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The mitochondrial pyruvate carrier mediates high fat diet-induced increases in hepatic TCA cycle capacity

OBJECTIVE: Excessive hepatic gluconeogenesis is a defining feature of type 2 diabetes (T2D). Most gluconeogenic flux is routed through mitochondria. The mitochondrial pyruvate carrier (MPC) transports pyruvate from the cytosol into the mitochondrial matrix, thereby gating pyruvate-driven gluconeogen...

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Autores principales: Rauckhorst, Adam J., Gray, Lawrence R., Sheldon, Ryan D., Fu, Xiaorong, Pewa, Alvin D., Feddersen, Charlotte R., Dupuy, Adam J., Gibson-Corley, Katherine N., Cox, James E., Burgess, Shawn C., Taylor, Eric B.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5681281/
https://www.ncbi.nlm.nih.gov/pubmed/29107293
http://dx.doi.org/10.1016/j.molmet.2017.09.002
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author Rauckhorst, Adam J.
Gray, Lawrence R.
Sheldon, Ryan D.
Fu, Xiaorong
Pewa, Alvin D.
Feddersen, Charlotte R.
Dupuy, Adam J.
Gibson-Corley, Katherine N.
Cox, James E.
Burgess, Shawn C.
Taylor, Eric B.
author_facet Rauckhorst, Adam J.
Gray, Lawrence R.
Sheldon, Ryan D.
Fu, Xiaorong
Pewa, Alvin D.
Feddersen, Charlotte R.
Dupuy, Adam J.
Gibson-Corley, Katherine N.
Cox, James E.
Burgess, Shawn C.
Taylor, Eric B.
author_sort Rauckhorst, Adam J.
collection PubMed
description OBJECTIVE: Excessive hepatic gluconeogenesis is a defining feature of type 2 diabetes (T2D). Most gluconeogenic flux is routed through mitochondria. The mitochondrial pyruvate carrier (MPC) transports pyruvate from the cytosol into the mitochondrial matrix, thereby gating pyruvate-driven gluconeogenesis. Disruption of the hepatocyte MPC attenuates hyperglycemia in mice during high fat diet (HFD)-induced obesity but exerts minimal effects on glycemia in normal chow diet (NCD)-fed conditions. The goal of this investigation was to test whether hepatocyte MPC disruption provides sustained protection from hyperglycemia during long-term HFD and the differential effects of hepatocyte MPC disruption on TCA cycle metabolism in NCD versus HFD conditions. METHOD: We utilized long-term high fat feeding, serial measurements of postabsorptive blood glucose and metabolomic profiling and (13)C-lactate/(13)C-pyruvate tracing to investigate the contribution of the MPC to hyperglycemia and altered hepatic TCA cycle metabolism during HFD-induced obesity. RESULTS: Hepatocyte MPC disruption resulted in long-term attenuation of hyperglycemia induced by HFD. HFD increased hepatic mitochondrial pyruvate utilization and TCA cycle capacity in an MPC-dependent manner. Furthermore, MPC disruption decreased progression of fibrosis and levels of transcript markers of inflammation. CONCLUSIONS: By contributing to chronic hyperglycemia, fibrosis, and TCA cycle expansion, the hepatocyte MPC is a key mediator of the pathophysiology induced in the HFD model of T2D.
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spelling pubmed-56812812017-11-20 The mitochondrial pyruvate carrier mediates high fat diet-induced increases in hepatic TCA cycle capacity Rauckhorst, Adam J. Gray, Lawrence R. Sheldon, Ryan D. Fu, Xiaorong Pewa, Alvin D. Feddersen, Charlotte R. Dupuy, Adam J. Gibson-Corley, Katherine N. Cox, James E. Burgess, Shawn C. Taylor, Eric B. Mol Metab Original Article OBJECTIVE: Excessive hepatic gluconeogenesis is a defining feature of type 2 diabetes (T2D). Most gluconeogenic flux is routed through mitochondria. The mitochondrial pyruvate carrier (MPC) transports pyruvate from the cytosol into the mitochondrial matrix, thereby gating pyruvate-driven gluconeogenesis. Disruption of the hepatocyte MPC attenuates hyperglycemia in mice during high fat diet (HFD)-induced obesity but exerts minimal effects on glycemia in normal chow diet (NCD)-fed conditions. The goal of this investigation was to test whether hepatocyte MPC disruption provides sustained protection from hyperglycemia during long-term HFD and the differential effects of hepatocyte MPC disruption on TCA cycle metabolism in NCD versus HFD conditions. METHOD: We utilized long-term high fat feeding, serial measurements of postabsorptive blood glucose and metabolomic profiling and (13)C-lactate/(13)C-pyruvate tracing to investigate the contribution of the MPC to hyperglycemia and altered hepatic TCA cycle metabolism during HFD-induced obesity. RESULTS: Hepatocyte MPC disruption resulted in long-term attenuation of hyperglycemia induced by HFD. HFD increased hepatic mitochondrial pyruvate utilization and TCA cycle capacity in an MPC-dependent manner. Furthermore, MPC disruption decreased progression of fibrosis and levels of transcript markers of inflammation. CONCLUSIONS: By contributing to chronic hyperglycemia, fibrosis, and TCA cycle expansion, the hepatocyte MPC is a key mediator of the pathophysiology induced in the HFD model of T2D. Elsevier 2017-09-18 /pmc/articles/PMC5681281/ /pubmed/29107293 http://dx.doi.org/10.1016/j.molmet.2017.09.002 Text en © 2017 The Authors http://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Original Article
Rauckhorst, Adam J.
Gray, Lawrence R.
Sheldon, Ryan D.
Fu, Xiaorong
Pewa, Alvin D.
Feddersen, Charlotte R.
Dupuy, Adam J.
Gibson-Corley, Katherine N.
Cox, James E.
Burgess, Shawn C.
Taylor, Eric B.
The mitochondrial pyruvate carrier mediates high fat diet-induced increases in hepatic TCA cycle capacity
title The mitochondrial pyruvate carrier mediates high fat diet-induced increases in hepatic TCA cycle capacity
title_full The mitochondrial pyruvate carrier mediates high fat diet-induced increases in hepatic TCA cycle capacity
title_fullStr The mitochondrial pyruvate carrier mediates high fat diet-induced increases in hepatic TCA cycle capacity
title_full_unstemmed The mitochondrial pyruvate carrier mediates high fat diet-induced increases in hepatic TCA cycle capacity
title_short The mitochondrial pyruvate carrier mediates high fat diet-induced increases in hepatic TCA cycle capacity
title_sort mitochondrial pyruvate carrier mediates high fat diet-induced increases in hepatic tca cycle capacity
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5681281/
https://www.ncbi.nlm.nih.gov/pubmed/29107293
http://dx.doi.org/10.1016/j.molmet.2017.09.002
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