# Isotype-selective roles of hepatic acetyl-CoA carboxylases in a mouse model of fatty liver disease

## TL;DR

This study explores how inhibiting specific liver enzymes (ACC1 and ACC2) can reverse fatty liver disease in mice, but also causes unwanted metabolic effects.

## Contribution

The study reveals that ACC1 inhibition drives metabolic issues while ACC2 inhibition alone is ineffective, suggesting a need for selective inhibition strategies.

## Key findings

- Dual inhibition of ACC1 and ACC2 reverses fatty liver disease and fibrosis but causes hypertriglyceridemia and glucose intolerance.
- ACC1 inhibition alone leads to metabolic dysregulation with limited efficacy in treating fatty liver.
- ACC2 inhibition alone has minimal effect on liver disease and no adverse metabolic effects.

## Abstract

Acetyl-CoA carboxylase enzymes ACC1 and ACC2 promote liver fat storage. Accordingly, ACC inhibition represents a strategy to reverse fatty liver disease and related disorders. Human and rodent studies show that targeting both ACC isotypes can reverse some fatty liver phenotypes, but also result in unwanted metabolic phenotypes including hypertriglyceridemia. The objective of this study was to determine whether liver-selective genetic inhibition of ACC1 or ACC2 individually can reverse fatty liver disease phenotypes without adverse metabolic phenotypes in a mouse model of fatty liver disease.

Four genotypes of male C57BL/6J mice floxed for ACC1, ACC2, both ACC alleles, or no ACC alleles were fed an Amylin diet for 28 weeks to induce fatty liver disease. After 20 weeks of Amylin feeding, ACC genes were deleted in the liver by adeno-associated virus 8 (AAV8)-mediated Cre recombinase expression. Mice were metabolically phenotyped and liver disease was assessed by histopathology.

Dual inhibition of ACC enzymes was necessary to achieve significant reversal of fatty liver disease and fibrosis; however, it also caused hypertriglyceridemia, weight gain, and glucose intolerance. ACC1 inhibition alone resulted in partial reversal of fatty liver disease phenotypes but drove all undesired metabolic phenotypes. In contrast, ACC2 inhibition alone had minimal effect on fatty liver, fibrosis, or metabolic phenotypes.

Our results indicate that complete inhibition of liver ACC activity is required to resolve fatty liver disease and fibrosis, with ACC1 inhibition being the dominant driver of unwanted metabolic dysregulation. Accordingly, selective inhibition of ACC2 with partial inhibition of ACC1 may represent a refined future approach to reverse fatty liver disease phenotypes while minimizing metabolic dysregulation.

Image 1

•Hepatic ACC1 and ACC2 deletion in adult mice reverses steatosis and fibrosis.•Hepatic ACC1 and ACC2 deletion triggers several undesired metabolic phenotypes.•Hepatic ACC1-specific deletion drives metabolic dysregulation with little efficacy.•Hepatic ACC2-specific deletion has no metabolic dysregulation but no efficacy.•Total ACC deletion effectively reverses MASH but ACC1 loss impairs metabolism.

Hepatic ACC1 and ACC2 deletion in adult mice reverses steatosis and fibrosis.

Hepatic ACC1 and ACC2 deletion triggers several undesired metabolic phenotypes.

Hepatic ACC1-specific deletion drives metabolic dysregulation with little efficacy.

Hepatic ACC2-specific deletion has no metabolic dysregulation but no efficacy.

Total ACC deletion effectively reverses MASH but ACC1 loss impairs metabolism.