Dietary fat intake attenuates vitamin A deficiency-associated elastic fiber remodeling and lipid reduction in the alveolar niche in mice.

Background: Vitamin A deficiency (VAD) and obesity are widespread nutrition-related health conditions that are independently associated with pulmonary remodeling processes linked to lung function decline and respiratory diseases.

Objective: This study tested the hypothesis that VAD-related pulmonary alterations are aggravated by diet-induced obesity.

Methods: 8-week-old C57BL/6J/129Sv mice with a deletion of lecithin-retinol-acyltransferase (Lrat-; impaired vitamin A storage) were fed vitamin A-deficient control diet (CD, n=13) or high-fat diet (HFD, n=15) to induce VAD in lean (CD-VAD, n=13) or obese (HFD-VAD, n=13) animals. Wild-type mice receiving vitamin A-containing CD or HFD served as controls. After 20 weeks, lungs were subjected to structural and molecular analyses by stereology, western blot and HPLC-MS. Statistics used was two-way-ANOVA.

Results: Pulmonary vitamin A reserves were efficiently depleted in CD-VAD and HFD-VAD (p <0.001 compared to controls). In CD-VAD, 76% of pulmonary elastic fibers appeared densely packed (CD: 53%, p <0.01) and expression of fibrillin was 110% higher compared to CD (p <0.01), indicating a higher septal microfibril content. Elastin expression was slightly reduced in HFD- groups (HFD: 14%, HFD-VAD: 16% of respective controls, both p <0.05), whereas neither diet nor VAD affected expression levels of collagen I or III. Lipid droplet volumes decreased by 32% in septal fibroblasts (p <0.05) and by 53% in alveolar epithelial type 2 (AE2) cells in CD-VAD, compared to CD. HFD alone led to a 20% reduction in lung airspace volume, a 13% decrease in septal surface area and a 15% reduction in AE2 cell numbers compared to CD. These VAD- and obesity-related changes were alleviated or absent in HFD-VAD.

Conclusion: VAD induced elastic fiber remodeling and lipid droplet reduction in the alveolar region of lean mice, whereas HFD resulted in smaller lungs containing less AE2 cells. Both VAD- and obesity-related effects were attenuated in HFD-VAD, indicating mutually mitigating effects.