Ethanol Suppresses Ureagenesis in Rat Hepatocytes

Holmuhamedov, Ekhson; Czerny, C.; Beeson, Craig C.; Lemasters, John J.

doi:10.1074/jbc.m111.293399

Cited by 49 publications

(47 citation statements)

References 54 publications

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“…Substrates entering the outer mitochondrial membrane pass through voltage-dependent anion channels (VDACs; Lemasters and Holmuhamedov, 2006;Lemasters et al, 2012;Holmuhamedov et al, 2012). During normal metabolism, it is assumed that VDACs are open, supporting the commonly accepted paradigm that small molecular weight molecules pass through the outer mitochondrial membrane freely.…”

Section: Discussionmentioning

confidence: 99%

Paradoxical anaerobism in desert pupfish

Heuton

Ayala

Burg

et al. 2015

Journal of Experimental Biology

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In order to estimate metabolic demands of desert pupfish for conservation purposes, we measured oxygen consumption in fish acclimated to the ecologically relevant temperatures of 28 or 33°C. For these experiments, we used fish derived from a refuge population of Devils Hole pupfish (Cyprinodon diabolis). Measurement of routine oxygen consumption (V O2,routine ) revealed some 33°C-acclimated fish (10% of 295 assayed fish) periodically exhibited periods of no measurable oxygen consumption despite available ambient oxygen tensions that were above the critical P O2 . We call this phenomenon paradoxical anaerobism. The longest observed continuous bout with no oxygen consumption was 149 min, although typical bouts were much shorter. Fish maintained normal posture and ventilation rate (>230 ventilations per minute) during paradoxical anaerobism. Fish rarely demonstrated a compensatory increase in oxygen use following a period of paradoxical anaerobism. In contrast, only one out of 262 sampled fish acclimated at 28°C spontaneously demonstrated paradoxical anaerobism. Muscle lactate concentration was not elevated during periods of paradoxical anaerobism. However, the amount of ethanol released by the 33°C-acclimated fish was 7.3 times greater than that released by the 28°C acclimation group, suggesting ethanol may be used as an alternative end product of anaerobic metabolism. Exposure to exogenous ethanol, in concentrations as low as 0.1%, produced periods of paradoxical anaerobism even in 28°C-acclimated fish.

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Section: Discussionmentioning

confidence: 99%

Paradoxical anaerobism in desert pupfish

Heuton

Ayala

Burg

et al. 2015

Journal of Experimental Biology

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“…There are three main alcohol metabolic pathways in the liver: alcohol dehydrogenase (ADH) [29], microsomal ethanol oxidation system (cytochrome P450 2E1) [30] and catalase [31]. Under conditions of chronic alcohol intake, the microsomal cytochrome P450 becomes activated and produces large amounts of aldehyde, 1-hydroxyethyl radical and other free radicals [32].…”

Section: Key Players In Aldmentioning

confidence: 99%

Key Events Participating in the Pathogenesis of Alcoholic Liver Disease

2017

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Alcoholic liver disease (ALD) is a leading cause of morbidity and mortality worldwide. It ranges from fatty liver to steatohepatitis, fibrosis, cirrhosis and hepatocellular carcinoma. The most prevalent forms of ALD are alcoholic fatty liver, alcoholic hepatitis (AH) and alcoholic cirrhosis, which frequently progress as people continue drinking. ALD refers to a number of symptoms/deficits that contribute to liver injury. These include steatosis, inflammation, fibrosis and cirrhosis, which, when taken together, sequentially or simultaneously lead to significant disease progression. The pathogenesis of ALD, influenced by host and environmental factors, is currently only partially understood. To date, lipopolysaccharide (LPS) translocation from the gut to the portal blood, aging, gender, increased infiltration and activation of neutrophils and bone marrow-derived macrophages along with alcohol plus iron metabolism, with its associated increase in reactive oxygen species (ROS), are all key events contributing to the pathogenesis of ALD. This review aims to introduce the reader to the concept of alcohol-mediated liver damage and the mechanisms driving injury.

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“…Donnan potentials depend on the asymmetrical distribution of non-permeant charged molecules, mainly proteins, and the magnitude of any Donnan potential forming is controversial because charged macromolecules reside on both sides of the outer membrane. Other factors also regulate VDAC conductance, including glutamate, protein kinase A, glycogen synthase 3β, hexokinase II, NADH, acetaldehyde, bcl 2 family members, ethanol and free tubulin (Azoulay-Zohar, et al, 2004;Das, et al, 2008;Gincel, et al, 2000;Lee, et al, 1994;Rostovtseva, et al, 2008;Vander Heiden, et al, 2000;Vander Heiden, et al, 2001; Holmuhamedov, et al, 2012;Lemasters, et al, 2012). …”

Section: Introductionmentioning

confidence: 99%

ATP/ADP ratio, the missed connection between mitochondria and the Warburg effect

2014

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Non-proliferating cells generate the bulk of cellular ATP by fully oxidizing respiratory substrates in mitochondria. Respiratory substrates cross the mitochondrial outer membrane through only one channel, the voltage dependent anion channel (VDAC). Once in the matrix, respiratory substrates are oxidized in the tricarboxylic acid cycle to generate mostly NADH that is further oxidized in the respiratory chain to generate a proton motive force comprised mainly of membrane potential (ΔΨ) to synthesize ATP. Mitochondrial ΔΨ then drives release of ATP−4 from the matrix in exchange for ADP−3 in the cytosol via the adenine nucleotide translocator (ANT) located in the mitochondrial inner membrane. Thus, mitochondrial function in non-proliferating cells drives a high cytosolic ATP/ADP ratio, essential to inhibit glycolysis. By contrast, the bioenergetics of the Warburg phenotype of proliferating cells is characterized by enhanced aerobic glycolysis and suppression of mitochondrial metabolism. Suppressed mitochondrial function leads to lower production of mitochondrial ATP and hence lower cytosolic ATP/ADP ratios that favor enhanced glycolysis. Thus, cytosolic ATP/ADP ratio is a key feature that determines if cell metabolism is predominantly oxidative or glycolytic. Here, we describe two novel mechanisms to explain the suppression of mitochondrial metabolism in cancer cells: the relative closure of VDAC by free tubulin and inactivation of ANT. Both mechanisms contribute to low ATP/ADP ratios that activate glycolysis.

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Ethanol Suppresses Ureagenesis in Rat Hepatocytes

Cited by 49 publications

References 54 publications

Paradoxical anaerobism in desert pupfish

Paradoxical anaerobism in desert pupfish

Key Events Participating in the Pathogenesis of Alcoholic Liver Disease

ATP/ADP ratio, the missed connection between mitochondria and the Warburg effect

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