Abstract
BackgroundFatty acids are precursors in the synthesis of surfactant phospholipids. Recently, we showed expression of apolipoprotein C-II (apoC-II), the essential cofactor of lipoprotein lipase (LPL), in the fetal mouse lung and found the protein on the day of the surge of surfactant synthesis (gestation day 17.5) in secretory granule-like structures in the distal epithelium. In the present study, we will answer the following questions: Does apoC-II protein localization change according to the stage of lung development, thus according to the need in surfactant? Are LPL molecules translocated to the luminal surface of capillaries? Do the sites of apoC-II and LPL gene expression change according to the stage of lung development and to protein localization?ResultsThe present study investigated whether the sites of apoC-II and LPL mRNA and protein accumulation are regulated in the mouse lung between gestation day 15 and postnatal day 10. The major sites of apoC-II and LPL gene expression changed over time and were found mainly in the distal epithelium at the end of gestation but not after birth. Accumulation of apoC-II in secretory granule-like structures was not systematically observed, but was found in the distal epithelium only at the end of gestation and soon after birth, mainly in epithelia with no or small lumina. A noticeable increase in surfactant lipid content was measured before the end of gestation day 18, which correlates temporally with the presence of apoC-II in secretory granules in distal epithelium with no or small lumina but not with large lumina. LPL was detected in capillaries at all the developmental times studied.ConclusionsThis study demonstrates that apoC-II and LPL mRNAs correlate temporally and geographically with surfactant lipid synthesis in preparation for birth and suggests that fatty acid recruitment from the circulation by apoC-II-activated LPL is regionally modulated by apoC-II secretion. We propose a model where apoC-II is retained in secretory granules in distal epithelial cells until the lumina reaches a minimum size, and is then secreted when the rate of surfactant production becomes optimal.
Highlights
Fatty acids are precursors in the synthesis of surfactant phospholipids
Does apoCII protein localization change according to the stage of lung development, according to the need in surfactant? Are lipoprotein lipase (LPL) molecules translocated to the luminal surface of capillaries? Do the sites of apolipoprotein C-II (apoC-II) and LPL gene expression change according to the stage of lung development and to protein localization? To answer these questions, we have performed in situ hybridization (ISH) and IHC of LPL and apoC-II from gestation days (GD) 15.5 to the first days of alveolarization
Results mRNA and protein localization of LPL and apoC-II during the pseudoglandular and the canalicular stages The surge of surfactant synthesis occurs on GD 17.5 in the mouse as indicated by the appearance of lamellar bodies [15], an increase in surface activity in the mouse lung homogenate [15], and by increases in the activity of some enzymes involved in pulmonary lipid metabolism [16,17]
Summary
We showed expression of apolipoprotein C-II (apoC-II), the essential cofactor of lipoprotein lipase (LPL), in the fetal mouse lung and found the protein on the day of the surge of surfactant synthesis (gestation day 17.5) in secretory granule-like structures in the distal epithelium. Fatty acids are precursor molecules in the synthesis of surfactant phospholipids They can be synthesized in the lung or originate from circulating triglycerides. In many tissues including adipose tissue and skeletal muscle, delivery of fatty acids from triglyceride-rich lipoproteins occurs by hydrolysis on the luminal surface of the capillary endothelium. This reaction is catalyzed by lipoprotein lipase (LPL) [7,8] and requires apolipoprotein C-II (apoC-II) as essential and specific cofactor [9,10]
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