An upstream enhancer regulates Gpihbp1 expression in a tissue-specific manner

J Lipid Res. 2019 Apr;60(4):869-879. doi: 10.1194/jlr.M091322. Epub 2018 Dec 31.

Abstract

Glycosylphosphatidylinositol-anchored high density lipoprotein-binding protein 1 (GPIHBP1), the protein that shuttles LPL to the capillary lumen, is essential for plasma triglyceride metabolism. When GPIHBP1 is absent, LPL remains stranded within the interstitial spaces and plasma triglyceride hydrolysis is impaired, resulting in severe hypertriglyceridemia. While the functions of GPIHBP1 in intravascular lipolysis are reasonably well understood, no one has yet identified DNA sequences regulating GPIHBP1 expression. In the current studies, we identified an enhancer element located ∼3.6 kb upstream from exon 1 of mouse Gpihbp1. To examine the importance of the enhancer, we used CRISPR/Cas9 genome editing to create mice lacking the enhancer (Gpihbp1 Enh/Enh). Removing the enhancer reduced Gpihbp1 expression by >90% in the liver and by ∼50% in heart and brown adipose tissue. The reduced expression of GPIHBP1 was insufficient to prevent LPL from reaching the capillary lumen, and it did not lead to hypertriglyceridemia-even when mice were fed a high-fat diet. Compound heterozygotes (Gpihbp1 Enh/- mice) displayed further reductions in Gpihbp1 expression and exhibited partial mislocalization of LPL (increased amounts of LPL within the interstitial spaces of the heart), but the plasma triglyceride levels were not perturbed. The enhancer element that we identified represents the first insight into DNA sequences controlling Gpihbp1 expression.

Keywords: chylomicrons; endothelial cells; fatty acid metabolism; glycosylphosphatidylinositol-anchored high density lipoprotein–binding protein 1; lipids; lipolysis; triglycerides.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipose Tissue, Brown / metabolism*
  • Animals
  • CRISPR-Cas Systems / genetics
  • Chromatin / genetics
  • Heart
  • Humans
  • Lipoprotein Lipase / metabolism*
  • Mice
  • Mice, Inbred Strains
  • Receptors, Lipoprotein / analysis
  • Receptors, Lipoprotein / genetics*
  • Receptors, Lipoprotein / metabolism
  • Sequence Analysis, DNA
  • Triglycerides / blood
  • Triglycerides / metabolism

Substances

  • Chromatin
  • GPI-HBP1 protein, mouse
  • GPIHBP1 protein, human
  • Receptors, Lipoprotein
  • Triglycerides
  • Lipoprotein Lipase