Non-enzymatic ABHD6 interacts with Akt-FoxO1 axis to regulate selective hepatic insulin resistance
Year: 2026
Type: preprint
Abstract: The enzymatic function of ABHD6 on insulin secretion and insulin resistance is well documented. However, its non-enzymatic function, especially its effects on selective hepatic insulin resistance and metabolic dysfunction-associated steatotic liver disease (MASLD) is completely unexplored. ABHD6 is elevated under conditions of diet-induced obesity and aging. 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 ABHD6 is an unidentified regulator of selective hepatic insulin resistance and contributes to MASLD and liver fibrosis. Furthermore, we found that non-enzymatic ABHD6, rather than its enzymatic form, contributes to this regulation. Mechanistically, we found that ABHD6 translocated into the nucleus and interacted with Akt/FoxO1 axis to regulate its function. In addition, knockdown of FoxO1 in primary hepatocytes or overexpression of constitutively active mutant FoxO1 by AAV approach could completely abolish the effects of ABHD6 on glucose tolerance and gluconeogenesis. 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 treat MASLD and liver fibrosis. Highlights ABHD6 expression in the liver is increased with obesity and aging. ABHD6 manipulation affects selective hepatic insulin resistance, MASLD and liver fibrosis. Non-enzymatic ABHD6 interacts with Akt/FoxO1 axis to regulate FoxO1 transcriptional activity. The effects of ABHD6 on glucose tolerance and hepatic gluconeogenesis are completely dependent on FoxO1 activity.
Authors: 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
Institutions: The University of Texas at San Antonio Health Science Center, The University of Texas Southwestern Medical Center, South Texas Veterans Health Care System, Centre Hospitalier de l’Université de Montréal, Université de Montréal, The University of Texas Health Science Center at Houston, Baylor College of Medicine, Children's Nutrition Research Center at Baylor College of Medicine
Language: English
Subfield: Epidemiology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Awards: Innate Immunity in NASH, Paracrine effects of leptin in regulating visceral fat expansion, San Antonio Nathan Shock Center of Excellence in the Biology of Aging, Postprandial activation of hyaluronan-MARCO axis contributes to systemic chronic inflammation, Impact of a Novel Secreted Enzyme J18 on Healthspan and Lifespan, Enhancing metabolic action of FGF21 through adipocyte Connexin43 gap junction channels, San Antonio Claude D. Pepper Older Americans Independence Center, Effects of leptin modulation on health span and lifespan
OpenAlex ID: W7128907404