Language

English

Publication Date

8-3-2026

Journal

Nature Communications

DOI

10.1038/s41467-026-76237-5

PMID

42675085

PMCID

PMC13530116

PubMedCentral® Posted Date

8-3-2026

PubMedCentral® Full Text Version

Post-print

Abstract

The enzymatic role of ABHD6 in insulin secretion and resistance is well documented. However, its non-enzymatic function, especially its effects on metabolic health, including selective hepatic insulin resistance and metabolic dysfunction-associated steatotic liver disease (MASLD), is poorly understood. To define the role of ABHD6 in liver physiology, we generated liver-specific ABHD6 knockout mice, as well as liver-specific native and enzymatically inactive mutant ABHD6 overexpression mouse models. We demonstrate that non-enzymatic ABHD6 contributes to the regulation of selective hepatic insulin resistance and MASLD progression. Mechanistically, we show that ABHD6 localizes to the nucleus and interacts with Akt/FoxO1 axis to regulate insulin signaling. Our findings identify a mechanism underlying selective hepatic insulin resistance and highlight a role for the non-enzymatic function of ABHD6 in this process. This study suggests that modulation of this non-enzymatic activity may represent a potential therapeutic strategy for improving metabolic health.

Keywords

Animals, Forkhead Box Protein O1, Liver, Insulin Resistance, Mice, Proto-Oncogene Proteins c-akt, Mice, Knockout, 1-Acylglycerol-3-Phosphate O-Acyltransferase, Signal Transduction, Fatty Liver, Insulin, Humans, Male, Mice, Inbred C57BL, Monoacylglycerol Lipases, Diseases, Obesity, Cell biology

Published Open-Access

yes

Download

Share

COinS
 
 

To view the content in your browser, please download Adobe Reader or, alternately,
you may Download the file to your hard drive.

NOTE: The latest versions of Adobe Reader do not support viewing PDF files within Firefox on Mac OS and if you are using a modern (Intel) Mac, there is no official plugin for viewing PDF files within the browser window.