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 language | English (US) |
|---|---|
| Pages (from-to) | 1291-1305.e8 |
| Journal | Cell Metabolism |
| Volume | 29 |
| Issue number | 6 |
| DOIs | |
| State | Published - Jun 4 2019 |
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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
Pyruvate-Carboxylase-Mediated Anaplerosis Promotes Antioxidant Capacity by Sustaining TCA Cycle and Redox Metabolism in Liver. / Cappel, David A.; Deja, Stanisław; Duarte, João A.G.; Kucejova, Blanka; Iñigo, Melissa; Fletcher, Justin A.; Fu, Xiaorong; Berglund, Eric D.; Liu, Tiemin; Elmquist, Joel K.; Hammer, Suntrea; Mishra, Prashant; Browning, Jeffrey D.; Burgess, Shawn C.
In: Cell Metabolism, Vol. 29, No. 6, 04.06.2019, p. 1291-1305.e8.Research output: Contribution to journal › Article
}
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
UR - http://www.scopus.com/inward/record.url?scp=85066266268&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85066266268&partnerID=8YFLogxK
U2 - 10.1016/j.cmet.2019.03.014
DO - 10.1016/j.cmet.2019.03.014
M3 - Article
C2 - 31006591
AN - SCOPUS:85066266268
VL - 29
SP - 1291-1305.e8
JO - Cell Metabolism
JF - Cell Metabolism
SN - 1550-4131
IS - 6
ER -