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

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.