Progress towards understanding the role of microsomal triglyceride transfer protein in apolipoprotein-B lipoprotein assembly.
The microsomal triglyceride transfer protein (MTP) is necessary for the proper assembly of the apolipoprotein B containing lipoproteins, very low density lipoprotein and chylomicrons. Recent research has significantly advanced our understanding of the role of MTP in these pathways at the molecular and cellular level. Biochemical studies suggest that initiation of lipidation of the nascent apolipoprotein B polypeptide may occur through a direct association with MTP. This early lipidation may be required to allow the nascent polypeptide to fold properly and therefore avoid ubiquitination and degradation. Concerning the addition of core neutral lipids in the later stages of lipoprotein assembly, cell culture studies show that MTP lipid transfer activity is not required for this to occur for apolipoprotein B-100 containing lipoproteins. Likewise, MTP does not appear to directly mediate addition of core neutral lipid to nascent apoB-48 particles. However, new data indicate that MTP is required to produce triglyceride rich droplets in the smooth endoplasmic reticulum which may supply the core lipids for conversion of nascent, dense apoB-48 particles to mature VLDL. In addition, assembly of dense apolipoprotein B-48 containing lipoproteins has been observed in mouse liver in the absence of MTP. As a result of these new data, an updated model for the role of MTP in lipoprotein assembly is proposed.
Gordon
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Division of Metabolic and Cardiovascular Drug Discovery, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543, USA. gordond@bms.com
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D000012:Abetalipoproteinemia / Q000235:genetics; D000818:Animals; D001055:Apolipoproteins B / Q000032:analysis / Q000737:chemistry / Q000378:metabolism*; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D053480:Cholesterol Ester Transfer Proteins; D004721:Endoplasmic Reticulum / Q000378:metabolism; D006023:Glycoproteins; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D008074:Lipoproteins / Q000737:chemistry*; D008079:Lipoproteins, VLDL / Q000737:chemistry / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008861:Microsomes / Q000378:metabolism*; D009420:Nervous System / Q000196:embryology / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology; D011485:Protein Binding; D017510:Protein Folding; D015017:Yolk Sac / Q000378:metabolism
D001055:Apolipoproteins B; C114701:BMS 192951; C506642:CETP protein, human; D002352:Carrier Proteins; D053480:Cholesterol Ester Transfer Proteins; D006023:Glycoproteins; D007211:Indoles; D008074:Lipoproteins; D008079:Lipoproteins, VLDL; D010880:Piperidines