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Dietary lipid stress aggravates obstructive lung injury involving epithelial IGF-1-Akt dysfunction and epithelial-endothelial crosstalk

ABSTRACT: Metabolic comorbidities are common in chronic obstructive pulmonary disease (COPD), but how systemic lipid excess affects lungs with established obstructive pathology remains unclear. We integrated a βENaC-transgenic muco-obstructive lung disease model, an elastase-induced emphysema model, whole-lung transcriptomics, epithelial and endothelial cell systems, and a health-screening cohort. A high-fat diet (HFD) increased body weight, glycemia, and adiposity in both wild-type and βENaC-transgenic mice, but further enlarged distal airspaces and reduced FEV0.1/FVC in βENaC-transgenic mice. Transcriptomic and tissue analyses revealed remodeling of lipid-handling, PI3K-Akt, and vascular programs, accompanied by reduced Akt phosphorylation, increased FOXO1 abundance and Fasl expression, and increased TUNEL positivity in epithelial regions. Palmitate attenuated IGF-1-induced Akt activation in bronchial epithelial cells, whereas IGF-1 receptor inhibition reproduced Akt suppression and apoptosis-related responses without recapitulating the full HFD phenotype. HFD preconditioning also increased subsequent elastase-induced airspace enlargement. Palmitate directly induced endothelial inflammatory and junction-associated responses, while conditioned medium from palmitate-exposed ENaC-hyperactive epithelial cells enhanced endothelial IL6 and VCAM1 expression. Hepatic steatosis coincided with lower percent-predicted FEV1 in men with airflow obstruction. These findings support a multicompartment model in which systemic lipid stress compromises epithelial survival signaling and vascular homeostasis in obstructive lung disease.

ORGANISM(S): Mus musculus

PROVIDER: GSE300375 | GEO | 2026/09/08

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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Dietary lipid stress aggravates obstructive lung injury involving epithelial IGF-1-Akt dysfunction and epithelial-endothelial crosstalk

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