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

The enzymatic function of ABHD6 on insulin secretion and insulin 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 completely unexplored. To define the role of ABHD6 in liver physiology, we generated liver-specific ABHD6 knockout mice, as well as liver-specific overexpression of native and enzymatic inactive mutant ABHD6 mouse models. We demonstrated that non-enzymatic ABHD6 is an unidentified regulator of selective hepatic insulin resistance and contributes to MASLD progression. Mechanistically, we found that ABHD6 located in the nucleus and interacted with Akt/FoxO1 axis to regulate insulin signaling. Our study reveals an entirely different mechanism underlying selective hepatic insulin resistance that involves a previously unknown non-enzymatic function of ABHD6. This study opens an avenue for the development of a novel class of ABHD6 inhibitors to improve metabolic health.