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Current Opinion in Gastroenterology May 2015It is our opinion that there is an unmet need in hepatology for a minimally or noninvasive test of liver function and physiology. Quantitative liver function tests... (Review)
Review
PURPOSE OF REVIEW
It is our opinion that there is an unmet need in hepatology for a minimally or noninvasive test of liver function and physiology. Quantitative liver function tests define the severity and prognosis of liver disease by measuring the clearance of substrates whose uptake or metabolism is dependent upon liver perfusion or hepatocyte function. Substrates with high-affinity hepatic transporters exhibit high 'first-pass' hepatic extraction and their clearance measures hepatic perfusion. In contrast, substrates metabolized by the liver have low first-pass extraction and their clearance measures specific drug metabolizing pathways.
RECENT FINDINGS
We highlight one quantitative liver function test, the dual cholate test, and introduce the concept of a disease severity index linked to clinical outcome that quantifies the simultaneous processes of hepatocyte uptake, clearance from the systemic circulation, clearance from the portal circulation, and portal-systemic shunting.
SUMMARY
It is our opinion that dual cholate is a relevant test for defining disease severity, monitoring the natural course of disease progression, and quantifying the response to therapy.
Topics: Cholates; Health Services Needs and Demand; Hepatocytes; Humans; Liver; Liver Diseases; Liver Function Tests; Metabolic Clearance Rate; Predictive Value of Tests; Severity of Illness Index
PubMed: 25714706
DOI: 10.1097/MOG.0000000000000167 -
Biochimica Et Biophysica Acta.... Mar 2022The mitochondrial respiratory chain (RC) enables many metabolic processes by regenerating both mitochondrial and cytosolic NAD and ATP. The oxidation by the RC of the...
The mitochondrial respiratory chain (RC) enables many metabolic processes by regenerating both mitochondrial and cytosolic NAD and ATP. The oxidation by the RC of the NADH metabolically produced in the cytosol involves redox shuttles as the malate-aspartate shuttle (MAS) and is of paramount importance for cell fate. However, the specific metabolic regulations allowing mitochondrial respiration to prioritize NADH oxidation in response to high NADH/NAD redox stress have not been elucidated. The recent discovery that complex I (NADH dehydrogenase), and not complex II (Succinate dehydrogenase), can assemble with other respiratory chain complexes to form functional entities called respirasomes, led to the assumption that this supramolecular organization would favour NADH oxidation. Unexpectedly, characterization of heart and liver mitochondria demonstrates that the RC systematically favours electrons provided by the 'respirasome free' complex II. Our results demonstrate that the preferential succinate driven respiration is tightly controlled by OAA levels, and that OAA feedback inhibition of complex II rewires RC fuelling increasing NADH oxidation capacity. This new regulatory mechanism synergistically increases RC's NADH oxidative capacity and rewires MDH2 driven anaplerosis of the TCA, preventing malate production from succinate to favour oxidation of cytosolic malate. This regulatory mechanism synergistically adjusts RC and TCA fuelling in response to extramitochondrial malate produced by the MAS.
Topics: Cell Respiration; Citric Acid Cycle; Electron Transport; NAD; Succinic Acid
PubMed: 35063410
DOI: 10.1016/j.bbabio.2022.148532 -
Nature Reviews. Drug Discovery Sep 2019Metabolic programming is emerging as a critical mechanism to alter immune cell activation, differentiation and function. Targeting metabolism does not completely... (Review)
Review
Metabolic programming is emerging as a critical mechanism to alter immune cell activation, differentiation and function. Targeting metabolism does not completely suppress or activate the immune system but selectively regulates immune responses. The different metabolic requirements of the diverse cells that constitute an immune response provide a unique opportunity to separate effector functions from regulatory functions. Likewise, cells can be metabolically reprogrammed to promote either their short-term effector functions or long-term memory capacity. Studies in the growing field of immunometabolism support a paradigm of 'cellular selectivity based on demand', in which generic inhibitors of ubiquitous metabolic processes selectively affect cells with the greatest metabolic demand and have few effects on other cells of the body. Targeting metabolism, rather than particular cell types or cytokines, in metabolically demanding processes such as autoimmunity, graft rejection, cancer and uncontrolled inflammation could lead to successful strategies in controlling the pathogenesis of these complex disorders.
Topics: Autoimmune Diseases; Autoimmunity; Graft Rejection; Humans; Immune System; Immunomodulation; Inflammation; Metabolism; Models, Biological; Neoplasms
PubMed: 31363227
DOI: 10.1038/s41573-019-0032-5 -
Frontiers in Immunology 2019Tumor microenvironments are rich in extracellular nucleotides that can be metabolized by ectoenzymes to produce adenosine, a nucleoside involved in controlling immune... (Review)
Review
Tumor microenvironments are rich in extracellular nucleotides that can be metabolized by ectoenzymes to produce adenosine, a nucleoside involved in controlling immune responses. Multiple myeloma, a plasma cell malignancy developed within a bone marrow niche, exploits adenosinergic pathways to customize the immune homeostasis of the tumor. CD38, a multifunctional protein that acts as both receptor and ectoenzyme, is overexpressed at all stages of myeloma. At neutral and acidic pH, CD38 catalyzes the extracellular conversion of NAD to regulators of calcium signaling. The initial disassembly of NAD is also followed by adenosinergic activity, if CD38 is operating in the presence of CD203a and CD73 nucleotidases. cAMP extruded from tumor cells provides another substrate for metabolizing nucleotidases to signaling adenosine. These pathways flank or bypass the canonical adenosinergic pathway subjected to the conversion of ATP by CD39. All of the adenosinergic networks can be hijacked by the tumor, thus controlling the homeostatic reprogramming of the myeloma in the bone marrow. In this context, adenosine assumes the role of a local hormone: cell metabolism is adjusted via low- or high-affinity purinergic receptors expressed by immune and bone cells as well as by tumor cells. The result is immunosuppression, which contributes to the failure of immune surveillance in cancer. A similar metabolic strategy silences immune effectors during the progression of indolent gammopathies to symptomatic overt multiple myeloma disease. Plasma from myeloma aspirates contains elevated levels of adenosine resulting from interactions between myeloma and other cells lining the niche and adenosine concentrations are known to increase as the disease progresses. This is statistically reflected in the International Staging System for multiple myeloma. Along with the ability to deplete CD38 malignant plasma cell populations which has led to their widespread therapeutic use, anti-CD38 antibodies are involved in the polarization and release of microvesicles characterized by the expression of multiple adenosine-producing molecules. These adenosinergic pathways provide new immune checkpoints for improving immunotherapy protocols by helping to restore the depressed immune response.
Topics: ADP-ribosyl Cyclase 1; Adenosine; Animals; Antineoplastic Agents, Immunological; Disease Management; Disease Progression; Disease Susceptibility; Drug Resistance, Neoplasm; Energy Metabolism; Humans; Immunomodulation; Membrane Glycoproteins; Metabolic Networks and Pathways; Molecular Targeted Therapy; Multiple Myeloma; Receptors, Purinergic; Signal Transduction
PubMed: 31068926
DOI: 10.3389/fimmu.2019.00760 -
American Journal of Physiology.... Feb 2017The subfornical organ (SFO) is a critical circumventricular organ involved in the control of cardiovascular and metabolic homeostasis. Despite the plethora of...
The subfornical organ (SFO) is a critical circumventricular organ involved in the control of cardiovascular and metabolic homeostasis. Despite the plethora of circulating signals continuously sensed by the SFO, studies investigating how these signals are integrated are lacking. In this study, we use patch-clamp techniques to investigate how the traditionally classified "cardiovascular" hormone ANG II, "metabolic" hormone CCK and "metabolic" signal glucose interact and are integrated in the SFO. Sequential bath application of CCK (10 nM) and ANG (10 nM) onto dissociated SFO neurons revealed that 63% of responsive SFO neurons depolarized to both CCK and ANG; 25% depolarized to ANG only; and 12% hyperpolarized to CCK only. We next investigated the effects of glucose by incubating and recording neurons in either hypoglycemic, normoglycemic, or hyperglycemic conditions and comparing the proportions of responses to ANG ( = 55) or CCK ( = 83) application in each condition. A hyperglycemic environment was associated with a larger proportion of depolarizing responses to ANG (, < 0.05), and a smaller proportion of depolarizing responses along with a larger proportion of hyperpolarizing responses to CCK (, < 0.01). Our data demonstrate that SFO neurons excited by CCK are also excited by ANG and that glucose environment affects the responsiveness of neurons to both of these hormones, highlighting the ability of SFO neurons to integrate multiple metabolic and cardiovascular signals. These findings have important implications for this structure's role in the control of various autonomic functions during hyperglycemia.
Topics: Angiotensin II; Animals; Cardiovascular Physiological Phenomena; Cells, Cultured; Cholecystokinin; Glucose; Male; Metabolic Flux Analysis; Metabolic Networks and Pathways; Neurons; Rats; Rats, Sprague-Dawley; Signal Transduction; Subfornical Organ
PubMed: 28003212
DOI: 10.1152/ajpregu.00423.2016 -
Yakugaku Zasshi : Journal of the... 2017Since more than 70% of clinically used drugs are excreted from the body through metabolic processes, drug metabolism is a key determinant of pharmacokinetics, drug... (Review)
Review
Since more than 70% of clinically used drugs are excreted from the body through metabolic processes, drug metabolism is a key determinant of pharmacokinetics, drug response and drug toxicity. Much progress has been made in understanding drug-drug interactions via the inhibition or induction of cytochrome P450s (P450, CYP), as well as the effects of genetic polymorphisms of P450s on pharmacokinetics, and this has facilitated the progress of optimized pharmacotherapy in the clinic. Now, similar information is needed for non-CYP enzymes, especially concerning Phase I enzymes, based on advanced basic and clinical studies. Recently, it was revealed that post-transcriptional regulation by microRNAs or RNA editing plays a significant role in regulating the expression of drug-metabolizing enzymes, thus conferring variability in the detoxification and metabolic activation of drugs or chemicals. Changes in the expression profile of microRNAs in tissues or body fluids can be a biomarker of drug response and toxicity; therefore, such studies could also be useful for drug repositioning. In addition, microRNAs are involved in pharmacogenetics, because single nucleotide polymorphisms in microRNA binding sites of mRNAs, or microRNAs themselves, may cause changes in gene expression. Some microRNA-related polymorphisms could be biomarkers of the clinical outcome of pharmacotherapy. In this review article, recent progress and future directions for drug metabolism studies are discussed.
Topics: Binding Sites; Cytochrome P-450 Enzyme System; Drug Interactions; Drug Therapy; Drug-Related Side Effects and Adverse Reactions; Humans; Inactivation, Metabolic; MicroRNAs; Pharmaceutical Preparations; Pharmacogenetics; Pharmacokinetics; Polymorphism, Genetic; Polymorphism, Single Nucleotide; RNA Editing; RNA Processing, Post-Transcriptional
PubMed: 28566576
DOI: 10.1248/yakushi.16-00250-5 -
Molecular and Cellular Neurosciences Sep 2020The brain is exceptionally demanding in terms of energy metabolism. Approximately 20% of the calories consumed are devoted to our cerebral faculties, with the lion's... (Review)
Review
The brain is exceptionally demanding in terms of energy metabolism. Approximately 20% of the calories consumed are devoted to our cerebral faculties, with the lion's share provided in the form of glucose. The brain's stringent energy dependency requires a high degree of harmonization between the elements responsible for supplying- and metabolizing energetic substrates. However, chronic stress may jeopardize this homeostatic energy balance by disruption of critical metabolic processes. In agreement, stress-related mental disorders have been linked with perturbations in energy metabolism. Prominent stress-induced metabolic alterations include the actions of hormones, glucose uptake and mitochondrial adjustments. Importantly, fundamental stress-responsive metabolic adjustments in humans and animal models bear a striking resemblance. Here, an overview is provided of key findings, demonstrating the pervasive impact of chronic stress on energy metabolism. Furthermore, I argue that medications, aimed primarily at restoring metabolic homeostasis, may constitute a novel approach to treat mental disorders.
Topics: Animals; Brain; Energy Metabolism; Glucose; Homeostasis; Humans; Mitochondria; Stress, Physiological
PubMed: 32629109
DOI: 10.1016/j.mcn.2020.103525 -
The Journal of Investigative... Dec 2002The stratum corneum is a complex tissue that is metabolically active, and undergoes dynamic structural modifications due to the presence of several self-regulating... (Review)
Review
The stratum corneum is a complex tissue that is metabolically active, and undergoes dynamic structural modifications due to the presence of several self-regulating enzymatic systems. A large number of defensive (protective) functions are embodied in this tissue, each with its own structural and biochemical basis. Moreover, the stratum corneum is responsive to external perturbations to the permeability barrier, upregulating a variety of metabolic processes aimed at restoring normal barrier function. Traditional drug delivery methods, which are of limited effectiveness, view the stratum corneum as a static, but semipermeable membrane. In contrast, newer metabolically based methods, which can be deployed alone, or in conjunction with standard methods, have been shown to expand the spectrum of drugs that can be delivered transdermally in hairless mouse epidermis. Yet, while these new approaches hold great promise, if equally effective in human skin, they pose new questions about the risks of a highly permeabilized stratum corneum.
Topics: Acids; Administration, Cutaneous; Animals; Drug Delivery Systems; Epidermis; Humans; Lipid Metabolism; Permeability
PubMed: 12518797
DOI: 10.1046/j.1523-1747.2002.19632.x -
Journal of Applied Physiology... Apr 2021Exercise is well appreciated as a therapeutic approach to improve health. Although chronic exercise training can change metabolism, even a single exercise session can...
Exercise is well appreciated as a therapeutic approach to improve health. Although chronic exercise training can change metabolism, even a single exercise session can have significant effects upon metabolism. Responses of adipose tissue lipolysis and skeletal muscle triacylglycerol (TAG) utilization have been well appreciated as components of the acute exercise response. However, there are other central components of the physiological response to be considered, as well. A robust and growing body of literature depicts a rapid responsiveness of hepatic TAG content to single bouts of exercise, and there is a remaining need to incorporate this information into our overall understanding of how exercise affects the liver. TAG content in the liver increases during an exercise session and can continue to rise for a few hours afterwards, followed by a fairly rapid return to baseline. Here, we summarize evidence that rapid responsiveness of hepatic TAG content to metabolic stress is a fundamental component of the exercise response. Adipose tissue lipolysis and plasma free fatty acid concentration are likely the major metabolic controllers of enhanced lipid storage in the liver after each exercise bout, and we discuss nutritional impacts as well as health implications. Although traditionally clinicians would be merely concerned with hepatic lipids in overnight-fasted, rested individuals, it is now apparent that the content of hepatic TAG fluctuates in response to metabolic challenges such as exercise, and these responses likely exert significant impacts on health and cellular homeostasis.
Topics: Adipose Tissue; Exercise; Humans; Lipolysis; Liver; Triglycerides
PubMed: 33475457
DOI: 10.1152/japplphysiol.00930.2020 -
Biotechnology and Bioengineering Feb 2019At early stages of the exponential growth phase in HEK293 cell cultures, the tricarboxylic acid cycle is unable to process all the amount of NADH generated in the...
At early stages of the exponential growth phase in HEK293 cell cultures, the tricarboxylic acid cycle is unable to process all the amount of NADH generated in the glycolysis pathway, being lactate the main by-product. However, HEK293 cells are also able to metabolize lactate depending on the environmental conditions. It has been recently observed that one of the most important modes of lactate metabolization is the cometabolism of lactate and glucose, observed even during the exponential growth phase. Extracellular lactate concentration and pH appear to be the key factors triggering the metabolic shift from glucose consumption and lactate production to lactate and glucose concomitant consumption. The hypothesis proposed for triggering this metabolic shift to lactate and glucose concomitant consumption is that HEK293 cells metabolize extracellular lactate as a response to both extracellular protons and lactate accumulation, by means of cotransporting them (extracellular protons and lactate) into the cytosol. At this point, there exists a considerable controversy about how lactate reaches the mitochondrial matrix: the first hypothesis proposes that lactate is converted into pyruvate in the cytosol, and afterward, pyruvate enters into the mitochondria; the second alternative considers that lactate enters first into the mitochondria, and then, is converted into pyruvate. In this study, lactate transport and metabolization into mitochondria is shown to be feasible, as evidenced by means of respirometry tests with isolated active mitochondria, including the depletion of lactate concentration of the respirometry assay. Although the capability of lactate metabolization by isolated mitochondria is demonstrated, the possibility of lactate being converted into pyruvate in the cytosol cannot be excluded from the discussion. For this reason, the calculation of the metabolic fluxes for an HEK293 cell line was performed for the different metabolic phases observed in batch cultures under pH controlled and noncontrolled conditions, considering both hypotheses. The main objective of this study is to evaluate the redistribution of cellular metabolism and compare the differences or similarities between the phases before and after the metabolic shift of HEK293 cells (shift observed when pH is not controlled). That is from a glucose consumption/lactate production phase to a glucose-lactate coconsumption phase. Interestingly, switching to a glucose and lactate cometabolization results in a better-balanced cell metabolism, with decreased glucose and amino acids uptake rates, affecting minimally cell growth. This behavior could be applied to further develop new approaches in terms of cell engineering and to develop improved cell culture strategies in the field of animal cell technology.
Topics: Cell Proliferation; Glucose; HEK293 Cells; Humans; Lactic Acid; Metabolic Flux Analysis
PubMed: 30411322
DOI: 10.1002/bit.26858