Non-enzymatic hepatic ABHD6 interacts with Akt-FoxO1 axis to regulate metabolic health

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.