scholarly journals More Than One HMG-CoA Lyase: The Classical Mitochondrial Enzyme Plus the Peroxisomal and the Cytosolic Ones

2019 ◽  
Vol 20 (24) ◽  
pp. 6124 ◽  
Author(s):  
Arnedo ◽  
Latorre-Pellicer ◽  
Lucia-Campos ◽  
Gil-Salvador ◽  
Antoñanzas-Peréz ◽  
...  
Keyword(s):  
Ketone Bodies ◽  
Endoplasmic Reticulum Membrane ◽  
Glucose Levels ◽  
Metabolic Remodeling ◽  
Lyase Activity ◽  
Cytosolic Side ◽  
Leucine Catabolism ◽  
The Common ◽  
The Brain

There are three human enzymes with HMG-CoA lyase activity that are able to synthesize ketone bodies in different subcellular compartments. The mitochondrial HMG-CoA lyase was the first to be described, and catalyzes the cleavage of 3-hydroxy-3-methylglutaryl CoA to acetoacetate and acetyl-CoA, the common final step in ketogenesis and leucine catabolism. This protein is mainly expressed in the liver and its function is metabolic, since it produces ketone bodies as energetic fuels when glucose levels are low. Another isoform is encoded by the same gene for the mitochondrial HMG-CoA lyase (HMGCL), but it is located in peroxisomes. The last HMG-CoA lyase to be described is encoded by a different gene, HMGCLL1, and is located in the cytosolic side of the endoplasmic reticulum membrane. Some activity assays and tissue distribution of this enzyme have shown the brain and lung as key tissues for studying its function. Although the roles of the peroxisomal and cytosolic HMG-CoA lyases remain unknown, recent studies highlight the role of ketone bodies in metabolic remodeling, homeostasis, and signaling, providing new insights into the molecular and cellular function of these enzymes.

scholarly journals Effects of Ketone Bodies on Brain Metabolism and Function in Neurodegenerative Diseases

2020 ◽  
Vol 21 (22) ◽  
pp. 8767
Author(s):  
Nicole Jacqueline Jensen ◽  
Helena Zander Wodschow ◽  
Malin Nilsson ◽  
Jørgen Rungby
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurodegenerative Diseases ◽  
Brain Metabolism ◽  
Ketone Bodies ◽  
Current Knowledge ◽  
Ketogenic Diets ◽  
Cognitive Benefits ◽  
The Brain

Under normal physiological conditions the brain primarily utilizes glucose for ATP generation. However, in situations where glucose is sparse, e.g., during prolonged fasting, ketone bodies become an important energy source for the brain. The brain’s utilization of ketones seems to depend mainly on the concentration in the blood, thus many dietary approaches such as ketogenic diets, ingestion of ketogenic medium-chain fatty acids or exogenous ketones, facilitate significant changes in the brain’s metabolism. Therefore, these approaches may ameliorate the energy crisis in neurodegenerative diseases, which are characterized by a deterioration of the brain’s glucose metabolism, providing a therapeutic advantage in these diseases. Most clinical studies examining the neuroprotective role of ketone bodies have been conducted in patients with Alzheimer’s disease, where brain imaging studies support the notion of enhancing brain energy metabolism with ketones. Likewise, a few studies show modest functional improvements in patients with Parkinson’s disease and cognitive benefits in patients with—or at risk of—Alzheimer’s disease after ketogenic interventions. Here, we summarize current knowledge on how ketogenic interventions support brain metabolism and discuss the therapeutic role of ketones in neurodegenerative disease, emphasizing clinical data.

scholarly journals Neural Control of Immunity in Hypertension: Council on Hypertension Mid Career Award for Research Excellence, 2019

Hypertension ◽  
2020 ◽  
Vol 76 (3) ◽  
pp. 622-628
Author(s):  
Daniela Carnevale
Keyword(s):  
Immune Response ◽  
Nervous System ◽  
Neural Control ◽  
Neural Signals ◽  
The Past ◽  
Target Organs ◽  
Long Time ◽  
The Common ◽  
The Brain

The nervous system and the immune system share the common ability to exert gatekeeper roles at the interfaces between internal and external environment. Although interaction between these 2 evolutionarily highly conserved systems has been recognized for long time, the investigation into the pathophysiological mechanisms underlying their crosstalk has been tackled only in recent decades. Recent work of the past years elucidated how the autonomic nervous system controls the splenic immunity recruited by hypertensive challenges. This review will focus on the neural mechanisms regulating the immune response and the role of this neuroimmune crosstalk in hypertension. In this context, the review highlights the components of the brain-spleen axis with a focus on the neuroimmune interface established in the spleen, where neural signals shape the immune response recruited to target organs of high blood pressure.

scholarly journals Nitric Oxide: The Common Link in Different Forms of Dementia

2021 ◽  
Vol 6 (3) ◽  
pp. 322-326
Author(s):  
Dipak Kumar Dhar
Keyword(s):  
Nitric Oxide ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Nitrosative Stress ◽  
Keywords Dementia ◽  
Neurotoxic Effects ◽  
The Common ◽  
Cellular Pathogenesis ◽  
The Brain

Dementia broadly refers to a global decline in cognitive and higher functions of the brain. With the gradually increasing number of aging population, the incidence of dementia has been steadily rising and expected to increase further in the coming years. The causes and forms of dementia are wide-ranging and diverse, with Alzheimer’s disease being its best studied form. With increasing knowledge about various effects and mechanisms of nitric oxide, this chemical neurotransmitter appears to be the connecting link in the cellular pathogenesis of dementia. An exhaustive search of research articles, commentaries and books published from 1990s onwards was performed with various words and combinations linked to dementia and nitric oxide. The existing medical literature shows both neuroprotective and neurotoxic effects of nitric oxide. The present article intends to delve into this topic and provide a lucid understanding of the role of nitric oxide in dementia. Keywords: Dementia, Nitric Oxide, Alzheimer’s disease, excitotoxicity, nitrosative stress.

Ketogenic Diet and PPARgamma

2016 ◽  
Author(s):  
Timothy A. Simeone
Keyword(s):  
Ketogenic Diet ◽  
Refractory Epilepsy ◽  
Ketone Bodies ◽  
Peroxisome Proliferator ◽  
Potential Therapeutic Target ◽  
Peroxisome Proliferator Activated Receptor ◽  
Nuclear Transcription Factor ◽  
Inflammatory Processes ◽  
The Brain

The ketogenic diet (KD) is an effective therapy for many patients with refractory epilepsy. It engages a wide array of antioxidant and anti-inflammatory processes and improves mitochondrial function, which is thought to underlie its neuroprotective, antiseizure, and disease-modifying effects. Potential roles of ketone bodies in these mechanisms are discussed elsewhere in this volume. This chapter focuses on the role of KD fatty acids as potential ligands for the nutritionally regulated nuclear transcription factor peroxisome proliferator activated receptor gamma (PPARgamma). PPARgamma regulates many of the pathways identified in the mechanism of the KD and, in recent years, has become a potential therapeutic target for neurodegenerative diseases. This chapter reviews what is known concerning PPARgamma in the brain, the evidence that PPARgamma has neuroprotective and antiseizure properties, and the evidence suggesting that PPARgamma may be involved in the antiseizure mechanisms of the ketogenic diet.

Brothers in arms: proBDNF/BDNF and sAPPα/Aβ-signaling and their common interplay with ADAM10, TrkB, p75NTR, sortilin, and sorLA in the progression of Alzheimer’s disease

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Simone Eggert ◽  
Stefan Kins ◽  
Kristina Endres ◽  
Tanja Brigadski
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neuronal Death ◽  
Common Features ◽  
Interaction Partners ◽  
The Central Nervous System ◽  
Bdnf Signaling ◽  
The Common ◽  
The Brain

Abstract Brain-derived neurotrophic factor (BDNF) is an important modulator for a variety of functions in the central nervous system (CNS). A wealth of evidence, such as reduced mRNA and protein level in the brain, cerebrospinal fluid (CSF), and blood samples of Alzheimer’s disease (AD) patients implicates a crucial role of BDNF in the progression of this disease. Especially, processing and subcellular localization of BDNF and its receptors TrkB and p75 are critical determinants for survival and death in neuronal cells. Similarly, the amyloid precursor protein (APP), a key player in Alzheimer’s disease, and its cleavage fragments sAPPα and Aβ are known for their respective roles in neuroprotection and neuronal death. Common features of APP- and BDNF-signaling indicate a causal relationship in their mode of action. However, the interconnections of APP- and BDNF-signaling are not well understood. Therefore, we here discuss dimerization properties, localization, processing by α- and γ-secretase, relevance of the common interaction partners TrkB, p75, sorLA, and sortilin as well as shared signaling pathways of BDNF and sAPPα.

scholarly journals Down-regulation of the mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase gene by insulin: the role of the forkhead transcription factor FKHRL1

2002 ◽  
Vol 366 (1) ◽  
pp. 289-297 ◽  
Author(s):  
Alícia NADAL ◽  
Pedro F. MARRERO ◽  
Diego HARO
Keyword(s):  
Ketone Bodies ◽  
Control Site ◽  
Luciferase Reporter ◽  
Acid Oxidation ◽  
Transcription Start ◽  
Forkhead Transcription Factor ◽  
The Brain

Normal physiological responses to carbohydrate shortages cause the liver to increase the production of ketone bodies from the acetyl-CoA generated from fatty acid oxidation. This allows the use of ketone bodies for energy, thereby preserving the limited glucose for use by the brain. This adaptative response is switched off by insulin rapidly inhibiting the expression of the mitochondrial 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) synthase (HMGCS2) gene, which is a key control site of ketogenesis. We decided to investigate the molecular mechanism of this inhibition. In the present study, we show that FKHRL1, a member of the forkhead in rhabdosarcoma (FKHR) subclass of the Fox family of transcription factors, stimulates transcription from transfected 3-hydroxy-3-methylglutaryl-CoA synthase promoter-luciferase reporter constructs, and that this stimulation is repressed by insulin. An FKHRL1-responsive sequence AAAAATA, located 211bp upstream of the HMGCS2 gene transcription start site, was identified by deletion analysis. It binds FKHRL1 in vivo and in vitro and confers FKHRL1 responsiveness on homologous and heterologous promoters. If it is mutated, it partially blocks the effect of insulin in HepG2 cells, both in the absence and presence of overexpressed FKHRL1. These results suggest that FKHRL1 contributes to the regulation of HMGCS2 gene expression by insulin.

scholarly journals Ingested Ketone Ester Leads to a Rapid Rise of Acetyl-CoA and Competes with Glucose Metabolism in the Brain of Non-Fasted Mice

2021 ◽  
Vol 22 (2) ◽  
pp. 524
Author(s):  
Laurent Suissa ◽  
Pavel Kotchetkov ◽  
Jean-Marie Guigonis ◽  
Emilie Doche ◽  
Ophélie Osman ◽  
...  
Keyword(s):  
Energy Homeostasis ◽  
Ketone Bodies ◽  
Neurological Diseases ◽  
Feedback Mechanism ◽  
Strongly Correlated ◽  
Acetyl Coa ◽  
First Time ◽  
The Brain ◽  
Ketone Ester

The role of ketone bodies in the cerebral energy homeostasis of neurological diseases has begun to attract recent attention particularly in acute neurological diseases. In ketogenic therapies, ketosis is achieved by either a ketogenic diet or by the administration of exogenous ketone bodies. The oral ingestion of the ketone ester (KE), (R)-3-hydroxybutyl (R)-3-hydroxybutyrate, is a new method to generate rapid and significant ketosis (i.e., above 6 mmol/L) in humans. KE is hydrolyzed into β-hydroxybutyrate (βHB) and its precursor 1,3-butanediol. Here, we investigate the effect of oral KE administration (3 mg KE/g of body weight) on brain metabolism of non-fasted mice using liquid chromatography in tandem with mass spectrometry. Ketosis (Cmax = 6.83 ± 0.19 mmol/L) was obtained at Tmax = 30 min after oral KE-gavage. We found that βHB uptake into the brain strongly correlated with the plasma βHB concentration and was preferentially distributed in the neocortex. We showed for the first time that oral KE led to an increase of acetyl-CoA and citric cycle intermediates in the brain of non-fasted mice. Furthermore, we found that the increased level of acetyl-CoA inhibited glycolysis by a feedback mechanism and thus competed with glucose under physiological conditions. The brain pharmacodynamics of this oral KE strongly suggest that this agent should be considered for acute neurological diseases.

CNS Regulation of Glucose Homeostasis

Physiology ◽  
2009 ◽  
Vol 24 (3) ◽  
pp. 159-170 ◽  
Author(s):  
Carol K. L. Lam ◽  
Madhu Chari ◽  
Tony K. T. Lam
Keyword(s):  
Glucose Homeostasis ◽  
Molecular Mechanisms ◽  
Neural Pathway ◽  
Lower Plasma ◽  
Glucose Levels ◽  
The Past ◽  
Lower Plasma Glucose ◽  
Nutrient Homeostasis ◽  
The Brain

The past decade has hosted a remarkable surge in research dedicated to the central control of homeostatic mechanisms. Evidence indicates that the brain, in particular the hypothalamus, directly senses hormones and nutrients to initiate behavioral and metabolic responses to control energy and nutrient homeostasis. Diabetes is chiefly characterized by hyperglycemia due to impaired glucose homeostatic regulation, and a primary therapeutic goal is to lower plasma glucose levels. As such, in this review, we highlight the role of the hypothalamus in the regulation of glucose homeostasis in particular and discuss the cellular and molecular mechanisms by which this neural pathway is orchestrated.

scholarly journals CURCUMIN ATTENUATES LEAD (Pb)–INDUCED NEUROBEHAVIORL AND NEUROBIOCHEMICAL DYSFUNCTION: A REVIEW

2018 ◽  
Vol 10 (8) ◽  
pp. 23 ◽  
Author(s):  
Gasem Mohammad Abu-taweel
Keyword(s):  
Chemical Elements ◽  
Curcuma Longa ◽  
Lead Toxicity ◽  
Neurotransmitter System ◽  
Behavioral Toxicity ◽  
Behavior Modifications ◽  
The Common ◽  
Living Organisms ◽  
The Brain

Lead is one of the common chemical elements that is assigned the symbol Pb which came from the Latin Plumbum. Pb is widely used in the field of coating, refine and glaze ceramics and pottery. It is still used in the production of products like water pipes, cooking utensils and cooking utensils. In addition it is also used in insulation of building ceilings, cable coverage and military industries. Lead enter the environment from those uses and from the environment it enter into the living organisms. Lead accumulates in many humanorgans, but the brain is the target organ of lead accumulation. Neurotoxicity of lead is, one of lead toxicity, caused many symptoms. There are many behavioral and biochemical modifications induced by lead toxicity like learning and memory deficits, anxiety disorders, social and sexual behavior modifications and neurotransmitter system deficits. Curcumin is a bioactive natural phytochemical phenolic compound (diferuloylmethane) extracted from the rhizome of Curcuma longa. Most studies indicated the role of curcumin in reducing the damage of lead toxicity. In the current review, emphasis was based on the toxicity of lead and its effect on behavior and some neurotransmitters related to behavior. The effect of curcumin is improving the neurotoxicity and behavioral toxicity of lead.

Role of brain kallikrein-kinin system in regulation of adrenocorticotropin release

1992 ◽  
Vol 262 (3) ◽  
pp. E312-E318 ◽  
Author(s):  
P. Madeddu ◽  
V. Anania ◽  
S. Alagna ◽  
C. Troffa ◽  
P. P. Parpaglia ◽  
...  
Keyword(s):  
Plasma Glucose ◽  
Corticotropin Releasing Factor ◽  
Similar Extent ◽  
Acth Secretion ◽  
Kinin System ◽  
Glucose Levels ◽  
Kallikrein Kinin System ◽  
The Brain ◽  
Acth Release

We evaluated whether the brain kallikrein-kinin system plays a role in the regulation of adrenocorticotropin (ACTH) release in rats. Intracerebroventricular (icv) injection of bradykinin (0.24 nmol) increased plasma immunoreactive ACTH (irACTH) levels (from 93 +/- 4 to 200 +/- 12 pg/ml, P less than 0.01). This effect was prevented by icv kinin antagonist at 15.4 nmol/h (from 98 +/- 5 to 108 +/- 6 pg/ml; not significant). The antagonist did not alter the increase in plasma irACTH levels induced by icv corticotropin-releasing factor (CRF), arginine vasopressin, or prostaglandin E2. Melittin (7 nmol/h icv) increased plasma irACTH from 95 +/- 4 to 268 +/- 7 pg/ml (P less than 0.01). This effect was prevented by icv kinin antagonist (15.4 nmol/h), kallikrein antibodies (13 pmol/h), or indomethacin (0.28 mmol/h). ACTH response to melittin was not altered by antagonists of CRF or vasopressin. Intra-arterial injection of insulin (0.3 IU/kg body wt) reduced plasma glucose levels to a similar extent in rats given icv kinin antagonist or vehicle; the ACTH response to insulin-induced hypoglycemia was slightly less in rats given kinin antagonist than in those given vehicle (55 +/- 5 vs. 86 +/- 4 pg/ml, P less than 0.05). The brain kallikrein-kinin system may play a role in the regulation of ACTH secretion in stimulated conditions.

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