GPIHBP1 and lipolysis: an update

Abstract

Purpose of review: This review will provide an update on the structure of GPIHBP1, a 28-kDa glycosylphosphatidylinositol-anchored glycoprotein, and its role in the lipolytic processing of triglyceride-rich lipoproteins.

Recent findings: Gpihbp1 knockout mice on a chow diet have milky plasma and plasma triglyceride levels of more than 3000 mg/dl. GPIHBP1 is located on the luminal surface of endothelial cells in tissues where lipolysis occurs: heart, skeletal muscle, and adipose tissue. The pattern of lipoprotein lipase (LPL) release into the plasma after an intravenous injection of heparin is abnormal in Gpihbp1-deficient mice, suggesting that GPIHBP1 plays a direct role in binding LPL within the tissues of mice. Transfection of CHO cells with a GPIHBP1 expression vector confers on cells the ability to bind both LPL and chylomicrons. Two regions of GPIHBP1 are required for the binding of LPL - an amino-terminal acidic domain and the cysteine-rich Ly6 domain. GPIHBP1 expression in mice changes with fasting and refeeding and is regulated in part by peroxisome proliferator-activated receptor-gamma.

Summary: GPIHBP1, an endothelial cell-surface glycoprotein, binds LPL and is required for the lipolytic processing of triglyceride-rich lipoproteins.

Figure 1. A schematic illustration of GPIHBP1, showing the amino-terminal acidic domain rich in aspartates and glutamates (dark gray), an Ly6 domain (black) containing 10 cysteines (each of these 10 cysteines is involved in a disulfide bond), and two linker segments (light gray)

A carboxyl-terminal hydrophobic domain is clipped off in the endoplasmic reticulum and replaced with a GPI anchor, which tethers the protein to the cell surface.

Figure 2. An abnormal pattern of lipoprotein lipase release into the plasma of Gpihbp1^−/− mice after an injection of heparin

In control mice, heparin enters the plasma very rapidly, and LPL levels (mean ± SD) peak within 1 min after the injection. In Gpihbp1^−/− mice, heparin levels were low at 1 min after the injection and increased slowly over 15 min. Gpihbp1^−/−, n = 7; Gpihbp1^+/−, n = 9; Gpihbp1^+/+, n = 7. LPL, lipoprotein lipase. Reproduced with permission [14••].

Figure 3. Increased expression of Gpihbp1 (n = 10 per group) in the tissues of mice after short-term treatment with a PPARγ agonist

Bars show the amount of Gpihbp1, Ucp3, and ap2 mRNA on a PPARγ agonist (mean ± SE), relative to those in vehicle-treated mice. Gpihbp1 expression in the PPARγ agonist-treated mice was increased in white adipose tissue (a) as well as brown adipose tissue (b), and heart (c) but not in liver (e). The increased Gpihbp1 expression in muscle (d) after treatment with a PPARγ agonist did not reach statistical significance. Reproduced with permission [17••].