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. Selective hepatic insulin resistance contributes to the development of metabolic disease, but the molecular mechanisms \remain unclear. Here, the authors identify a nonenzymatic role for ABHD6 in promoting selective hepatic insulin resistance through modulation of Akt–FoxO1 signaling.
Authors
- Ziying Xu (ORCID: https://orcid.org/0000-0003-3725-7726)
- Nisi Jiang (ORCID: https://orcid.org/0000-0003-1837-7618)
- Jiyuan Yin
- Chanmin Joung (ORCID: https://orcid.org/0000-0003-0004-3441)
- James F. Nelson (ORCID: https://orcid.org/0000-0002-7439-3033)
- Pengju Cao (ORCID: https://orcid.org/0000-0002-0714-7000)
- Jan‐Bernd Funcke (ORCID: https://orcid.org/0000-0002-2596-3167)
- Marc Prentki (ORCID: https://orcid.org/0000-0002-0499-3324)
- Adam B. Salmon (ORCID: https://orcid.org/0000-0002-1475-7843)
- Juli Bai (ORCID: https://orcid.org/0000-0002-1193-8155)
- Shangang Zhao (ORCID: https://orcid.org/0000-0002-9209-8206)
- Xianlin Han (ORCID: https://orcid.org/0000-0002-8615-2413)
- Guannan Li (ORCID: https://orcid.org/0000-0002-6070-5008)
- Sijia He (ORCID: https://orcid.org/0000-0003-3786-8770)
- S.R. Murthy Madiraju (ORCID: https://orcid.org/0000-0002-2613-2074)
- Mbolle Ekane
- Laurence T. Maeyens (ORCID: https://orcid.org/0009-0000-0629-8109)
- Maria Paula Lopez
- Ting Wu
- Ruizhen Li
- Yi Zhu
- Xin Li
Institutions
- The University of Texas at San Antonio Health Science Center (US)
- Geriatric Research Education and Clinical Center (US)
- Children's Nutrition Research Center at Baylor College of Medicine (US)
- Centre Hospitalier de l’Université de Montréal (CA)
- South Texas Veterans Health Care System (US)
- The University of Texas Health Science Center (US)
- Université de Montréal (CA)
- The University of Texas Southwestern Medical Center (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2026-08-03
- DOI
- https://doi.org/10.1038/s41467-026-76237-5
- Primary Topic
- FOXO transcription factor regulation
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Max and Minnie Tomerlin Voelcker Fund
- National Institutes of Health
- National Institute on Aging
- National Institute of Diabetes and Digestive and Kidney Diseases