Effects of hepatic mitochondrial pyruvate carrier deficiency on de novo lipogenesis and gluconeogenesis in mice
Nicole K.H. Yiew,
Stanislaw Deja,
Daniel Ferguson,
Kevin Cho,
Chaowapong Jarasvaraparn,
Miriam Jacome-Sosa,
Andrew J. Lutkewitte,
Sandip Mukherjee,
Xiaorong Fu,
Jason M. Singer,
Gary J. Patti,
Shawn C. Burgess,
Brian N. Finck
Affiliations
Nicole K.H. Yiew
Department of Medicine, Center for Human Nutrition, Washington University in St. Louis, St. Louis, MO 63110, USA
Stanislaw Deja
Center for Human Nutrition, University of Texas Southwestern, Dallas, TX 75390, USA
Daniel Ferguson
Department of Medicine, Center for Human Nutrition, Washington University in St. Louis, St. Louis, MO 63110, USA
Kevin Cho
Department of Chemistry, Siteman Cancer Center, Center for Metabolomics and Isotope Tracing, Washington University in St. Louis, St. Louis, MO 63110, USA
Chaowapong Jarasvaraparn
Department of Medicine, Center for Human Nutrition, Washington University in St. Louis, St. Louis, MO 63110, USA
Miriam Jacome-Sosa
Department of Medicine, Center for Human Nutrition, Washington University in St. Louis, St. Louis, MO 63110, USA
Andrew J. Lutkewitte
Department of Medicine, Center for Human Nutrition, Washington University in St. Louis, St. Louis, MO 63110, USA
Sandip Mukherjee
Department of Medicine, Center for Human Nutrition, Washington University in St. Louis, St. Louis, MO 63110, USA
Xiaorong Fu
Center for Human Nutrition, University of Texas Southwestern, Dallas, TX 75390, USA
Jason M. Singer
Department of Medicine, Center for Human Nutrition, Washington University in St. Louis, St. Louis, MO 63110, USA
Gary J. Patti
Department of Chemistry, Siteman Cancer Center, Center for Metabolomics and Isotope Tracing, Washington University in St. Louis, St. Louis, MO 63110, USA
Shawn C. Burgess
Center for Human Nutrition, University of Texas Southwestern, Dallas, TX 75390, USA
Brian N. Finck
Department of Medicine, Center for Human Nutrition, Washington University in St. Louis, St. Louis, MO 63110, USA; Corresponding author
Summary: The liver coordinates the systemic response to nutrient deprivation and availability by producing glucose from gluconeogenesis during fasting and synthesizing lipids via de novo lipogenesis (DNL) when carbohydrates are abundant. Mitochondrial pyruvate metabolism is thought to play important roles in both gluconeogenesis and DNL. We examined the effects of hepatocyte-specific mitochondrial pyruvate carrier (MPC) deletion on the fasting-refeeding response. Rates of DNL during refeeding were impaired by hepatocyte MPC deletion, but this did not reduce intrahepatic lipid content. During fasting, glycerol is converted to glucose by two pathways; a direct cytosolic pathway and an indirect mitochondrial pathway requiring the MPC. Hepatocyte MPC deletion reduced the incorporation of 13C-glycerol into TCA cycle metabolites, but not into new glucose. Furthermore, suppression of glycerol and alanine metabolism did not affect glucose concentrations in fasted hepatocyte-specific MPC-deficient mice, suggesting multiple layers of redundancy in glycemic control in mice.
