Overexpression of Apolipoprotein A-IV Enhances Lipid Secretion in IPEC-1 Cells by Increasing Chylomicron Size

Abstract

Basolateral apoB secretion decreased. Using the same expression system, fulllength human apoA-IV (376 amino acids); a "pig-like" human apoA-IV, lacking the C-terminal EQQQ repeats (361 amino acids); and a "chicken-like" apoA-IV, further truncated to 343 amino acids, were expressed in IPEC-1 cells. With increasing protein secretion, cells expressing the full-length human apoA-IV displayed a 2-fold increase in TG secretion; in sharp contrast, cells expressing the piglike human apoA-IV displayed a 25-fold increase in TG secretion and a 27-fold increase in lipoprotein diameter. When human apoA-IV was further truncated to yield a chicken-like protein, TG secretion was inhibited. We conclude that overexpression of swine apoA-IV enhances basolateral TG secretion in a dose-dependent manner by increasing the size of secreted lipoproteins. These data suggest that the region in the human apoA-IV protein from residues 344 to 354 is critical to its ability to enhance lipid secretion, perhaps by enabling the packaging of additional core TG into chylomicron particles. The EQQQ-rich region may play an inhibitory or modulatory role in chylomicron packaging in humans.

The expression of genes involved in jejunal lipogenesis and lipoprotein synthesis is altered in morbidly obese subjects with insulin resistance

“…Apo A-IV is a lipid-binding protein that is incorporated into the nascent chylomicrons and enhances basolateral triglyceride secretion in a dose-dependent manner. 6 This increase found in apo A-IV mRNA expression is according to other research showing an increase in the assembly and secretion of apoB48-containing lipoproteins in insulin-resistant states in humans with insulin resistance 29 but with a lower content in triglycerides. Although the expression and synthesis of apo A-IV is very specific for intestine, no significant correlation was found between apo A-IV mRNA expression and serum levels.…”

“…3 Apo A-IV has an important role in enhancing the secretion of chylomicrons and associated lipids in newborn enterocytes. 6 A dysregulation of intestinal lipoprotein metabolism in insulin-resistant states has also been shown in animal models 7 and humans. 8 Insulin resistance and T2DM might enhance intestinal lipoprotein production, involving increased de novo lipogenesis and chylomicron production.…”

Chronic high-fat diet affects intestinal fat absorption and postprandial triglyceride levels in the mouse

“…Chylomicron size is highly dependent on expression levels of a few LBPs and apolipoproteins. For instance, FAT/CD36 knockout mice secrete smaller chylomicrons than wild-type mice (30), and the induction of intestinal apoA-IV has been reported to lead to larger particles (27,31). According to these data, the fat-mediated increase of genes encoding FAT/CD36 and apoA-IV might produce large chylomicrons rapidly hydrolyzed by LPL.…”

“…Indeed, an intestine-specific MTP gene invalidation produces a dramatic decrease in chylomicron synthesis and secretion (5). Finally, the induction of apoA-IV expression found in lipid-fed mice might also facilitate intestinal lipoprotein production (27). Altogether, these lipid-mediated changes in gene expression must improve the intestinal lipid absorption and, thereby, deeply affect the postprandial triglyceridemia.…”

Modulation of Apolipoprotein A-IV Lipid Binding by an Interaction between the N and C Termini

“…However, when apoA-IV release from the endoplasmic reticulum is genetically disrupted, apoB and lipoprotein secretion is inhibited (4). On the other hand, overexpression of human apoA-IV in porcine intestinal cells enhances basolateral lipid secretion via production of larger chylomicron-like particles (5). In addition, certain naturally occurring polymorphisms of apoA-IV result in altered chylomicron clearance after the particles have reached the circulation (6).…”