Keratinocyte Growth Factor and the Transcription Factors C/EBP Alpha, C/EBP Delta, and SREBP-1c Regulate Fatty Acid Synthesis in Alveolar Type II Cells

J Clin Invest. 2003 Jul;112(2):244-55. doi: 10.1172/JCI16793.

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 phosphatidylcholine, 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 alpha (C/EBPalpha) and C/EBPdelta as well as SREBP-1c (ADD-1), but not PPARgamma. These changes in C/EBPalpha and C/EBPdelta 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/EBPalpha, C/EBPdelta, 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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Blotting, Western
  • CCAAT-Enhancer-Binding Protein-alpha / metabolism*
  • CCAAT-Enhancer-Binding Protein-delta
  • CCAAT-Enhancer-Binding Proteins / metabolism*
  • Collagen / pharmacology
  • DNA / metabolism
  • DNA-Binding Proteins / metabolism*
  • Dose-Response Relationship, Drug
  • Drug Combinations
  • Fatty Acids / metabolism*
  • Fibroblast Growth Factor 7
  • Fibroblast Growth Factors / physiology*
  • Immunoblotting
  • In Situ Hybridization
  • Laminin / pharmacology
  • Lipid Metabolism
  • Liver X Receptors
  • Male
  • Oligonucleotide Array Sequence Analysis
  • Oligonucleotides / chemistry
  • Orphan Nuclear Receptors
  • Phospholipids / metabolism
  • Protein Isoforms
  • Proteoglycans / pharmacology
  • RNA, Messenger / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Cytoplasmic and Nuclear / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Sterol Regulatory Element Binding Protein 1
  • Sterol Regulatory Element Binding Protein 2
  • Transcription Factors / metabolism

Substances

  • CCAAT-Enhancer-Binding Protein-alpha
  • CCAAT-Enhancer-Binding Proteins
  • Cebpd protein, rat
  • DNA-Binding Proteins
  • Drug Combinations
  • Fatty Acids
  • Fgf7 protein, rat
  • Laminin
  • Liver X Receptors
  • Oligonucleotides
  • Orphan Nuclear Receptors
  • Phospholipids
  • Protein Isoforms
  • Proteoglycans
  • RNA, Messenger
  • Receptors, Cytoplasmic and Nuclear
  • Srebf1 protein, rat
  • Sterol Regulatory Element Binding Protein 1
  • Sterol Regulatory Element Binding Protein 2
  • Transcription Factors
  • matrigel
  • Fibroblast Growth Factor 7
  • CCAAT-Enhancer-Binding Protein-delta
  • Fibroblast Growth Factors
  • Collagen
  • DNA