ACLY facilitates alanine flux in the livers of db/db mice: a hyperpolarized [1-13C]pyruvate MRS study

Non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM) feature paradoxical increases in both gluconeogenesis and lipogenesis. ATP citrate lyase (ACLY) supports both processes by generating cytosolic acetyl-CoA and oxaloacetate from citrate. While ACLY's role in lipogenesis is well established, its involvement in amino acid-driven gluconeogenesis remains unclear.

Using hyperpolarized [1-¹³C]pyruvate magnetic resonance spectroscopy (MRS), we observed [1-¹³C]alanine labeling in the livers of db/db mice. To test the effect of ACLY inhibition, mice were treated with BMS-303141, and blood glucose responses, hyperpolarized alanine labeling, and aminotransferase activity were evaluated. Western blotting was performed to assess ACLY phosphorylation.

Hyperpolarized alanine labeling was markedly elevated in db/db livers, reflecting enhanced transamination capacity. Pharmacologic ACLY inhibition attenuated alanine- and glutamine-induced hyperglycemia and normalized alanine labeling within 2-4 h, without altering aminotransferase gene expression. These in vivo changes correlated with increased hepatic ACLY phosphorylation and ex vivo ALT assay results.

Together, these findings support a model in which ACLY facilitates amino acid-driven gluconeogenesis through metabolic control of ALT-mediated transamination, consistent with increased pyruvate-alanine exchange. Hyperpolarized [1-¹³C]pyruvate MRS thereby provides a sensitive, translational readout of dynamic hepatic metabolism relevant to NAFLD and T2DM.