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Mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase: a control enzyme in ketogenesis
Open accessAbstract
Cytosolic and mitochondrial 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) synthases were first recognized as different chemical entities in 1975, when they were purified and characterized by Lane's group. Since then, the two enzymes have been studied extensively, one as a control site of the cholesterol biosynthetic pathway and the other as an important control site of ketogenesis. This review describes some key developments over the last 25 years that have led to our current understanding of the physiology of mitochondrial HMG-CoA synthase in the HMG-CoA pathway and in ketogenesis in the liver and small intestine of suckling animals. The enzyme is regulated by two systems: succinylation and desuccinylation in the short term, and transcriptional regulation in the long term. Both control mechanisms are influenced by nutritional and hormonal factors, which explains the incidence of ketogenesis in diabetes and starvation, during intense lipolysis, and in the foetal-neonatal and suckling-weaning transitions. The DNA-binding properties of the peroxisome-proliferator-activated receptor and other transcription factors on the nuclear-receptor-responsive element of the mitochondrial HMG-CoA synthase promoter have revealed how ketogenesis can be regulated by fatty acids. Finally, the expression of mitochondrial HMG-CoA synthase in the gonads and the correction of auxotrophy for mevalonate in cells deficient in cytosolic HMG-CoA synthase suggest that the mitochondrial enzyme may play a role in cholesterogenesis in gonadal and other tissues.
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Cites
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Newman, J. C., & Verdin, E. (2014) · Trends in Endocrinology & Metabolism · doi:10.1016/j.tem.2013.09.002 · Cited by 966
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Newman, J. C., & Verdin, E. (2017) · Annual Review of Nutrition · doi:10.1146/annurev-nutr-071816-064916 · Cited by 872
“HMGCS2 gene expression is also regulated indirectly by the target of rapamycin complex mTORC1; mTORC1 inhibition is required for the activation of peroxisome proliferator-activated receptor alpha (PPARα) and fibroblast growth factor 21 (FGF21), both of which are required to induce ketogenesis (3, 4, 49, 117).”
Shimazu, T., Hirschey, M. D., Hua, L., Dittenhafer-Reed, K. E., Schwer, B., Lombard, D. B., Li, Y., Bunkenborg, J., Alt, F. W., Denu, J. M., et al. (2010) · Cell Metabolism · doi:10.1016/j.cmet.2010.11.003 · Cited by 484
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Crawford, P. A., Crowley, J. R., Sambandam, N., Muegge, B. D., Costello, E. K., Hamady, M., Knight, R., & Gordon, J. I. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0902366106 · Cited by 278
Nuclear receptors CAR and PXR: Molecular, functional, and biomedical aspects
di Masi, A., Marinis, E. D., Ascenzi, P., & Marino, M. (2009) · Molecular Aspects of Medicine · doi:10.1016/j.mam.2009.04.002 · Cited by 288
Ketone body metabolism and sleep homeostasis in mice
Chikahisa, S., Shimizu, N., Shiuchi, T., & Séi, H. (2014) · Neuropharmacology · doi:10.1016/j.neuropharm.2013.12.009 · Cited by 37
Hu, L.-T., Zhu, B.-L., Lai, Y.-J., Long, Y., Zha, J.-S., Hu, X.-T., Zhang, J. H., & Chen, G.-J. (2017) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2017.03.069 · Cited by 35
Ketogenesis supports hepatic polyunsaturated fatty acid homeostasis via fatty acid elongation
Queathem, E. D., Moazzami, Z., Stagg, D. B., Nelson, A. B., Fulghum, K., Hayir, A., Seay, A., Gillingham, J. R., d’Avignon, D. A., Han, X., et al. (2025) · Science Advances · doi:10.1126/sciadv.ads0535 · Cited by 30
HMGCS2-Induced Autophagic Degradation of Tau Involves Ketone Body and ANKRD24
Hu, L.-T., Xie, X.-Y., Zhou, G.-F., Wen, Q.-X., Song, L., Luo, B., Deng, X.-J., Pan, Q.-L., & Chen, G.-J. (2023) · Journal of Alzheimer's Disease · doi:10.3233/jad-220640 · Cited by 14
Metadata
- Authors
- Hegardt, F. G.
- Venue
- Biochemical Journal
- Publisher
- Portland Press
- Published
- 1999-03-08
- Volume
- 338
- Issue
- 3
- Pages
- 569-569
- ISSN
- 0264-6021 (ISSN-L)
- OpenAlex
- W1994864081
- Cited by
- 374
- References
- 4
- FWCI
- 9.08
- Type
- journal article
- Language
- en
- Open access
- bronze
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