Carbohydrate-response element-binding protein deletion alters substrate utilization producing an energy-deficient liver.
Livers from mice lacking the carbohydrate-responsive element-binding protein (ChREBP) were compared with wild type (WT) mice to determine the effect of this transcription factor on hepatic energy metabolism. The pyruvate dehydrogenase complex was considerably more active in ChREBP(-/-) mice because of diminished pyruvate dehydrogenase kinase activity. Greater pyruvate dehydrogenase complex activity caused a stimulation of lactate and pyruvate oxidation, and it significantly impaired fatty acid oxidation in perfused livers from ChREBP(-/-) mice. This shift in mitochondrial substrate utilization led to a 3-fold reduction of the free cytosolic [NAD(+)]/[NADH] ratio, a 1.7-fold increase in the free mitochondrial [NAD(+)]/[NADH] ratio, and a 2-fold decrease in the free cytosolic [ATP]/[ADP][P(i)] ratio in the ChREBP(-/-) liver compared with control. Hepatic pyruvate carboxylase flux was impaired with ChREBP deletion secondary to decreased fatty acid oxidation, increased pyruvate oxidation, and limited pyruvate availability because of reduced activity of liver pyruvate kinase and malic enzyme, which replenish pyruvate via glycolysis and pyruvate cycling. Overall, the shift from fat utilization to pyruvate and lactate utilization resulted in a decrease in the energy of ATP hydrolysis and a hypo-energetic state in the livers of ChREBP(-/-) mice.
Department of Pharmacology, University of Texas Southwestern Medical School, Dallas, Texas 75390-8854.
Shawn C
SC
Burgess
Department of Biochemistry, Advanced Imaging Research Center, Dallas, Texas 75390-8854.
Katsumi
K
Iizuka
Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana 46202-5122.
Nam Ho
NH
Jeoung
Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana 46202-5122.
Robert A
RA
Harris
Laboratory of Metabolic Control, NIAAA, National Institutes of Health, Rockville, Maryland 20892-8115.
Yoshihiro
Y
Kashiwaya
Laboratory of Metabolic Control, NIAAA, National Institutes of Health, Rockville, Maryland 20892-8115.
Richard L
RL
Veech
Department of Biochemistry, Advanced Imaging Research Center, Dallas, Texas 75390-8854.
Tatsuya
T
Kitazume
Department of Biochemistry, Advanced Imaging Research Center, Dallas, Texas 75390-8854; Department of Veterans Affairs Medical Center, Dallas, Texas 75390-8854. Electronic address: kuyeda6400@aol.com.
Kosaku
K
Uyeda
D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D015153:Blotting, Western; D003600:Cytosol / Q000378:metabolism; D004734:Energy Metabolism; D005227:Fatty Acids / Q000378:metabolism; D017353:Gene Deletion; D008099:Liver / Q000201:enzymology / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D009687:Nuclear Proteins / Q000172:deficiency*; D009711:Nucleotides / Q000378:metabolism; D010084:Oxidation-Reduction; D010085:Oxidative Phosphorylation; D010101:Oxygen Consumption; D010477:Perfusion; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D011768:Pyruvate Dehydrogenase Complex / Q000378:metabolism; D011773:Pyruvates / Q000378:metabolism; D013379:Substrate Specificity; D014157:Transcription Factors / Q000172:deficiency*
D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D005227:Fatty Acids; C506001:Mlxipl protein, mouse; D009687:Nuclear Proteins; D009711:Nucleotides; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D011768:Pyruvate Dehydrogenase Complex; D011773:Pyruvates; D014157:Transcription Factors; D017346:Protein Serine-Threonine Kinases