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.

Original languageEnglish (US)
Pages (from-to)1291-1305.e8
JournalCell Metabolism
Volume29
Issue number6
DOIs
StatePublished - Jun 4 2019

Fingerprint

Pyruvate Carboxylase
Oxidation-Reduction
Antioxidants
Liver
Gluconeogenesis
Knockout Mice
Urea
Hyperammonemia
NADP
Aspartic Acid
Hyperglycemia
Glutathione
Insulin Resistance
Oxidative Stress
Diet
Inflammation
Kidney

Keywords

  • anaplerosis
  • gluconeogenesis
  • high-fat diet
  • liver physiology
  • metabolic flux
  • oxidative stress
  • pyruvate carboxylase
  • TCA cycle
  • urea cycle

ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Cell Biology

Cite this

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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 = "anaplerosis, gluconeogenesis, high-fat diet, liver physiology, metabolic flux, oxidative stress, pyruvate carboxylase, TCA cycle, urea cycle",
author = "Cappel, {David A.} and Stanisław 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.}",
year = "2019",
month = "6",
day = "4",
doi = "10.1016/j.cmet.2019.03.014",
language = "English (US)",
volume = "29",
pages = "1291--1305.e8",
journal = "Cell Metabolism",
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number = "6",

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TY - JOUR

T1 - Pyruvate-Carboxylase-Mediated Anaplerosis Promotes Antioxidant Capacity by Sustaining TCA Cycle and Redox Metabolism in Liver

AU - Cappel, David A.

AU - Deja, Stanisław

AU - Duarte, João A.G.

AU - Kucejova, Blanka

AU - Iñigo, Melissa

AU - Fletcher, Justin A.

AU - Fu, Xiaorong

AU - Berglund, Eric D.

AU - Liu, Tiemin

AU - Elmquist, Joel K.

AU - Hammer, Suntrea

AU - Mishra, Prashant

AU - Browning, Jeffrey D.

AU - Burgess, Shawn C.

PY - 2019/6/4

Y1 - 2019/6/4

N2 - 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.

AB - 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.

KW - anaplerosis

KW - gluconeogenesis

KW - high-fat diet

KW - liver physiology

KW - metabolic flux

KW - oxidative stress

KW - pyruvate carboxylase

KW - TCA cycle

KW - urea cycle

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