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

Abstract

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.