Journal
CELL METABOLISM
Volume 22, Issue 4, Pages 682-694Publisher
CELL PRESS
DOI: 10.1016/j.cmet.2015.07.028
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Funding
- NIH [R01 DK078187, R01 DK104735, R42 AA021228, R01 DK078184, P01 DK058398]
- Barnes Jewish Hospital Foundation
- Digestive Diseases Research Core Center at the Washington University School of Medicine [P30 DK52574]
- Diabetes Research Center at the Washington University School of Medicine [P30 DK20579]
- Nutrition Obesity Research Center at the Washington University School of Medicine [P30 DK56341]
- Robert A. Welch Foundation [I-1804-01]
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Pyruvate transport across the inner mitochondrial membrane is believed to be a prerequisite for gluconeogenesis in hepatocytes, which is important for the maintenance of normoglycemia during prolonged food deprivation but also contributes to hyperglycemia in diabetes. To determine the requirement for mitochondrial pyruvate import in gluconeogenesis, mice with liver-specific deletion of mitochondrial pyruvate carrier 2 (LS-Mpc2(-/-)) were generated. Loss of MPC2 impaired, but did not completely abolish, hepatocyte conversion of labeled pyruvate to TCA cycle intermediates and glucose. Unbiased metabolomic analyses of livers from fasted LS-Mpc2(-/-) mice suggested that alterations in amino acid metabolism, including pyruvate-alanine cycling, might compensate for the loss of MPC2. Indeed, inhibition of pyruvate-alanine transamination further reduced mitochondrial pyruvate metabolism and glucose production by LS-Mpc2(-/-) hepatocytes. These data demonstrate an important role for MPC2 in controlling hepatic gluconeogenesis and illuminate a compensatory mechanism for circumventing a block in mitochondrial pyruvate import.
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