Is microsomal triglyceride transfer protein the missing link in abetalipoproteinemia?

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Abstract
In the study reported by Wetterau et al., a recently characterized heterodimeric protein called microsomal triglyceride transfer protein was undetectable on immunoblotting of samples from intestinal biopsies of human subjects with the genetic disorder abetalipoproteinemia. With only one fourth to one fifth the soluble proteins of homogenized intestinal biopsy specimens of normal human subjects and patients with different fat-absorption defects, the 88-kD subunit of microsomal triglyceride transfer protein was clearly detectable. Protein disulfide isomerase, the 55-kD subunit of microsomal triglyceride transfer protein, was present in tissue of all subjects tested, including those with abetalipoproteinemia. Consistent results were obtained with an in vitro assay that measures triglyceride transfer between phospholipid membranes: triglyceride transfer continued at constant rates for more than 1 hr in samples from biopsies in normal human subjects, whereas no measurable triglyceride transfer was detected in the same material from abetalipoproteinemia patients. The apparent absence of the 88-kD subunit of microsomal triglyceride transfer protein most likely explains this debilitating disorder. This new observation coincides with the recent articulation of a novel hypothesis about the subcellular mechanisms by which enterocytes and hepatocytes assemble triglyceride-rich particles containing the large hydrophobic protein apolipoprotein B in two steps. In the first step, a small (≈ 200 Å), apolipoprotein B-rich microemulsion particle containing small amounts of triglycerides and cholesteryl esters in its core is formed and released into the lumen of the rough endoplasmic reticulum. The second step requires the synthesis of larger triglyceride-rich particles lacking apolipoprotein B in the smooth endoplasmic reticulum. Fusion of these two particles is postulated to yield nascent very low density lipoproteins or chylomicrons that can be secreted by hepatocytes and enterocytes, respectively. In classic abetalipoproteinemia patients, no apolipoprotein B is found in blood plasma, and chylomicrons, very low density lipoproteins and low-density lipoproteins are absent. The two-step model of triglyceride-rich particle formation predicts that, in the absence of microsomal triglyceride transfer protein, newly synthesized apolipoprotein B bound to the rough endoplasmic reticulum membrane cannot be core-lipidated and thus cannot be efficiently dissociated from the rough endoplasmic reticulum membrane. In other words, the first step cannot occur in the absence of microsomal triglyceride transfer protein. Consequently, apolipoprotein B-containing lipoproteins cannot be produced and sequestered in the lumen of the endoplasmic reticulum in abetalipoproteinemia, and no such lipoproteins are secreted.