the transfer of electrons between two molecules and in this work refer to commonly shared molecules, reflective of energy state, that can readily lose electrons to increase or gain electrons to decrease the oxidation state of molecules including NAD(P), NAD(P)H, and thiols. Metabolism alters such redox molecules to impact metabolic function in many tissues, thus, responding to anabolic and catabolic stimuli appropriately and synergistically. It is also important to consider environmental factors that have arisen or increased in recent decades as putative modifiers of redox and reactive oxygen species (ROS) and thus metabolic state. ROS are highly reactive, controlled by the thiol redox state and influence the function of thousands of proteins. Lactate (L) and pyruvate (P) in cells are present in a ratio of about 10 reflective of the cytosolic NADH to NAD ratio. Equilibrium is maintained in cells because lactate dehydrogenase is highly expressed and near equilibrium. The major source of circulating lactate and pyruvate is muscle, although other tissues also contribute. Acetoacetate (A) is produced primarily by liver mitochondria where β-hydroxybutyrate dehydrogenase is highly expressed, and maintains a ratio of β-hydroxybutyrate (β) to A of about 2, reflective of the mitochondrial NADH to NAD ratio. All four metabolites as well as the thiols, cysteine and glutathione, are transported into and out of cells, due to high expression of relevant transporters. Our model supports regulation of all collaborating metabolic organs through changes in circulating redox metabolites, regardless of whether change was initiated exogenously or by a single organ. Validation of these predictions suggests novel ways to understand function by monitoring and impacting redox state.
The Night the Spirit Moved Uncle Elijah Okonkwo, Jude T
JAMA : the journal of the American Medical Association,
11/2019, Letnik:
322, Številka:
19
Journal Article
We hypothesize that basal hyperinsulinemia is synergistically mediated by an interplay between increased oxidative stress and excess lipid in the form of reactive oxygen species (ROS) and long-chain ...acyl-CoA esters (LC-CoA). In addition, ROS production may increase in response to inflammatory cytokines and certain exogenous environmental toxins that mislead β-cells into perceiving nutrient excess when none exists. Thus, basal hyperinsulinemia is envisioned as an adaptation to sustained real or perceived nutrient excess that only manifests as a disease when the excess demand can no longer be met by an overworked β-cell. In this article we will present a testable hypothetical mechanism to explain the role of lipids and ROS in basal hyperinsulinemia and how they differ from glucose-stimulated insulin secretion (GSIS). The model centers on redox regulation, via ROS, and
-acylation-mediated trafficking via LC-CoA. These pathways are well established in neural systems but not β-cells. During GSIS, these signals rise and fall in an oscillatory pattern, together with the other well-established signals derived from glucose metabolism; however, their precise roles have not been defined. We propose that failure to either increase or decrease ROS or LC-CoA appropriately will disturb β-cell function.
Displacement of Bromodomain and Extra-Terminal (BET) proteins from chromatin has promise for cancer and inflammatory disease treatments, but roles of BET proteins in metabolic disease remain ...unexplored. Small molecule BET inhibitors, such as JQ1, block BET protein binding to acetylated lysines, but lack selectivity within the BET family (Brd2, Brd3, Brd4, Brdt), making it difficult to disentangle contributions of each family member to transcriptional and cellular outcomes. Here, we demonstrate multiple improvements in pancreatic β-cells upon BET inhibition with JQ1 or BET-specific siRNAs. JQ1 (50-400 nM) increases insulin secretion from INS-1 cells in a concentration dependent manner. JQ1 increases insulin content in INS-1 cells, accounting for increased secretion, in both rat and human islets. Higher concentrations of JQ1 decrease intracellular triglyceride stores in INS-1 cells, a result of increased fatty acid oxidation. Specific inhibition of both Brd2 and Brd4 enhances insulin transcription, leading to increased insulin content. Inhibition of Brd2 alone increases fatty acid oxidation. Overlapping yet discrete roles for individual BET proteins in metabolic regulation suggest new isoform-selective BET inhibitors may be useful to treat insulin resistant/diabetic patients. Results imply that cancer and diseases of chronic inflammation or disordered metabolism are related through shared chromatin regulatory mechanisms.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Accumulation of depolarized mitochondria within β‐cells has been associated with oxidative damage and development of diabetes. To determine the source and fate of depolarized mitochondria, individual ...mitochondria were photolabeled and tracked through fusion and fission. Mitochondria were found to go through frequent cycles of fusion and fission in a ‘kiss and run’ pattern. Fission events often generated uneven daughter units: one daughter exhibited increased membrane potential (Δψm) and a high probability of subsequent fusion, while the other had decreased membrane potential and a reduced probability for a fusion event. Together, this pattern generated a subpopulation of non‐fusing mitochondria that were found to have reduced Δψm and decreased levels of the fusion protein OPA1. Inhibition of the fission machinery through DRP1K38A or FIS1 RNAi decreased mitochondrial autophagy and resulted in the accumulation of oxidized mitochondrial proteins, reduced respiration and impaired insulin secretion. Pulse chase and arrest of autophagy at the pre‐proteolysis stage reveal that before autophagy mitochondria lose Δψm and OPA1, and that overexpression of OPA1 decreases mitochondrial autophagy. Together, these findings suggest that fission followed by selective fusion segregates dysfunctional mitochondria and permits their removal by autophagy.
Reactive Oxygen Species as a Signal in Glucose-Stimulated Insulin Secretion
Jingbo Pi 1 ,
Yushi Bai 1 ,
Qiang Zhang 2 ,
Victoria Wong 3 ,
Lisa M. Floering 1 ,
Kiefer Daniel 1 ,
Jeffrey M. Reece 4 ,
...Jude T. Deeney 5 ,
Melvin E. Andersen 2 ,
Barbara E. Corkey 5 and
Sheila Collins 1
1 Endocrine Biology Program, The Hamner Institutes for Health Sciences, Research Triangle Park, North Carolina
2 Division of Computational Biology, The Hamner Institutes for Health Sciences, Research Triangle Park, North Carolina
3 Flow Cytometry and Confocal Core, The Hamner Institutes for Health Sciences, Research Triangle Park, North Carolina
4 Laboratory of Signal Transduction, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina
5 Obesity Research Center, Boston University School of Medicine, Boston, Massachusetts
Address correspondence and reprint requests to Sheila Collins, PhD, or Jingbo Pi, MD, PHD, Endocrine Biology Program, The
Hamner Institutes for Health Sciences, 6 Davis Dr., Research Triangle Park, NC 27709. E-mail: scollins{at}thehamner.org or jpi{at}thehamner.org
Abstract
One of the unique features of β-cells is their relatively low expression of many antioxidant enzymes. This could render β-cells
susceptible to oxidative damage but may also provide a system that is sensitive to reactive oxygen species as signals. In
isolated mouse islets and INS-1(832/13) cells, glucose increases intracellular accumulation of H 2 O 2 . In both models, insulin secretion could be stimulated by provision of either exogenous H 2 O 2 or diethyl maleate, which raises intracellular H 2 O 2 levels. Provision of exogenous H 2 O 2 scavengers, including cell permeable catalase and N -acetyl- l -cysteine, inhibited glucose-stimulated H 2 O 2 accumulation and insulin secretion (GSIS). In contrast, cell permeable superoxide dismutase, which metabolizes superoxide
into H 2 O 2 , had no effect on GSIS. Because oxidative stress is an important risk factor for β-cell dysfunction in diabetes, the relationship
between glucose-induced H 2 O 2 generation and GSIS was investigated under various oxidative stress conditions. Acute exposure of isolated mouse islets or
INS-1(832/13) cells to oxidative stressors, including arsenite, 4-hydroxynonenal, and methylglyoxal, led to decreased GSIS.
This impaired GSIS was associated with increases in a battery of endogenous antioxidant enzymes. Taken together, these findings
suggest that H 2 O 2 derived from glucose metabolism is one of the metabolic signals for insulin secretion, whereas oxidative stress may disturb
its signaling function.
CAT, catalase
CM-H2DCFDA, 5-(and-6)-chloromethyl-2′, 7′-dichlorodihydrofluorescein diacetate, acetyl ester
DEM, diethyl maleate
FBS, fetal bovine serum
GCLC, γ-glutamate cysteine ligase catalytic subunit
GPx, glutathione peroxidase
GSH, reduced glutathione
GSIS, glucose-stimulated insulin secretion
GSSG, oxidized glutathione
HNE, 4-hydroxynonenal
HO-1, heme oxygenase 1
MGO, methylglyoxal
NAC, N-acetyl-L-cysteine
NQO-1, NAD(P)H:quinone oxidoreductase 1
Nrf2, transcription factor NF-E2–related factor 2
·O2−, superoxide
PEG-CAT, CAT-polyethylene glycol
PEG-SOD, SOD-polyethylene glycol
RIA, radioimmunoassay
ROS, reactive oxygen species
SOD, superoxide dismutase
Footnotes
Published ahead of print at http://diabetes.diabetesjournals.org on 27 March 2007. DOI: 10.2337/db06-1601.
Additional information for this article can be found in an online appendix at http://dx.doi.org/10.2337/db06-1601 .
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore
be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Accepted March 24, 2007.
Received November 15, 2006.
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