Keratinocyte growth factor and the transcription factors C/EBPα, C/EBPδ, and SREBP-1c regulate fatty acid synthesis in alveolar type II cells
Robert J. Mason, … , Michael R. Eckart, Steven Neben
Robert J. Mason, … , Michael R. Eckart, Steven Neben
Published July 15, 2003
Citation Information: J Clin Invest. 2003;112(2):244-255. https://doi.org/10.1172/JCI16793.
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Article Pulmonology

Keratinocyte growth factor and the transcription factors C/EBPα, C/EBPδ, and SREBP-1c regulate fatty acid synthesis in alveolar type II cells

Abstract

Strategies to stimulate endogenous surfactant production require a detailed understanding of the regulation of lipogenesis in alveolar type II cells. We developed culture conditions in which keratinocyte growth factor (KGF) stimulates fatty acid and phospholipid synthesis. KGF stimulated acetate incorporation into phosphatidylcholine, disaturated phosphatidylcholin, and phosphatidylglycerol more than 5% rat serum alone. To determine the mRNA levels of lipogenic enzymes and transport proteins, we analyzed gene expression by oligonucleotide microarrays. KGF increased the mRNA levels for fatty acid synthase, stearoyl-CoA desaturase-1 (SCD-1), and epidermal fatty acid–binding protein more than rat serum alone. In addition, KGF increased the mRNA levels of the transcription factors CCAAT/enhancer-binding protein α (C/EBPα) and C/EBPδ as well as SREBP-1c (ADD-1), but not PPARγ. These changes in C/EBPα and C/EBPδ were confirmed by in situ hybridization. SCD-1 was also found to be highly expressed in alveolar type II cells in vivo. Furthermore, KGF increased protein levels of fatty acid synthase, C/EBPα, C/EBPδ, SREBP-1, epidermal fatty acid–binding protein, and SCD. Finally, the liver X receptor agonist T0901317 increased acetate incorporation and SREBP-1 but not SREBP-2 protein levels. In summary, KGF stimulates lipogenesis in type II cells by a coordinated expression of lipogenic enzymes and transport proteins regulated by C/EBP isoforms and SREBP-1c.

Authors

Robert J. Mason, Tianli Pan, Karen E. Edeen, Larry D. Nielsen, Feijie Zhang, Malinda Longphre, Michael R. Eckart, Steven Neben

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Fatty acid synthesis is stimulated by the LXR agonist T0901317. Type II ...
Fatty acid synthesis is stimulated by the LXR agonist T0901317. Type II cells were plated on Matrigel in 5% RS and then cultured in 1% CS-FBS with or without KGF and with or without varying doses of T0901317 and appropriate vehicle controls. (a) T0901317 increased acetate incorporation in a dose-dependent manner in 1% CS-FBS and at the highest dose in the presence of KGF. The results are normalized to the value of 1% CS-FBS and are means ± SEM for five independent experiments. *P < 0.05 vs. the appropriate DMSO control without the LXR agonist. (b) Protein expression is shown by immunoblotting. The conditions are the same as in a. Lanes 1, 2, 7, and 8 contain DMSO without T0901317 as shown in a. Protein loading is normalized to the amount of actin. A representative sample of five independent experiments is shown.