The enzymatic functions of ABHD6 in metabolic disorders have been well documented. However, the non-enzymatic functions of ABHD6 remain largely unexplored. In this study, Guannan Li, PhD, identified a previously unrecognized role of ABHD6 in interacting with FoxO1 to regulate selective hepatic insulin resistance and metabolic health. These findings reveal an important non-enzymatic function of ABHD6 and may have significant implications for the development of next-generation ABHD6 inhibitors for the treatment of obesity and diabetes.
Dr. Li is an Assistant Professor (Research) at the Sam and Ann Barshop Institute for Longevity and Aging Studies and joined the Shangang Zhao, PhD, laboratory approximately three years ago. Since joining the lab, he has been highly productive and has made significant contributions to our research program.
Non-enzymatic hepatic ABHD6 interacts with Akt-FoxO1 axis to regulate metabolic health
Guannan Li, Laurence T Maeyens, Jiyuan Yin, Jan-Bernd Funcke, Chanmin Joung, Ruizhen Li, Ziying Xu, Ting Wu, Xin Li, Nisi Jiang, Mbolle Ekane, Maria Paula Lopez, Pengju Cao, Sijia He, Adam B Salmon, S R Murthy Madiraju, Marc Prentki, Juli Bai, James F Nelson, Xianlin Han, Yi Zhu, Shangang Zhao
Nat Commun. 2026 Aug 3;17(1):9335. doi: 10.1038/s41467-026-76237-5.
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.