Why does the gut choose apolipoprotein B48 but not B100 for chylomicron formation?

Abstract

Chylomicrons produced by the human gut contain apolipoprotein (apo) B48, whereas very-low-density lipoproteins made by the liver contain apo B100. To study how these molecules function during lipid absorption, we examined the process as it occurs in apobec-1 knockout mice (able to produce only apo B100; KO) and in wild-type mice (of which the normally functioning intestine makes apo B48, WT). Using the lymph fistula model, we studied the process of lipid absorption when animals were intraduodenally infused with a lipid emulsion (4 or 6 micromol/h of triolein). KO mice transported triacylglycerol (TG) as efficiently as WT mice when infused with the lower lipid dose; when infused with 6 micromol/h of triolein, however, KO mice transported significantly less TG to lymph than WT mice, leading to the accumulation of mucosal TG. Interestingly, the size of lipoprotein particles from both KO and WT mice were enlarged to chylomicron-size particles during absorption of the higher dose. These increased-size particles produced by KO mice were not associated with increased apo AIV secretion. However, we found that the gut of the KO mice secreted fewer apo B molecules to lymph (compared with WT), during both fasting and lipid infusion, leading us to conclude that the KO gut produced fewer numbers of TG-rich lipoproteins (including chylomicron) than the wild-type animals. The reduced apo B secretion in KO mice was not related to reduced microsomal triglyceride transfer protein lipid transfer activity. We propose that apo B48 is the preferred protein for the gut to coat chylomicrons to ensure efficient chylomicron formation and lipid absorption.

Recent advances in physiological lipoprotein metabolism

“…ApoB100 has 4536 amino acids. ApoB48 results from a post-transcriptional modification of the apoB mRNA, through the action of the APOB mRNA editing complex (APOBEC1) which forms a stop codon at approximately 48% of the full length coding sequence [43]. The truncated form of ApoB100, ApoB48 lacks the C-terminus which contains the domain recognized by the LDL receptor.…”

Molecular processes that handle — and mishandle — dietary lipids

“…The C terminus of apoB 100 contains the domain recognized by the LDL receptor, thereby mediating high-affinity clearance of these particles from plasma. In contrast, essentially all of the apoB from human intestine appears as a truncated form, apoB 48 , that is missing the C-terminal 52% (37), and so CMs and CM remnants rely on exchangeable proteins, particularly lipoprotein lipase (LpL; refs. 38-41), hepatic lipase (42,43), and apoE (44)(45)(46), to serve as ligands for cell surface receptors.…”

“…Polymorphisms of each of these exchangeable proteins affect fasting lipoprotein concentrations (47) and the postprandial response (43). Intestinal apoB 48 comes from the same gene as apoB 100 through the action of the APOB mRNA editing complex-1 (APOBEC1), which deaminates a single cytidine into a uridine, thereby creating a nongenomic inframe stop codon (UAA) roughly in the middle of the RNA coding region ( Figure 2 and ref. 48).…”

“…Intestinal apoB 48 comes from the same gene as apoB 100 through the action of the APOB mRNA editing complex-1 (APOBEC1), which deaminates a single cytidine into a uridine, thereby creating a nongenomic inframe stop codon (UAA) roughly in the middle of the RNA coding region ( Figure 2 and ref. 48). Far more details are known about the cellular processes in the liver that allow this huge, hydrophobic protein to become cotranslationally and posttranslationally assembled with lipids (49) and what regulates its subsequent secretion (50).…”

Genetically Modified Animal Models for Lipoprotein Research

“…A deficiency of apobec-1 in the intestine resulted in reduction in the secretion and assembly of chylomicron particles (Kendrick, 2001). These results from apobec-1-KO mice suggested that apoB-48 is involved in the assembly of chylomicron particles (Lo, 2008). Finally, absorbed lipids and synthesized apolipoproteins are assembled by MTP.…”