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

Area of Science:

• Molecular Biology
• Genetics
• Metabolic Research

Background:

• Glycosylphosphatidylinositol-anchored high density lipoprotein-binding protein 1 (GPIHBP1) is vital for triglyceride metabolism by transporting lipoprotein lipase (LPL) to capillaries.
• Absence of GPIHBP1 leads to impaired triglyceride hydrolysis and severe hypertriglyceridemia due to LPL mislocalization.

Purpose of the Study:

• To identify DNA sequences that regulate the expression of the GPIHBP1 gene.
• To investigate the functional significance of a newly identified enhancer element upstream of the mouse Gpihbp1 gene.

Main Methods:

• CRISPR/Cas9 genome editing was employed to create mice lacking the identified enhancer element (Gpihbp1Enh/Enh).
• Gene expression levels of Gpihbp1 and LPL localization were analyzed in wild-type and genetically modified mice.
• Plasma triglyceride levels were measured under normal and high-fat diet conditions.

Main Results:

• Deletion of the enhancer element significantly reduced Gpihbp1 expression in the liver (>90%) and other tissues (~50%).
• Reduced GPIHBP1 expression did not cause hypertriglyceridemia or prevent LPL from reaching capillary lumens, even on a high-fat diet.
• Compound heterozygotes showed further Gpihbp1 reduction and partial LPL mislocalization, but plasma triglycerides remained normal.

Conclusions:

• The identified enhancer is the first regulatory DNA sequence discovered for Gpihbp1.
• The identified enhancer plays a role in controlling Gpihbp1 expression levels.
• The study provides novel insights into the genetic regulation of GPIHBP1 and its impact on triglyceride metabolism.