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

## TL;DR

This study shows that ACLY helps convert amino acids into glucose in diabetic mice livers, and blocking it reduces harmful metabolic effects.

## Contribution

Demonstrates ACLY's role in amino acid-driven gluconeogenesis and its inhibition as a therapeutic strategy in diabetes.

## Key findings

- ACLY inhibition reduced amino acid-induced hyperglycemia and normalized alanine labeling in db/db mice.
- Hyperpolarized [1-13C]pyruvate MRS detected increased alanine flux linked to ACLY activity in diabetic livers.
- ACLY phosphorylation correlated with metabolic changes, suggesting a regulatory role in transamination.

## Abstract

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.

ACLY promotes ALT1-mediated alanine flux and gluconeogenesis in the diabetic liver. Its inhibition reverses both amino-acid and lipid-driven metabolic dysregulation, as visualized by [1-13C]pyruvate MRS.