Distribution of pyruvate carboxylase and phosphoenol‐pyruvate carboxikinase in human liver

Wieland, O.; Evertz-Prüsse, E.; Stukowski, Barbara

doi:10.1016/0014-5793(68)80091-2

Cited by 25 publications

(7 citation statements)

References 4 publications

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“…However, the mitochondrial isoform makes up about half of the total hepatic PEPCK activity in other mammals, including humans [14-16]. In marked contrast to rat mitochondria that produced little or no PEP, mitochondria from these other species exhibit high rates of PEP production and export from TCA cycle intermediates [17-21].…”

Section: Introductionmentioning

confidence: 99%

PEPCK-M expression in mouse liver potentiates, not replaces, PEPCK-C mediated gluconeogenesis

Méndez-Lucas

Duarte

Sunny

et al. 2013

Journal of Hepatology

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Background & Aims Hepatic gluconeogenesis helps maintain systemic energy homeostasis by compensating for discontinuities in nutrient supply. Liver specific deletion of cytosolic phosphoenolpyruvate carboxykinase (PEPCK-C) abolishes gluconeogenesis from mitochondrial substrates, deregulates lipid metabolism and affects TCA cycle. While, mouse liver almost exclusively expresses PEPCK-C, humans equally present a mitochondrial isozyme (PEPCK-M). Despite clear relevance to human physiology, the role of PEPCK-M and its gluconeogenic potential remain unknown. Here, we test the significance of PEPCK-M in gluconeogenesis and TCA cycle function in liver-specific PEPCK-C knockout and WT mice. Methods The effects of the overexpression of PEPCK-M were examined by a combination of tracer studies and molecular biology techniques. Partial PEPCK-C re-expression was used as a positive control. Metabolic fluxes were evaluated in isolated livers by NMR using 2H and 13C tracers. Gluconeogenic potential, together with metabolic profiling, were investigated in vivo and in primary hepatocytes. Results PEPCK-M expression partially rescued defects in lipid metabolism, gluconeogenesis and TCA cycle function impaired by PEPCK-C deletion, while ~10% re-expression of PEPCK-C normalized most parameters. When PEPCK-M was expressed in the presence of PEPCK-C, the mitochondrial isozyme amplified total gluconeogenic capacity, suggesting autonomous regulation of oxaloacetate to phosphoenolpyruvate fluxes by the individual isoforms. Conclusions We conclude that PEPCK-M has gluconeogenic potential per se, and cooperates with PEPCK-C to adjust gluconeogenic/TCA flux to changes in substrate or energy availability, hinting at a role in the regulation of glucose and lipid metabolism in human liver.

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Section: Introductionmentioning

confidence: 99%

PEPCK-M expression in mouse liver potentiates, not replaces, PEPCK-C mediated gluconeogenesis

Méndez-Lucas

Duarte

Sunny

et al. 2013

Journal of Hepatology

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“…In liver and kidney the relative intracellular distribution varies widely with the species. Thus in rat liver 80-90 % of total PCK activity is cytosolic and 10-20 % mitochondrial [3][4][5], in human liver 30-50 % is cytosolic and 50-70 % mitochondrial [6][7][8], in guinea pig liver 15-20 % is cytosolic and 80-85 % mitochondrial [2,4,9], and in chicken liver approx. 95 % is mitochondrial [10].…”

Section: Introductionmentioning

confidence: 99%

Human mitochondrial phosphoenolpyruvate carboxykinase 2 gene

Modaressi

Brechtel

Christ

et al. 1998

Biochemical Journal

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The mitochodrial (mt) phosphoenolpyruvate carboxykinase 2 (PCK2) gene was isolated by screening a human genomic library with a rat cytosolic (cy) PCK1 cDNA probe comprising sequences from exons 2-9 and by PCR amplification of human genomic DNA spanning consecutive exons with known primer pairs from mtPCK2 cDNA containing sequences from two putative neighbouring exons. The mtPCK2 gene spans approx. 10 kb and consists of ten exons and nine introns. All exon-intron junction sequences match the classical GT/AG rule. Northern blot analysis of poly(A)+ and total RNA from various tissues revealed one mRNA species of approx. 2.4 kb. The gene is expressed in a variety of human tissues, mainly in liver, kidney, pancreas, intestine and fibroblasts. In contrast with the cytosolic isoenzyme, the mitochondrial form might not have a purely gluconeogenic function. The mtPCK2 gene maps to chromosome 14q11.2-q12, in contrast with the cyPCK1 gene located on 20q13.2-q13.31.

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“…Studies on human liver clinical biopsy material using histochemical and micro-dissection techniques have shown that the activities of glucose-6-phosphatase and fructose bisphosphatase predominate in the periportal zone [6,7], as in rat liver, whereas the activity of phosphoenolpyruvate carboxykinase appears to be uniform across the portal to venous axis of the acinus [8]. In human liver, a high proportion of the total activity of phosphoenolpyruvate carboxykinase activity is present in the mitochondria [9][10][11], unlike in the rat, where the activity is predominantly in the cytosol [12][13][14]. Since the cytosolic and mitochondrial activities of phosphoenolpyruvate carboxykinase represent distinct proteins with no immune cross-reactivity between them [15,16] and are regulated differently in response to hormones [13], the question arises whether differences in the acinar zonation of the total cellular activity of phosphoenolpyruvate carboxykinase between rat and human liver [8] could be related to differences in the relative activities of the cytosolic and mitochondrial enzymes in the two species.…”

Section: Introductionmentioning

confidence: 99%

Acinar zonation of cytosolic but not organelle-bound activities of phosphoenolpyruvate carboxykinase and aspartate aminotransferase in guinea-pig liver

Agius

Tosh

1990

Biochemical Journal

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In human liver, unlike in rat liver, there is no apparent acinar heterogeneity of total cellular activity of phosphoenolpyruvate carboxykinase [Wimmer, Luttringer & Columbi (1990) Histochemistry 93, 409-415]. Since the intracellular compartmentation of phosphoenolpyruvate carbonxykinase differs in rat and human liver, we examined the acinar heterogeneity of cytosolic and organelle-bound activities of this enzyme in the guinea pig, which shows a more similar intracellular compartmentation of enzyme activity to human liver than does the rat. Cytosolic phosphoenolpyruvate carboxykinase activity was higher in periportal than in perivenous hepatocytes, whereas the organelle-bound activity was similar in the two cell populations. Aspartate aminotransferase and alanine aminotransferase activities showed a similar distribution to phosphoenolpyruvate carboxykinase, with a higher cytosolic activity in periportal than in perivenous hepatocytes but a similar organelle-bound activity in the two cell populations. Data on the acinar zonation of enzymes determined in whole cells or tissue should be interpreted cautiously if the enzyme activity is present in more than one subcellular compartment.

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Distribution of pyruvate carboxylase and phosphoenol‐pyruvate carboxikinase in human liver

Cited by 25 publications

References 4 publications

PEPCK-M expression in mouse liver potentiates, not replaces, PEPCK-C mediated gluconeogenesis

PEPCK-M expression in mouse liver potentiates, not replaces, PEPCK-C mediated gluconeogenesis

Human mitochondrial phosphoenolpyruvate carboxykinase 2 gene

Acinar zonation of cytosolic but not organelle-bound activities of phosphoenolpyruvate carboxykinase and aspartate aminotransferase in guinea-pig liver

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