Deletion of the Transmembrane Transporter ABCG1 Results in Progressive Pulmonary Lipidosis

Abstract

We show that mice lacking the ATP-binding cassette transmembrane transporter ABCG1 show progressive and age-dependent severe pulmonary lipidosis that recapitulates the phenotypes of different respiratory syndromes in both humans and mice. The lungs of chow-fed Abcg1 ؊/؊ mice, >6-months old, exhibit extensive subpleural cellular accumulation, macrophage, and pneumocyte type 2 hypertrophy, massive lipid deposition in both macrophages and pneumocytes and increased levels of surfactant. No such abnormalities are observed at 3 months of age. However, gene expression profiling reveals significant changes in the levels of mRNAs encoding key genes involved in lipid metabolism in both 3-and 8-month-old Abcg1 ؊/؊ mice. These data suggest that the lungs of young Abcg1 ؊/؊ mice maintain normal lipid levels by repressing lipid biosynthetic pathways and that such compensation is inadequate as the mice mature. Studies with A-549 cells, a model for pneumocytes type 2, demonstrate that overexpression of ABCG1 specifically stimulates the efflux of cellular cholesterol by a process that is dependent upon phospholipid secretion. In addition, we demonstrate that Abcg1 ؊/؊ , but not wild-type macrophages, accumulate cholesterol ester droplets when incubated with surfactant. Together, these data provide a mechanism to explain the lipid accumulation in the lungs of Abcg1 ؊/؊ mice. In summary, our results demonstrate that ABCG1 plays essential roles in pulmonary lipid homeostasis.

Adipocyte ATP-Binding Cassette G1 Promotes Triglyceride Storage, Fat Mass Growth, and Human Obesity

“…This study supports the notion that although the role of Abcg1 in cellular free cholesterol efflux mechanisms is crucial in maintaining tissue lipid homeostasis in a cholesterol-rich environment (2), Abcg1 contributes to cellular lipid (mostly TGs) accumulation and storage in highfat metabolic states (4,5). Thus, Abcg1 deficiency (30)(31)(32) as well as expression of human ABCG1 in mice (2,33) fed an atherogenic diet enriched in cholesterol highlights the role of Abcg1 in protecting tissues, especially the lung, from lipid accumulation without any apparent changes in adipose tissue mass or adiposity. By contrast, and consistent with the mechanism described in the current study, Abcg1 KO mice fed a high-fat diet devoid of cholesterol did not accumulate lipids in tissues but rather exhibited reduced adipose tissue formation and were protected against diet-induced obesity (5).…”

A Critical Role for ABCG1 in Macrophage Inflammation and Lung Homeostasis

“…Recently, a role for ABCG1 in pulmonary function was discovered (24). The lung phenotype of older (8 mo of age) Abcg1 Ϫ/Ϫ mice is similar to that observed for Abca1 Ϫ/Ϫ mice (25).…”

Total Body ABCG1 Expression Protects Against Early Atherosclerotic Lesion Development in Mice

“…We observed in the ABCG1 Ϫ/Ϫ mice on a diet with 15% fat, 1% cholesterol and 0.5% cholate for 12 weeks a marked change in lung morphology attributable to excessive accumulation of lipids in macrophages localized to the subpleural region. Baldán et al 16 demonstrated that macrophages from ABCG1 Ϫ/Ϫ mice accumulate cholesterol ester droplets when incubated with surfactant and that macrophage ABCG1 plays an essential role in pulmonary lipid homeostasis, consistent with the tissue-specific phenotype. In addition to the lung, we also ϩ/ϩ mice (Student t test and Mann-Whitney test, respectively).…”