Research

Jump to: Review

15 pages, 4809 KiB

Open AccessArticle

miR-27b Modulates Insulin Signaling in Hepatocytes by Regulating Insulin Receptor Expression

by Asier Benito-Vicente, Kepa B. Uribe, Noemi Rotllan, Cristina M. Ramírez, Shifa Jebari-Benslaiman, Leigh Goedeke, Alberto Canfrán-Duque, Unai Galicia-García, Diego Saenz De Urturi, Patricia Aspichueta, Yajaira Suárez, Carlos Fernández-Hernando and Cesar Martín

Int. J. Mol. Sci. 2020, 21(22), 8675; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21228675 - 17 Nov 2020

Cited by 16 | Viewed by 2617

Abstract

Insulin resistance (IR) is one of the key contributing factors in the development of type 2 diabetes mellitus (T2DM). However, the molecular mechanisms leading to IR are still unclear. The implication of microRNAs (miRNAs) in the pathophysiology of multiple cardiometabolic pathologies, including obesity, [...] Read more.

Insulin resistance (IR) is one of the key contributing factors in the development of type 2 diabetes mellitus (T2DM). However, the molecular mechanisms leading to IR are still unclear. The implication of microRNAs (miRNAs) in the pathophysiology of multiple cardiometabolic pathologies, including obesity, atherosclerotic heart failure and IR, has emerged as a major focus of interest in recent years. Indeed, upregulation of several miRNAs has been associated with obesity and IR. Among them, miR-27b is overexpressed in the liver in patients with obesity, but its role in IR has not yet been thoroughly explored. In this study, we investigated the role of miR-27b in regulating insulin signaling in hepatocytes, both in vitro and in vivo. Therefore, assessment of the impact of miR-27b on insulin resistance through the hepatic tissue is of special importance due to the high expression of miR-27b in the liver together with its known role in regulating lipid metabolism. Notably, we found that miR-27b controls post-transcriptional expression of numerous components of the insulin signaling pathway including the insulin receptor (INSR) and insulin receptor substrate 1 (IRS1) in human hepatoma cells. These results were further confirmed in vivo showing that overexpression and inhibition of hepatic miR-27 enhances and suppresses hepatic INSR expression and insulin sensitivity, respectively. This study identified a novel role for miR-27 in regulating insulin signaling, and this finding suggests that elevated miR-27 levels may contribute to early development of hepatic insulin resistance. Full article

(This article belongs to the Special Issue Progress in Glucose Metabolism)

► Show Figures

Figure 1

20 pages, 2639 KiB

Open AccessArticle

Thermodynamics and Kinetics of Glycolytic Reactions. Part I: Kinetic Modeling Based on Irreversible Thermodynamics and Validation by Calorimetry

by Kristina Vogel, Thorsten Greinert, Monique Reichard, Christoph Held, Hauke Harms and Thomas Maskow

Int. J. Mol. Sci. 2020, 21(21), 8341; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21218341 - 06 Nov 2020

Cited by 3 | Viewed by 3217

Abstract

In systems biology, material balances, kinetic models, and thermodynamic boundary conditions are increasingly used for metabolic network analysis. It is remarkable that the reversibility of enzyme-catalyzed reactions and the influence of cytosolic conditions are often neglected in kinetic models. In fact, enzyme-catalyzed reactions [...] Read more.

In systems biology, material balances, kinetic models, and thermodynamic boundary conditions are increasingly used for metabolic network analysis. It is remarkable that the reversibility of enzyme-catalyzed reactions and the influence of cytosolic conditions are often neglected in kinetic models. In fact, enzyme-catalyzed reactions in numerous metabolic pathways such as in glycolysis are often reversible, i.e., they only proceed until an equilibrium state is reached and not until the substrate is completely consumed. Here, we propose the use of irreversible thermodynamics to describe the kinetic approximation to the equilibrium state in a consistent way with very few adjustable parameters. Using a flux-force approach allowed describing the influence of cytosolic conditions on the kinetics by only one single parameter. The approach was applied to reaction steps 2 and 9 of glycolysis (i.e., the phosphoglucose isomerase reaction from glucose 6-phosphate to fructose 6-phosphate and the enolase-catalyzed reaction from 2-phosphoglycerate to phosphoenolpyruvate and water). The temperature dependence of the kinetic parameter fulfills the Arrhenius relation and the derived activation energies are plausible. All the data obtained in this work were measured efficiently and accurately by means of isothermal titration calorimetry (ITC). The combination of calorimetric monitoring with simple flux-force relations has the potential for adequate consideration of cytosolic conditions in a simple manner. Full article

(This article belongs to the Special Issue Progress in Glucose Metabolism)

► Show Figures

Graphical abstract

20 pages, 3113 KiB

Open AccessArticle

Thermodynamics and Kinetics of Glycolytic Reactions. Part II: Influence of Cytosolic Conditions on Thermodynamic State Variables and Kinetic Parameters

by Kristina Vogel, Thorsten Greinert, Monique Reichard, Christoph Held, Hauke Harms and Thomas Maskow

Int. J. Mol. Sci. 2020, 21(21), 7921; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21217921 - 25 Oct 2020

Cited by 3 | Viewed by 2348

Abstract

For systems biology, it is important to describe the kinetic and thermodynamic properties of enzyme-catalyzed reactions and reaction cascades quantitatively under conditions prevailing in the cytoplasm. While in part I kinetic models based on irreversible thermodynamics were tested, here in part II, the [...] Read more.

For systems biology, it is important to describe the kinetic and thermodynamic properties of enzyme-catalyzed reactions and reaction cascades quantitatively under conditions prevailing in the cytoplasm. While in part I kinetic models based on irreversible thermodynamics were tested, here in part II, the influence of the presumably most important cytosolic factors was investigated using two glycolytic reactions (i.e., the phosphoglucose isomerase reaction (PGI) with a uni-uni-mechanism and the enolase reaction with an uni-bi-mechanism) as examples. Crowding by macromolecules was simulated using polyethylene glycol (PEG) and bovine serum albumin (BSA). The reactions were monitored calorimetrically and the equilibrium concentrations were evaluated using the equation of state ePC-SAFT. The pH and the crowding agents had the greatest influence on the reaction enthalpy change. Two kinetic models based on irreversible thermodynamics (i.e., single parameter flux-force and two-parameter Noor model) were applied to investigate the influence of cytosolic conditions. The flux-force model describes the influence of cytosolic conditions on reaction kinetics best. Concentrations of magnesium ions and crowding agents had the greatest influence, while temperature and pH-value had a medium influence on the kinetic parameters. With this contribution, we show that the interplay of thermodynamic modeling and calorimetric process monitoring allows a fast and reliable quantification of the influence of cytosolic conditions on kinetic and thermodynamic parameters. Full article

(This article belongs to the Special Issue Progress in Glucose Metabolism)

► Show Figures

Graphical abstract

24 pages, 2478 KiB

Open AccessArticle

Reproductive Potential of Yeast Cells Depends on Overall Action of Interconnected Changes in Central Carbon Metabolism, Cellular Biosynthetic Capacity, and Proteostasis

by Roman Maslanka and Renata Zadrag-Tecza

Int. J. Mol. Sci. 2020, 21(19), 7313; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21197313 - 03 Oct 2020

Cited by 9 | Viewed by 3133

Abstract

Carbon metabolism is a crucial aspect of cell life. Glucose, as the primary source of energy and carbon skeleton, determines the type of cell metabolism and biosynthetic capabilities, which, through the regulation of cell size, may affect the reproductive capacity of the yeast [...] Read more.

Carbon metabolism is a crucial aspect of cell life. Glucose, as the primary source of energy and carbon skeleton, determines the type of cell metabolism and biosynthetic capabilities, which, through the regulation of cell size, may affect the reproductive capacity of the yeast cell. Calorie restriction is considered as the most effective way to improve cellular physiological capacity, and its molecular mechanisms are complex and include several nutrient signaling pathways. It is widely assumed that the metabolic shift from fermentation to respiration is treated as a substantial driving force for the mechanism of calorie restriction and its influence on reproductive capabilities of cells. In this paper, we propose another approach to this issue based on analysis the connection between energy-producing and biomass formation pathways which are closed in the metabolic triangle, i.e., the respiration-glycolysis-pentose phosphate pathway. The analyses were based on the use of cells lacking hexokinase 2 (∆hxk2) and conditions of different glucose concentration corresponding to the calorie restriction and the calorie excess. Hexokinase 2 is the key enzyme involved in central carbon metabolism and is also treated as a calorie restriction mimetic. The experimental model used allows us to explain both the role of increased respiration as an effect of calorie restriction but also other aspects of carbon metabolism and the related metabolic flux in regulation of reproductive potential of the cells. The obtained results reveal that increased respiration is not a prerequisite for reproductive potential extension but rather an accompanying effect of the positive role of calorie restriction. More important seems to be the changes connected with fluxes in central carbon metabolic pathways resulting in low biosynthetic capabilities and improved proteostasis. Full article

(This article belongs to the Special Issue Progress in Glucose Metabolism)

► Show Figures

Figure 1

Review

Jump to: Research

17 pages, 1731 KiB

Open AccessReview

Rethinking the Citric Acid Cycle: Connecting Pyruvate Carboxylase and Citrate Synthase to the Flow of Energy and Material

by Dirk Roosterman and Graeme Stuart Cottrell

Int. J. Mol. Sci. 2021, 22(2), 604; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22020604 - 09 Jan 2021

Cited by 22 | Viewed by 4990

Abstract

In 1937, Sir H. A Krebs first published the Citric Acid Cycle, a unidirectional cycle with carboxylic acids. The original concept of the Citric Acid Cycle from Krebs’ 1953 Nobel Prize lecture illustrates the unidirectional degradation of lactic acid to water, carbon dioxide [...] Read more.

In 1937, Sir H. A Krebs first published the Citric Acid Cycle, a unidirectional cycle with carboxylic acids. The original concept of the Citric Acid Cycle from Krebs’ 1953 Nobel Prize lecture illustrates the unidirectional degradation of lactic acid to water, carbon dioxide and hydrogen. Here, we add the heart lactate dehydrogenase•proton-linked monocarboxylate transporter 1 complex, connecting the original Citric Acid Cycle to the flow of energy and material. The heart lactate dehydrogenase•proton-linked monocarboxylate transporter 1 complex catalyses the first reaction of the Citric Acid Cycle, the oxidation of lactate to pyruvate, and thus secures the provision of pyruvic acid. In addition, we modify Krebs’ original concept by feeding the cycle with oxaloacetic acid. Our concept enables the integration of anabolic processes and allows adaption of the organism to recover ATP faster. Full article

(This article belongs to the Special Issue Progress in Glucose Metabolism)

► Show Figures

Figure 1

21 pages, 2131 KiB

Open AccessReview

Connections between Metabolism and Epigenetic Modification in MDSCs

by Haiyan Dai, Huaxi Xu, Shengjun Wang and Jie Ma

Int. J. Mol. Sci. 2020, 21(19), 7356; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21197356 - 05 Oct 2020

Cited by 13 | Viewed by 3380

Abstract

Myeloid-derived suppressor cells (MDSCs) are major immunosuppressive cells in the tumor microenvironment (TME). During the differentiation and development of MDSCs from myeloid progenitor cells, their functions are also affected by a series of regulatory factors in the TME, such as metabolic reprogramming, epigenetic [...] Read more.

Myeloid-derived suppressor cells (MDSCs) are major immunosuppressive cells in the tumor microenvironment (TME). During the differentiation and development of MDSCs from myeloid progenitor cells, their functions are also affected by a series of regulatory factors in the TME, such as metabolic reprogramming, epigenetic modification, and cell signaling pathways. Additionally, there is a crosstalk between these regulatory factors. This review mainly introduces the metabolism (especially glucose metabolism) and significant epigenetic modification of MDSCs in the TME, and briefly introduces the connections between metabolism and epigenetic modification in MDSCs, in order to determine the further impact on the immunosuppressive effect of MDSCs, so as to serve as a more effective target for tumor therapy. Full article

(This article belongs to the Special Issue Progress in Glucose Metabolism)

► Show Figures

Figure 1

18 pages, 2241 KiB

Open AccessReview

Emerging Roles of BRD7 in Pathophysiology

by Sang Won Park and Junsik M. Lee

Int. J. Mol. Sci. 2020, 21(19), 7127; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21197127 - 27 Sep 2020

Cited by 13 | Viewed by 3177

Abstract

Bromodomain is a conserved structural module found in many chromatin-associated proteins. Bromodomain-containing protein 7 (BRD7) is a member of the bromodomain-containing protein family, and was discovered two decades ago as a protein that is downregulated in nasopharyngeal carcinoma. Since then, BRD7 has been [...] Read more.

Bromodomain is a conserved structural module found in many chromatin-associated proteins. Bromodomain-containing protein 7 (BRD7) is a member of the bromodomain-containing protein family, and was discovered two decades ago as a protein that is downregulated in nasopharyngeal carcinoma. Since then, BRD7 has been implicated in a variety of cellular processes, including chromatin remodeling, transcriptional regulation, and cell cycle progression. Decreased BRD7 activity underlies the pathophysiological properties of various diseases in different organs. BRD7 plays an important role in the pathogenesis of many cancers and, more recently, its roles in the regulation of metabolism and obesity have also been highlighted. Here, we review the involvement of BRD7 in a variety of pathophysiological conditions, with a focus on glucose homeostasis, obesity, and cancer. Full article

(This article belongs to the Special Issue Progress in Glucose Metabolism)

► Show Figures

Figure 1

19 pages, 4388 KiB

Open AccessReview

The Precious Few Grams of Glucose During Exercise

by George A. Brooks

Int. J. Mol. Sci. 2020, 21(16), 5733; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21165733 - 10 Aug 2020

Cited by 27 | Viewed by 7293

Abstract

As exercise intensity exceeds 65% of maximal oxygen uptake carbohydrate energy sources predominate. However, relative to the meager 4–5 g blood glucose pool size in a postabsorptive individual (0.9–1.0 g·L⁻¹ × 5 L blood = 18–20 kcal), carbohydrate (CHO) oxidation rates of [...] Read more.

As exercise intensity exceeds 65% of maximal oxygen uptake carbohydrate energy sources predominate. However, relative to the meager 4–5 g blood glucose pool size in a postabsorptive individual (0.9–1.0 g·L⁻¹ × 5 L blood = 18–20 kcal), carbohydrate (CHO) oxidation rates of 20 kcal·min⁻¹ can be sustained in a healthy and fit person for one hour, if not longer, all the while euglycemia is maintained. While glucose rate of appearance (i.e., production, Ra) from splanchnic sources in a postabsorptive person can rise 2–3 fold during exercise, working muscle and adipose tissue glucose uptake must be restricted while other energy substrates such as glycogen, lactate, and fatty acids are mobilized and utilized. If not for the use of alternative energy substrates hypoglycemia would occur in less than a minute during hard exercise because blood glucose disposal rate (Rd) could easily exceed glucose production (Ra) from hepatic glycogenolysis and gluconeogenesis. The goal of this paper is to present and discuss the integration of physiological, neuroendocrine, circulatory, and biochemical mechanisms necessary for maintenance of euglycemia during sustained hard physical exercise. Full article

(This article belongs to the Special Issue Progress in Glucose Metabolism)

► Show Figures

Figure 1

Journal Menu

Journal Browser

Progress in Glucose Metabolism

Share This Special Issue

Special Issue Editor

Special Issue Information

Keywords

Published Papers (8 papers)

Research

Review

Further Information

Guidelines

MDPI Initiatives

Follow MDPI