ABCG1 regulates pulmonary surfactant metabolism in mice and men

Thomas Q De Aguiar Vallim,Elinor Lee,David J Merriott,Christopher N Goulbourne,Joan Cheng,Angela Cheng,Ayelet Gonen,Ryan M Allen,Elisa N.D Palladino,David A Ford,Tisha Wang,Ángel Baldán,Elizabeth J Tarling

doi:10.1194/jlr.m075101

Abstract

Idiopathic pulmonary alveolar proteinosis (PAP) is a rare lung disease characterized by accumulation of surfactant. Surfactant synthesis and secretion are restricted to epithelial type 2 (T2) pneumocytes (also called T2 cells). Clearance of surfactant is dependent upon T2 cells and macrophages. ABCG1 is highly expressed in both T2 cells and macrophages. ABCG1-deficient mice accumulate surfactant, lamellar body-loaded T2 cells, lipid-loaded macrophages, B-1 lymphocytes, and immunoglobulins, clearly demonstrating that ABCG1 has a critical role in pulmonary homeostasis. We identify a variant in the ABCG1 promoter in patients with PAP that results in impaired activation of ABCG1 by the liver X receptor α, suggesting that ABCG1 basal expression and/or induction in response to sterol/lipid loading is essential for normal lung function. We generated mice lacking ABCG1 specifically in either T2 cells or macrophages to determine the relative contribution of these cell types on surfactant lipid homeostasis. These results establish a critical role for T2 cell ABCG1 in controlling surfactant and overall lipid homeostasis in the lung and in the pathogenesis of human lung disease.

Highlights

Idiopathic pulmonary alveolar proteinosis (PAP) is a rare lung disease characterized by accumulation of surfactant
It is estimated that most of the surfactant phospholipids are synthesized in situ by type 2 (T2) cells, whereas cholesterol is derived from serum lipoproteins with less than 1% being derived from de novo synthesis [9]
Based on the high expression of ABCG1 in pulmonary T2 cells and the critical role these cells play in surfactant metabolism, we have reevaluated the role of ABCG1 in T2 cell function and pulmonary lipidosis

Summary

Introduction

Idiopathic pulmonary alveolar proteinosis (PAP) is a rare lung disease characterized by accumulation of surfactant. ABCG1-deficient mice accumulate surfactant, lamellar body-loaded T2 cells, lipid-loaded macrophages, B-1 lymphocytes, and immunoglobulins, clearly demonstrating that ABCG1 has a critical role in pulmonary homeostasis. We generated mice lacking ABCG1 in either T2 cells or macrophages to determine the relative contribution of these cell types on surfactant lipid homeostasis. These results establish a critical role for T2 cell ABCG1 in controlling surfactant and overall lipid homeostasis in the lung and in the pathogenesis of human lung disease.—de Aguiar Vallim, T. Surfactant lipids are synthesized and secreted by epithelial type 2 (T2) pneumocytes ( called T2 cells). It is estimated that most of the surfactant phospholipids are synthesized in situ by T2 cells, whereas cholesterol is derived from serum lipoproteins with less than 1% being derived from de novo synthesis [9]

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Conclusion