Abstract
A better understanding of intracellular lipoprotein assembly may help identify proteins with important roles in lipid disorders. apoB-containing lipoproteins (B-lps) are macromolecular lipid and protein micelles that act as specialized transport vehicles for hydrophobic lipids. They are assembled predominantly in enterocytes and hepatocytes to transport dietary and endogenous fat, respectively, to different tissues. Assembly occurs in the endoplasmic reticulum (ER) and is dependent on lipid resynthesis in the ER and on a chaperone, namely, microsomal triglyceride transfer protein (MTTP). Precursors for lipid synthesis are obtained from extracellular sources and from cytoplasmic lipid droplets. MTTP is the major and essential lipid transfer protein that transfers phospholipids and triacylglycerols to nascent apoB for the assembly of lipoproteins. Assembly is aided by cell death-inducing DFF45-like effector B and by phospholipid transfer protein, which may facilitate additional deposition of triacylglycerols and phospholipids, respectively, to apoB. Here, we summarize the current understanding of the different steps in the assembly of B-lps and discuss the role of lipid transfer proteins in these steps to help identify new clinical targets for lipid-associated disorders, such as heart disease.
Highlights
A better understanding of intracellular lipoprotein assembly may help identify proteins with important roles in lipid disorders. apoB-containing lipoproteins (B-lps) are macromolecular lipid and protein micelles that act as specialized transport vehicles for hydrophobic lipids
We propose that cell death-inducing DFF45-like effector B (CIDEB) may facilitate lateral diffusion of triacylglycerols from cytoplasmic lipid droplet (cLD) to the endoplasmic reticulum (ER) membrane at contact sites and, within the ER membrane, from the site of lipid synthesis to apoB
We are starting to piece together the early events and identify proteins involved in the early stages of B-lp assembly, very little is known about the second step of lipoprotein core expansion
Summary
Triacylglycerol synthesis and phospholipid synthesis in the smooth endoplasmic reticulum (ER) are critical for B-lp assembly because inhibition of their synthesis or ablation of genes involved in their biosynthesis adversely affects B-lp assembly [14,15,16,17,18]. Glycerol, and monoacylglycerols are important precursors for their synthesis and are obtained from two sources These precursors are taken up by cells from the extracellular environment via transporters present on the plasma membrane, such as CD36 and fatty acid transport proteins [10, 19,20,21], and are carried by cytoplasmic proteins, e.g., fatty acid-binding proteins [10, 22], from the plasma membrane to the ER. Once juxtaposed with the ER, fatty acids hydrolyzed from cLDs can be taken up by the ER for lipid resynthesis and lipoprotein assembly It remains to be determined whether lipids diffuse from cLDs to the ER through contact sites and become incorporated in B-lps. Resynthesis of triacylglycerols from adipose tissue-derived free fatty acids may be the major source of lipids for VLDL assembly during fasting
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