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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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Detalles Bibliográficos
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
Descripción
Sumario: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.