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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE332974 | GEO | 2026/05/26

REPOSITORIES: GEO

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Project description:Objective: Metabolic dysfunction-associated steatotic liver disease (MASLD) is characterized by hepatic insulin resistance (IR) and impaired lipid–glucose metabolism. Sodium butyrate (NaB), a short-chain fatty acid (SCFA), may improve metabolic homeostasis, but its actions in MASLD-related IR remain unclear. This study investigated the therapeutic effects and mechanisms of NaB in palmitate (PA)-induced insulin-resistant hepatocytes and high-fat diet (HFD)-induced MASLD mice. Methods: PA-treated HepG2 cells received NaB (0.5–1.5 mM). Lipid accumulation, glucose uptake, glycogen content, and metabolic gene and protein expression were analyzed using biochemical assays, staining, qPCR, Western blotting, and RNA-seq. In vivo, C57BL/6 mice were fed an HFD for 16 weeks and then treated orally with NaB (200 or 400 mg/kg/day) for 8 weeks. Metabolic phenotypes, liver histology, and major signaling pathways were analyzed. Results: In PA-induced HepG2 cells, NaB dose-dependently decreased triglyceride, total cholesterol, low-density lipoprotein cholesterol, and non-esterified fatty acid levels, while increasing high-density lipoprotein cholesterol, glucose uptake, and glycogen storage. NaB suppressed lipogenesis (↓SREBP1c, ↓FASN), enhanced fatty acid oxidation (↑PGC-1α, ↑PPARα, ↑CPT1A), restored GPR43–CaMKK2–adenosine monophosphate-activated protein kinase (AMPK)α–SIRT1 signaling, and activated PI3K/AKT signaling (↑p-IRS1, ↑p-PI3K, ↑p-AKT, ↑GLUT2), thereby reducing gluconeogenic markers (↓FOXO1, ↓PCK1, ↓G6PC1) and increasing glycogen synthase (↑GS). Transcriptomics confirmed enrichment of PPARα and metabolic pathways. In HFD-fed mice, NaB reduced body weight, improved lipid profiles, alleviated steatosis, improved glucose tolerance and insulin sensitivity, and restored liver glycogen, with greater effects at the higher dose. Conclusion: NaB alleviates hepatic steatosis and IR in MASLD by activating AMPK and PI3K/AKT pathways, promoting fatty acid oxidation, and enhancing glycogen synthesis. NaB may serve as a promising multi-target metabolic modulator for MASLD.

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

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