Role of hepatic carbonic anhydrase in <i>de novo</i> lipogenesis

Lynch, Christopher J.; Fox, Heather L.; Hazen, Stacy A.; Stanley, Bruce A.; Dodgson, Susanna J.; LaNoue, Kathryn F.

doi:10.1042/bj3100197

Cited by 94 publications

(77 citation statements)

References 29 publications

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“…A time-dependent decrease in carbonic anhydrase activity was reported in fish exposed to chlorpyrifos (35). Carbonic anhydrase in hepatocyte mitochondria plays a vital role in the regulation of ionic balance, which is required in metabolic reactions, production of ATP, and transport processes (102).…”

Section: Biochemical Evidence Of Op Hepatotoxicitymentioning

confidence: 99%

Adverse effects of organophosphorus pesticides on the liver: a brief summary of four decades of research

Karami‐Mohajeri

Ahmadipour

Rahimi

et al. 2017

Archives of Industrial Hygiene and Toxicology

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Organophosphorus pesticides (OPs) are widely used volatile pesticides that have harmful effects on the liver in acute and chronic exposures. This review article summarises and discusses a wide collection of studies published over the last 40 years reporting on the effects of OPs on the liver, in an attempt to propose general mechanisms of OP hepatotoxicity and possible treatment. Several key biological processes have been reported as involved in OP-induced hepatotoxicity such as disturbances in the antioxidant defence system, oxidative stress, apoptosis, and mitochondrial and microsomal metabolism. Most studies show that antioxidants can attenuate oxidative stress and the consequent changes in liver function. However, few studies have examined the relationship between OP structures and the severity and mechanism of their action. We hope that future in vitro, in vivo, and clinical trials will answer the remaining questions about the mechanisms of OP hepatotoxicity and its management.

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Section: Biochemical Evidence Of Op Hepatotoxicitymentioning

confidence: 99%

Adverse effects of organophosphorus pesticides on the liver: a brief summary of four decades of research

Karami‐Mohajeri

Ahmadipour

Rahimi

et al. 2017

Archives of Industrial Hygiene and Toxicology

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“…Weakly acidic metabo!ites labelled with 14C were separated by ion-exchange chromatography on Dowex 1 chloride columns as described previously (Lynch et al, 1995). Chromatographic peaks were identified based on parallel column runs with radiolabelled standards and/or assays of the peak fractions by luminometric or fluorometric methods (Williamson and Corkey, 1969).…”

Section: Chromatographic Separation Of 14c-labelled Metabolitesmentioning

confidence: 99%

“…Values range from 13% (Lapidot and Gopher, 1994) to 5% (Shank et a!., 1993). Recent studies from this laboratory demonstrate that carbonic anhydrase inhibitors, such as ethoxyzo!amide, when added to hepatocytes (Lynch et a!., 1995), adipocytes (Hazen eta!., 1996), or astrocytes (Hazen eta!., 1997) lower flux through pyruvate carboxylase by limiting its access to bicarbonate (HCO 3~). As carbonic anhydrase inhibitors are sometimes used to treat epilepsy, it may be possible that these drugs are effective because they lower glutamate and g!utamine levels in brain by !owering flux through pyruvate carboxy!ase in astrocytes.…”

mentioning

confidence: 99%

Role of Pyruvate Carboxylase in Facilitation of Synthesis of Glutamate and Glutamine in Cultured Astrocytes

Gamberino

Berkich

Lynch

et al. 1997

Journal of Neurochemistry

101

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CO 2 fixation was measured in cultured astrocytes isolated from neonatal rat brain to test the hypothesis that the activity of pyruvate carboxylase influences the rate of de novo glutamate and glutamine synthesis in astrocytes. Astrocytes were incubated with 14002 and the incorporation of 140 into medium or cell extract products was determined. After chromatographic separation of 140-Iabelled products, the fractions of 140 cycled back to pyruvate, incorporated into citric acid cycle intermediates, and converted to the amino acids glutamate and glutamine were determined as a function of increasing pyruvate carboxylase flux. The consequences of increasing pyruvate, bicarbonate, and ammonia were investigated. Increasing extracellular pyruvate from 0 to 5 mM increased pyruvate carboxylase flux as observed by increases in the 140 incorporated into pyruvate and citric acid cycle intermediates, but incorporation into glutamate and glutamine, although relatively high at low pyruvate levels, did not increase as pyruvate carboxylase flux increased. Increasing added bicarbonate from 15 to 25 mM almost doubled 002 fixation. When 25 mM bicarbonate plus 0.5 mM pyruvate increased pyruvate carboxylase flux to approximately the same extent as 15 mM bicarbonate pIus 5 mM pyruvate, the rate of appearance of [14C]glutamate and glutamine was higher with the lower level of pyruvate. The conclusion was drawn that, in addition to stimulating pyruvate carboxylase, added pyruvate (but not added bicarbonate) increases alanine aminotransferase flux in the direction of glutamate utilization, thereby decreasing glutamate as pyruvate + glutamate -~a-ketoglutarate + alanine. In contrast to previous in vivo studies, the addition of ammonia (0.1 and 5 mM) had no effect on net 14002 fixation, but did alter the distribution of 14C-labelled products by decreasing glutamate and increasing glutamine. Rather unexpectedly, ammonia did not increase the sum of glutamate plus glutamine (mass amounts or 140 incorporation). Low rates of conversion of cr- [140]ketoglutarate to [14C]glutamate,even in the presence of excess added ammonia, suggested that reductive amination of a-ketoglutarate is inactive under conditions studied in these cultured astrocytes. We conclude that pyruvate carboxylase is required for de novo synthesis of glutamate plus glutamine, but that conversion of aketoglutarate to glutamate may frequently be the ratelimiting step in this process of glutamate synthesis.

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“…In addition, Herbert and Coulson (1983) demonstrated that de novo fatty acid synthesis (measured by [ 14 C]acetate incorporation into total lipid) in liver of American chameleons (Anolis carolinensis) was inhibited by CA-specific inhibitors (ethoxyzolamide and acetazolamide). CA was suggested to play a role in de novo lipogenesis in hepatocytes by increasing the rate of CO 2 hydration to bicarbonate for ACCase (Dodgson et al, 1984), and Lynch et al (1995) reported a reduction of [ 14 C]acetate incorporation into total lipid in rat hepatocytes incubated with CA inhibitors trifluoromethylsulphonamide and ethoxyzolamide. Together, these results support the notion that CA assists in providing HCO 3 Ϫ for lipid biosynthesis in animal systems.…”

mentioning

confidence: 99%

Biochemical and Molecular Inhibition of Plastidial Carbonic Anhydrase Reduces the Incorporation of Acetate into Lipids in Cotton Embryos and Tobacco Cell Suspensions and Leaves

Hoang

Chapman

2002

Plant Physiology

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Two cDNAs encoding functional carbonic anhydrase (CA) enzymes were recently isolated from a non-photosynthetic, cotyledon library of cotton (Gossypium hirsutum) seedlings with putative plastid-targeting sequences (GenBank accession nos. AF132854 and AF132855). Relative CA transcript abundance and enzyme activity increased 9 and 15 times, respectively, in cotton embryos during the maximum period of reserve oil accumulation. Specific sulfonamide inhibitors of CA activity significantly reduced the rate of [ 14 C]acetate incorporation into total lipids in cotton embryos in vivo, and in embryo plastids in vitro, suggesting a role for CA in plastid lipid biosynthesis. CA inhibitors did not affect acetyl-coenzyme A carboxylase activity or total storage protein synthesis. Similar results were obtained for two other plant systems: cell suspensions (and isolated plastids therefrom) of tobacco (Nicotiana tabacum), and chloroplasts isolated from leaves of transgenic CA antisensesuppressed tobacco plants (5% of wild-type CA activity). In addition, tobacco cell suspensions treated with the CA inhibitor ethoxyzolamide showed a substantial loss of CO 2 compared with controls. The rate of [ 14 C]acetate incorporation into lipid in cell suspensions was reduced by limiting external [CO 2 ] (scrubbed air), and this rate was further reduced in the presence of ethoxyzolamide. Together, these results indicate that a reduction of CA activity (biochemical or molecular inhibition) impacts the rate of plant lipid biosynthesis from acetate, perhaps by impairing the ability of CA to efficiently "trap" inorganic carbon inside plastids for utilization by acetyl-coenzyme A carboxylase and the fatty acid synthesis machinery.Carbonic anhydrase (CA, EC 4.2.1.1) is a zinccontaining metalloenzyme that catalyzes the reversible hydration of CO 2 to HCO 3 Ϫ . The widespread abundance of CA isoforms in plants, animals, and microorganisms suggest that this enzyme has many diverse roles in biological processes. CA plays a critical role in biological systems because CO 2 gas is the membrane permeable form of inorganic carbon for cells, and, in general, the uncatalyzed interconversion between HCO 3 Ϫ and CO 2 is slow when compared with the required rate in living cells (Badger and Price, 1994).In photosynthetic organisms, one generally accepted physiological role of CA is to provide sufficient levels of inorganic carbon as part of a CO 2 -concentrating mechanism for improved photosynthetic efficiency. In Chlamydomonas reinhardtii, Badger and Price (1992) suggested that chloroplastic CA plays a role in photosynthetic carbon assimilation by converting accumulated pools of HCO 3 Ϫ to CO 2 , which is the substrate for Rubisco. Moroney et al. (1985) revealed that the reduction of periplasmic CA activity by using CAspecific inhibitors significantly reduced the efficiency of external inorganic carbon utilization for photosynthesis. Like green algae, CA in cyanobacteria plays an important role in the CO 2 -concentrating mechanism and in photosynthesis (Badger an...

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Role of hepatic carbonic anhydrase in de novo lipogenesis

Cited by 94 publications

References 29 publications

Adverse effects of organophosphorus pesticides on the liver: a brief summary of four decades of research

Adverse effects of organophosphorus pesticides on the liver: a brief summary of four decades of research

Role of Pyruvate Carboxylase in Facilitation of Synthesis of Glutamate and Glutamine in Cultured Astrocytes

Biochemical and Molecular Inhibition of Plastidial Carbonic Anhydrase Reduces the Incorporation of Acetate into Lipids in Cotton Embryos and Tobacco Cell Suspensions and Leaves

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