Hidden metabolic effects of acetyl-CoA carboxylase inhibition

Abstract

Section snippets

Background and context

Metabolic dysfunction-associated steatotic liver disease (MASLD) affects up to one-third of the global population, yet effective therapeutic options remain limited.¹ This unmet clinical need has driven significant interest in the development of pharmacological therapies for MASLD, including small-molecule inhibitors targeting acetyl-CoA carboxylase (ACC). These inhibitors have demonstrated potential in preclinical studies by reducing hepatic lipid accumulation and fibrosis.^2,3ACC, a key enzyme

Objectives, methods, and findings

Deja et al. hypothesized that malonyl-CoA may have broader metabolic roles beyond its established functions in fatty acid synthesis and oxidation. Specifically, they proposed that it may regulate gluconeogenesis by influencing metabolic substrates and enzymatic pathways. Using liver-specific genetic and pharmacological approaches, combined with targeted metabolomics and stable isotope tracing, the authors systematically explored the effects of ACC1/2 inhibition on hepatic metabolism.Their

Significance of findings

Taken together, the findings by Deja et al. provide critical new insights into the multifaceted roles of ACC inhibition in hepatic metabolism. Beyond its established effects on DNL and β-oxidation, the authors clearly demonstrated that ACC also acts as a key regulator of gluconeogenesis, mediating its effects via acetyl-CoA activation of pyruvate carboxylase and increased availability of gluconeogenic substrates through intrahepatic proteolysis.This study raises several important questions for

Financial support

Dr. Luukkonen was supported by the Academy of Finland (350545), the Sigrid Jusélius Foundation, the Novo Nordisk Foundation (NNF22OC0074397), the Emil Aaltonen Foundation, the Finnish Medical Foundation, the Wilhelm and Else Stockmann's Foundation and the Early Career Investigator fund of the University of Helsinki.

Declaration of AI-assisted technologies in the writing process

During the preparation of this work the author used ChatGPT in order to proofread the manuscript. After using this tool, the author reviewed and edited the content as needed and takes full responsibility for the content of the publication.

Conflict of interest

The author has served as a consultant for AstraZeneca, Boehringer Ingelheim and Bluejay Therapeutics. He is on the speakers' bureau for Novartis, Johnson & Johnson and Sandoz.Please refer to the accompanying ICMJE disclosure forms for further details.