Apolipoprotein AIV: a potent endogenous inhibitor of lipid oxidation

Abstract

Overexpression of apolipoprotein (apo) AIV in transgenic mice confers significant protection against atherosclerosis in apoE knockout animals even in the presence of a more severe atherogenic lipid profile. Because lipoprotein oxidation has been recognized to be pivotal in development of atherosclerosis, the antioxidative activity of apoAIV was investigated. Fasting intestinal lymph was used to mimic conditions in the interstitial fluid, the potential site for lipoprotein oxidation in vivo. ApoAIV (10 μg/ml) significantly inhibited copper-mediated oxidation of lymph. This inhibitory effect was further evaluated using purified low-density lipoprotein. Addition of apoAIV (2.5 μg/ml) increased the time of 50% conjugated diene formation by 2.4-fold, whereas apoE or BSA did not show such a protection even at 20 μg/ml. Addition of apoAIV during the propagation phase also resulted in a dose-dependent inhibition. ApoAIV also protected macrophage-induced oxidation of fasting lymph. These results provide the first evidence that apoAIV is a potent endogenous antioxidant.

Small-angle X-ray Scattering of Apolipoprotein A-IV Reveals the Importance of Its Termini for Structural Stability

“…In addition to HDL particle formation, apoA-IV has been shown to have a variety of unique biological roles not shared by other apolipoproteins; for example, in response to lipid absorption, apoA-IV is highly expressed in the intestine and is associated with apoB secretion (8,9). Furthermore, apoA-IV functions as a satiety signal (10,11), an antioxidant (12), and an anti-inflammatory agent (13). Recently, apoA-IV has also been shown to regulate insulin secretion, specifically during elevated glucose levels (14).…”

Specific Sequences in the N and C Termini of Apolipoprotein A-IV Modulate Its Conformation and Lipid Association

“…Human apolipoprotein (apo) 3 A-IV is a 46-kDa glycoprotein that is the largest member of the exchangeable apolipoprotein family. It is synthesized by enterocytes of the small intestine in response to lipid absorption and is secreted into circulation on the surface of chylomicrons.…”

The apolipoprotein A-IV Gln360His polymorphism predicts progression of coronary artery calcification in patients with type 1 diabetes

“…We can only speculate as to whether the pro-atherogenic effect of the APOA4 His360 allele in type 1 diabetic subjects is dependent on defective antioxidant properties of the APOA4-2 isoform [17,22]. In this case, the diminished protective role of APOA4 could be more pronounced in situations when production of reactive oxygen species is increased (such as with poorly controlled diabetes), while in subjects with relatively lower oxidative stress, the significance of this genetic variant in rapid progression of atherosclerosis is less important [31,43].…”

“…Apolipoprotein A-IV (APOA4), a structural glycoprotein found in chylomicrons, HDL and VLDL, present in the circulation as a lipoprotein-free form, was suggested to have potent anti-atherogenic properties [17,18]. APOA4 plays an important role in reverse cholesterol transport from peripheral cells to the liver by promoting cholesterol efflux from cells (including macrophages) [19] and by enhancing formation of HDL via activation of lecithin-cholesterol acyl transferase [20].…”