Disrupted metabolic flux balance between pyruvate dehydrogenase and pyruvate carboxylase in human fatty liver

• Published in: Metabolism, clinical and experimental Vol. 165; p. 156151
• Main Authors: Park, Jae Mo, Lin, Sung-Han, Baxter, Jeannie D., Harrison, Crystal E., Leary, Jennine, Mozingo, Corey, Liticker, Jeff, Malloy, Craig R., Jin, Eunsook S.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.04.2025
• Subjects: Adult; Carbon Isotopes; Fatty liver; Fatty Liver - enzymology; Fatty Liver - metabolism; Female; Glycerol - metabolism; Glyceroneogenesis; Humans; Hyperpolarized; Lactic Acid - metabolism; Liver - metabolism; Male; Middle Aged; Pyruvate carboxylase; Pyruvate Carboxylase - metabolism; Pyruvate dehydrogenase; Pyruvate Dehydrogenase Complex - metabolism; Pyruvic Acid - metabolism; Triglycerides - blood; Triglycerides - metabolism; Pyruvate dehydrogenase; Hyperpolarized; Fatty liver; Glyceroneogenesis; Pyruvate carboxylase
• ISSN: 0026-0495; 1532-8600; 1532-8600
• DOI: 10.1016/j.metabol.2025.156151

Hepatic metabolism involving pyruvate carboxylase (PC) and pyruvate dehydrogenase (PDH) may be abnormal in fatty livers. In this study, [13C]bicarbonate production from [1-13C1]pyruvate in the liver and glycerol glyceroneogenesis were examined in relation to hepatic fat content using hyperpolarized [1-13C1]pyruvate and oral [U-13C3]glycerol. After an overnight fast, 15 subjects with a range of hepatic fat content received hyperpolarized [1-13C1]pyruvate intravenously to assess its conversion to [1-13C1]lactate and [13C]bicarbonate in the liver. They also received oral [U-13C3]glycerol, followed by venous blood sampling to examine glucose and the glycerol backbone of the triglycerides released primarily from the liver. From hyperpolarized [1-13C1]pyruvate, participants with high intrahepatic fat fraction produced higher [1-13C1]lactate and lower [13C]bicarbonate than those with low liver fat. The fraction of plasma triglycerides derived from oral [U-13C3]glycerol via the TCA cycle was similar between groups. The fraction of plasma [5,6-13C2]glucose, which reflects PC flux, decreased in subjects with fatty liver. In contrast, the fraction of [4,5-13C2]glucose + [6-13C1]glucose, which can be produced via either PC or PDH, was comparable between groups. The study results suggest a shift in pyruvate metabolism in fatty liver, with a decreased metabolic flux ratio of PC/PDH. The methodology in this study provides insights into fatty liver metabolism of human subjects inaccessible previously and is applicable to advanced liver diseases such as cirrhosis and hepatomas. [Display omitted] •Metabolic flux ratio of PC/PDH decreased in fatty liver.•Simultaneous 13C-glycerol and hyperpolarized 13C-pyruvate are feasible in humans.•Hyperpolarized [13C]bicarbonate negatively correlated with hepatic fat content.