Liver Glutamate Dehydrogenase Controls Whole-Body Energy Partitioning Through Amino Acid-Derived Gluconeogenesis and Ammonia Homeostasis

Diabetes
Melis KaracaPierre Maechler

Abstract

Ammonia detoxification and gluconeogenesis are major hepatic functions mutually connected through amino acid metabolism. The liver is rich in glutamate dehydrogenase (GDH) that catalyzes the reversible oxidative deamination of glutamate to α-ketoglutarate and ammonia, thus bridging amino acid-to-glucose pathways. Here we generated inducible liver-specific GDH-knockout mice (HepGlud1-/- ) to explore the role of hepatic GDH on metabolic homeostasis. Investigation of nitrogen metabolism revealed altered ammonia homeostasis in HepGlud1-/- mice characterized by increased circulating ammonia associated with reduced detoxification process into urea. The abrogation of hepatic GDH also modified energy homeostasis. In the fasting state, HepGlud1-/- mice could barely produce glucose in response to alanine due to impaired liver gluconeogenesis. Compared with control mice, lipid consumption in HepGlud1-/- mice was favored over carbohydrates as a compensatory energy fuel. The changes in energy partitioning induced by the lack of liver GDH modified the circadian rhythm of food intake. Overall, this study demonstrates the central role of hepatic GDH as a major regulator for the maintenance of ammonia and whole-body energy homeostasis.

References

Aug 1, 1991·The Journal of Histochemistry and Cytochemistry : Official Journal of the Histochemistry Society·I P Maly, D Sasse
Jul 1, 1990·Physiological Reviews·A J MeijerR A Chamuleau
Mar 19, 1970·The New England Journal of Medicine·G F Cahill
Jan 1, 1995·The Journal of Clinical Investigation·N NurjhanJ E Gerich
Oct 3, 1999·The Journal of Biological Chemistry·I NissimJ T Brosnan
Jan 25, 2000·American Journal of Physiology. Endocrinology and Metabolism·Y BurelleX Leverve
Mar 11, 2000·American Journal of Physiology. Endocrinology and Metabolism·D YangH Brunengraber
Jan 30, 2004·The American Journal of Clinical Nutrition·Marcel C G van de PollCornelis H C Dejong
Jul 30, 2004·Genesis : the Journal of Genetics and Development·Michael SchulerDaniel Metzger
Jul 20, 2006·Annual Review of Nutrition·George F Cahill
Jul 25, 2009·The American Journal of Clinical Nutrition·Margaret E Brosnan, John T Brosnan
Nov 6, 2009·American Journal of Physiology. Endocrinology and Metabolism·Matthew D BrussMarc K Hellerstein
Mar 25, 2010·American Journal of Physiology. Endocrinology and Metabolism·Jason R TrebergJohn T Brosnan
Aug 3, 2010·Liver International : Official Journal of the International Association for the Study of the Liver·Gavin WrightRajiv Jalan
Aug 28, 2012·Metabolism: Clinical and Experimental·Maria M AdevaCristóbal Donapetry
Apr 3, 2014·Comprehensive Physiology·Liangyou Rui
Nov 10, 2015·Molecular Aspects of Medicine·Kfir SharabiPere Puigserver
Dec 8, 2015·Journal of Hepatology·Ahmed GhallabJan G Hengstler

❮ Previous
Next ❯

Citations

Nov 7, 2019·Molecular and Cellular Biology·Eisha ShawUllas Kolthur-Seetharam
Feb 29, 2020·Diabetes, Metabolic Syndrome and Obesity : Targets and Therapy·Raquel Benedé-UbietoYulia A Nevzorova
Oct 23, 2020·International Journal of Molecular Sciences·Xavier Remesar, Marià Alemany
Feb 6, 2021·BioMed Research International·Meng ZhangZhigang Wang
Aug 8, 2020·Neurochemistry International·Yun ZhouNiels Christian Danbolt
Aug 28, 2021·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Xiaoyu LiaoRui Liu
Jul 17, 2021·Annual Review of Nutrition·Melissa InigoShawn C Burgess
Jul 4, 2021·Nature Communications·Franziska R TraubeThomas Carell
Dec 4, 2021·Nature Communications·Ozren StojanovićMirko Trajkovski

❮ Previous
Next ❯

Related Concepts

Related Feeds

American Diabetes Association Journals

Discover the latest diabetes research published by the journals from the American Diabetes Association.

© 2022 Meta ULC. All rights reserved