@article{d884c7d9992c4387b2f4859801d95dcd,
title = "Pyruvate-Carboxylase-Mediated Anaplerosis Promotes Antioxidant Capacity by Sustaining TCA Cycle and Redox Metabolism in Liver",
abstract = "The hepatic TCA cycle supports oxidative and biosynthetic metabolism. This dual responsibility requires anaplerotic pathways, such as pyruvate carboxylase (PC), to generate TCA cycle intermediates necessary for biosynthesis without disrupting oxidative metabolism. Liver-specific PC knockout (LPCKO)mice were created to test the role of anaplerotic flux in liver metabolism. LPCKO mice have impaired hepatic anaplerosis, diminution of TCA cycle intermediates, suppressed gluconeogenesis, reduced TCA cycle flux, and a compensatory increase in ketogenesis and renal gluconeogenesis. Loss of PC depleted aspartate and compromised urea cycle function, causing elevated urea cycle intermediates and hyperammonemia. Loss of PC prevented diet-induced hyperglycemia and insulin resistance but depleted NADPH and glutathione, which exacerbated oxidative stress and correlated with elevated liver inflammation. Thus, despite catalyzing the synthesis of intermediates also produced by other anaplerotic pathways, PC is specifically necessary for maintaining oxidation, biosynthesis, and pathways distal to the TCA cycle, such as antioxidant defenses.",
keywords = "TCA cycle, anaplerosis, gluconeogenesis, high-fat diet, liver physiology, metabolic flux, oxidative stress, pyruvate carboxylase, urea cycle",
author = "Cappel, {David A.} and Stanis{\l}aw Deja and Duarte, {Jo{\~a}o A.G.} and Blanka Kucejova and Melissa I{\~n}igo and Fletcher, {Justin A.} and Xiaorong Fu and Berglund, {Eric D.} and Tiemin Liu and Elmquist, {Joel K.} and Suntrea Hammer and Prashant Mishra and Browning, {Jeffrey D.} and Burgess, {Shawn C.}",
note = "Funding Information: The authors acknowledge the UT Southwestern Metabolic Phenotyping Core for their assistance with the calorimetry studies. Tianteng He, Xiaoli Lin, and Wei Zhang provided surgical expertise for the liver perfusion studies. PCf/f mice were created with support from UT Southwestern Medical Center (S.C.B.). Metabolic analysis was supported by NIH R01DK078184 (S.C.B.), P41EB015908 (S.C.B. and S.D.)and the Robert A. Welch Foundation I-1804 (S.C.B. and S.D.). D.A.C. was supported by F32DK105741. Conceptualization, S.C.B. S.D. and D.A.C.; Methodology, J.A.G.D. T.L. S.D. B.K. J.A.F. M.I. and X.F.; Investigation, D.A.C. S.D. X.F. and S.H.; Resources, P.M. E.D.B. and J.K.E.; Writing – Original Draft, S.C.B. and D.A.C.; Writing – Review & Editing, S.C.B. D.A.C. and S.D. Funding Acquisition, S.C.B. and D.A.C.; Supervision, S.C.B. J.D.B. and J.K.E. The authors declare no competing interests. Funding Information: The authors acknowledge the UT Southwestern Metabolic Phenotyping Core for their assistance with the calorimetry studies. Tianteng He, Xiaoli Lin, and Wei Zhang provided surgical expertise for the liver perfusion studies. PC f/f mice were created with support from UT Southwestern Medical Center (S.C.B.). Metabolic analysis was supported by NIH R01DK078184 (S.C.B.), P41EB015908 (S.C.B. and S.D.) and the Robert A. Welch Foundation I-1804 (S.C.B. and S.D.). D.A.C. was supported by F32DK105741 . ",
year = "2019",
month = jun,
day = "4",
doi = "10.1016/j.cmet.2019.03.014",
language = "English (US)",
volume = "29",
pages = "1291--1305.e8",
journal = "Cell Metabolism",
issn = "1550-4131",
publisher = "Cell Press",
number = "6",
}