Non-enzymatic hepatic ABHD6 interacts with Akt-FoxO1 axis to regulate metabolic health
Selective hepatic insulin resistance contributes to the development of metabolic disease, but the molecular mechanisms \remain unclear. Here, the authors identify a nonenzymatic role for ABHD6 in promoting selective hepatic insulin resistance through modulation of Akt–FoxO1 signaling.
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.