Molecular physiology of the regulation of hepatic gluconeogenesis and glycolysis.
Abstract
Understanding the regulation of hepatic glucose metabolism had its foundation in the elucidation of several pathways, but recent advances have come from the application of molecular genetics. Five years ago little was known about the primary structure of the key regulatory enzymes. Since then, the primary sequence of liver GK, 6-PF-1-K, Fru-1,6-P2ase, PK, PEPCK, and 6-PF-2-K/Fru-2,6-P2ase have been derived from cDNA sequences and/or determined by direct protein sequencing. This has provided new insights into the molecular mechanisms of catalysis and the regulation of these enzymes by covalent modification. Isolation of the cDNAs for these enzymes also has allowed for the quantitation of specific mRNAs and permitted analysis of hormonal control of specific gene expression. The genes for these enzymes have been isolated and sequenced, and their promoter regions are being identified and characterized. Hormone response elements have been delineated in several of the promoters. The promoter regions for 6-PF-2-K/Fru-2,6-P2ase and Fru-1,6-P2ase have also been identified, and future research will focus on the elucidation of the mechanisms whereby hormones regulate the expression of these genes. A number of generalizations can be made about the regulation of gene expression of glycolytic/gluconeogenic enzymes. First, there is coordinate hormonal regulation of gene expression and these effects are consonant with their physiologic actions. Insulin induces the mRNAs that encode glycolytic enzymes and represses the mRNAs that encode gluconeogenic enzymes; cAMP has opposite effects. Both can increase or decrease transcription. Whereas insulin and cAMP affect all of these mRNAs, glucocorticoids appear to have a more restricted action. Second, transcriptional and posttranscriptional regulatory mechanisms are involved. The synthesis of all of the mRNAs discussed is regulated by hormones. Relatively little is known about how mRNA stability is regulated in general, but it is clear that PEPCK mRNA is stabilized by agents that increase the rate of transcription of the gene. Under appropriate metabolic signals this dual control of mRNA synthesis and stability provides for a long-term increase in PEPCK mRNA and protein. Studies with PK mRNA are less direct, but suggest a similar dual mechanism. It will be interesting to see whether multilevel regulation is restricted to these two mRNAs, both of which are involved in the same substrate cycle, or whether the stability of other mRNAs involved in hepatic glucose metabolism is also affected. Third, glucose appears to be important in the regulation of these hepatic genes.(ABSTRACT TRUNCATED AT 400 WORDS)
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The kinetics of the interconvertible enzymes, and consequently also the hepatic glucose metabolism, depends on their phosphorylation state, which is altered by the hormones.
“The kinetics of the interconvertible enzymes, and consequently also the hepatic glucose metabolism, depends on their phosphorylation state [2], [14] which is altered by the hormones.”
From Quantifying the Contribution of the Liver to Glucose Homeostasis: A Detailed Kinetic Model of Human Hepatic Glucose Metabolism (2012) · cites this paper as [14]
Cites
Hormonal control of pyruvate kinase activity and of gluconeogenesis in isolated hepatocytes.
Feliú, J. E., Hue, L., & Hers, H. G. (1976) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.73.8.2762 · Cited by 220 · see citing works
Decaux, J. F., Antoine, B., & Kahn, A. (1989) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)80103-x · Cited by 172 · see citing works
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Sapolsky, R. M., Romero, L. M., & Munck, A. U. (2000) · Endocrine Reviews · doi:10.1210/edrv.21.1.0389 · Cited by 7,541 · see citing works
Insulin signalling and the regulation of glucose and lipid metabolism
Saltiel, A. R., & Kahn, C. R. (2001) · Nature · doi:10.1038/414799a · Cited by 5,326 · see citing works
Control of hepatic gluconeogenesis through the transcriptional coactivator PGC-1
Yoon, J. C., Puigserver, P., Chen, G., Donovan, J., Wu, Z., Rhee, J., Adelmant, G., Stafford, J., Kahn, C. R., Granner, D. K., et al. (2001) · Nature · doi:10.1038/35093050 · Cited by 1,821 · see citing works
Self-citationDefects in Adaptive Energy Metabolism with CNS-Linked Hyperactivity in PGC-1α Null Mice
Lin, J., Wu, P.-H., Tarr, P. T., Lindenberg, K. S., St-Pierre, J., Zhang, C.-Y., Mootha, V. K., Jäger, S., Vianna, C. R., Reznick, R. M., et al. (2004) · Cell · doi:10.1016/j.cell.2004.09.013 · Cited by 1,162 · see citing works
Cole, T. J., Blendy, J. A., Monaghan, A. P., Krieglstein, K., Schmid, W., Aguzzi, A., Fantuzzi, G., Hummler, E., Unsicker, K., & Schütz, G. (1995) · Genes & Development · doi:10.1101/gad.9.13.1608 · Cited by 946 · see citing works
Regulation of glucose homeostasis by glucocorticoids
Kuo, T., McQueen, A., Chen, T.-C., & Wang, J.-C. (2015) · Advances in Experimental Medicine and Biology · doi:10.1007/978-1-4939-2895-8_5 · Cited by 723 · see citing works
Perry, R. J., Camporez, J.-P. G., Kursawe, R., Titchenell, P. M., Zhang, D., Perry, C. J., Jurczak, M. J., Abudukadier, A., Han, M. S., Zhang, X.-M., et al. (2015) · Cell · doi:10.1016/j.cell.2015.01.012 · Cited by 719 · see citing works
Glucocorticoids, metabolism and metabolic diseases
Vegiopoulos, A., & Herzig, S. (2007) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2007.05.015 · Cited by 535 · see citing works
Physiology of Proglucagon Peptides: Role of Glucagon and GLP-1 in Health and Disease
Sandoval, D. A., & D'Alessio, D. A. (2015) · Physiological Reviews · doi:10.1152/physrev.00013.2014 · Cited by 498 · see citing works
Insulin signaling in health and disease
Saltiel, A. R. (2021) · Journal of Clinical Investigation · doi:10.1172/jci142241 · Cited by 446 · see citing works
Unraveling the regulation of hepatic gluconeogenesis
Zhang, X., Yang, S., Chen, J., & Su, Z. (2019) · Frontiers in Endocrinology · doi:10.3389/fendo.2018.00802 · Cited by 314 · see citing works
Xin, C., Liu, J., Zhang, J., Zhu, D., Wang, H., Xiong, L., Lee, Y., Ye, J., Lian, K., Xu, C., et al. (2016) · International Journal of Obesity · doi:10.1038/ijo.2015.199 · Cited by 248 · see citing works
PGC-1β in the Regulation of Hepatic Glucose and Energy Metabolism
Lin, J., Tarr, P. T., Yang, R., Rhee, J., Puigserver, P., Newgard, C. B., & Spiegelman, B. M. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m303643200 · Cited by 242 · see citing works
Intracerebroventricular Leptin Regulates Hepatic but Not Peripheral Glucose Fluxes
Liu, L., Karkanias, G. B., Morales, J. C., Hawkins, M., Barzilai, N., Wang, J., & Rossetti, L. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.47.31160 · Cited by 222 · see citing works
König, M., Bulik, S., & Holzhütter, H.-G. (2012) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1002577 · Cited by 202 · see citing works
MicroRNA 33 Regulates Glucose Metabolism
Ramírez, C. M., Goedeke, L., Rotllan, N., Yoon, J.-H., Cirera-Salinas, D., Mattison, J. A., Suárez, Y., de Cabo, R., Gorospe, M., & Fernández-Hernando, C. (2013) · Molecular and Cellular Biology · doi:10.1128/mcb.00016-13 · Cited by 154 · see citing works
A review of low-carbohydrate ketogenic diets
Westman, E. C., Mavropoulos, J., Yancy, W. S., & Volek, J. S. (2003) · Current Atherosclerosis Reports · doi:10.1007/s11883-003-0038-6 · Cited by 133 · see citing works
Signalling mechanisms linking hepatic glucose and lipid metabolism
Weickert, M. O., & Pfeiffer, A. F. H. (2006) · Diabetologia · doi:10.1007/s00125-006-0295-3 · Cited by 127 · see citing works
Mechanism of fat-induced hepatic gluconeogenesis: effect of metformin
Song, S., Andrikopoulos, S., Filippis, C., Thorburn, A. W., Khan, D., & Proietto, J. (2001) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.2001.281.2.e275 · Cited by 122 · see citing works
van den Hoek, A. M., Voshol, P. J., Karnekamp, B. N., Buijs, R. M., Romijn, J. A., Havekes, L. M., & Pijl, H. (2004) · Diabetes · doi:10.2337/diabetes.53.10.2529 · Cited by 109 · see citing works
Thorn, S. R., Brown, L. D., Rozance, P. J., Hay, W. W., & Friedman, J. E. (2013) · Diabetes · doi:10.2337/db11-1727 · Cited by 89 · see citing works
Schmoll, D., Allan, B. B., & Burchell, A. (1996) · FEBS Letters · doi:10.1016/0014-5793(96)00224-4 · Cited by 78 · see citing works
Hannon, M. J., Sherlock, M., & Thompson, C. J. (2011) · Best Practice & Research Clinical Endocrinology & Metabolism · doi:10.1016/j.beem.2011.06.001 · Cited by 69 · see citing works
Warrier, M., Hinds, T. D., Ledford, K. J., Cash, H. A., Patel, P. R., Bowman, T. A., Stechschulte, L. A., Yong, W., Shou, W., Najjar, S. M., et al. (2010) · Endocrinology · doi:10.1210/en.2009-1158 · Cited by 57 · see citing works
Liu, G., Grifman, M., Keily, B., Chatterton, J. E., Staal, F.-W., & Li, Q.-X. (2006) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2006.02.065 · Cited by 28 · see citing works
- Authors
- Pilkis, S. J., & Granner, D. K.
- Affiliations
- Stony Brook University (US)
- Venue
- Annual Review of Physiology
- Publisher
- Annual Reviews
- Published
- 1992-10
- Volume
- 54
- Issue
- 1
- Pages
- 885-909
- ISSN
- 0066-4278 (ISSN-L)
- 1545-1585
- OpenAlex
- W2175518322
- Cited by
- 865
- References
- 2
- Citations by year
- 2026: 8 · 2025: 13 · 2024: 15 · 2023: 24 · 2022: 15 · 2021: 35 · 2020: 25 · 2019: 14 · 2018: 38 · 2017: 30 · 2016: 31 · 2015: 47 · 2014: 37 · 2013: 39 · 2012: 46
- FWCI
- 4.37
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Annual Review of Physiology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Health Sciences › Medicine › Rheumatology › Glycogen Storage Diseases and Myoclonus
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Keywords
- hepatic gluconeogenesis, hepatic glycolysis, hepatic glucose metabolism, glucose-6-phosphatase, fructose-1,6-bisphosphatase, fructose-2,6-bisphosphatase, phosphoenolpyruvate carboxykinase, pyruvate kinase, cyclic AMP, insulin, glucocorticoids, hormone response elements, gene expression regulation, mRNA stability, post-translational regulation, enzyme regulation, cDNA sequencing
- MeSH terms
- Animals, Enzymes, Gene Expression Regulation, Gluconeogenesis, Glycolysis, Humans, Liver, Substrate Cycling
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