ApoB containing lipoproteins
From LipidomicsWiki
Apolipoprotein B-containing lipoprotein assembly and secretion is critical for lipid absorptionand triglyceride homeostasis, and plays a role in atherogenesis and the pathobiology of type2 diabetes and obesity.
Until recently it was assumed that microsomal triglyceride transfer protein-dependent apolipoprotein B-containing lipoprotein assembly was a unique adaptation associated with vertebrate lipid homeostasis. However, it is now clear that microsomal triglyceride transfer protein (MTP) exists in species whose last common ancestor diverged over 550 million years ago. In its long evolutionary history, the MTP gene has given rise to a series of paralogous lipid transport proteins, all of which require MTP for their biogenesis. During its evolution, MTP has acquired new functions, enabling it to participate in a disparate array of lipid mobilization and transport pathways, ranging from primitive lipoprotein assembly to antigenic lipid presentation.
[Figure 81: Alternative pathways for initiation of lipoprotein Assembly In one view (red arrows), the open side of the apolipoprotein (apo) B lipid binding cavity is closed by a helix-turn-helix motif that is stabilized by residues between amino acids 997 and 1000 of apoB. This cavity is filled mainly with phospholipid and then converted to a nascent emulsion particle as the translation of apoB continues and apoB acquires additional neutral lipid. In an alternative view (green arrows), the open lipovitellinlike pocket exposes hydrophobic surfaces with strong interfacial properties. These surfaces interact with the endoplasmic reticulum membrane nucleating triglyceride droplet formation. The nascent particle is then desorbed as a preformed emulsion particle to be enlarged during subsequent apoB translation. TG, Triglycerides; Vtg, vitellogenin (Shelness and Ledford 2005).]
In addition to the complex and multifunctional role of MTP in apolipoprotein B assembly, other factors responsible for the generation of secretion-coupled lipids and the modulation of
apolipoprotein B production are emerging.
ApoB-containing lipoprotein assembly has its evolutionary origins in vitellogenesis, the process by which lipids and other nutrients are transported by vitellogenin from extraovarian tissues to the developing oocyte in oviparous vertebrates and invertebrates. The sequence similarity between vitellogenin and apoB was first noted by Baker in 1988 (Baker 1988), and has since been extended to include microsomal triglyceride transfer protein (MTP) and apolipophorin II/I (apoLpII/I), the major carrier of lipids in insects (Shoulders et al. 1994). Members of this extended gene family are termed collectively large lipid transfer proteins (LLTPs) (Babin et al. 1999). Because of vitellogenin’s wide evolutionary distribution, it was presumed to be the ancestral member of the LLTP gene family, giving rise via gene duplication to MTP and apoB (Mann et al. 1999). However, recent findings suggest that MTP may be the oldest LLTP family member, which over its long evolutionary history has given rise to a series of paralogous lipid transport proteins, including vitellogenin, apoLpII/I, and apoB (Fig. 81).
Although MTP has more substrates than originally anticipated, they are predominantly members of the extended LLTP gene family. However, recent evidence suggests that CD1d, and perhaps other members of the CD1 family of lipid-antigen-presenting molecules, are also MTP substrates. The CD1 proteins present endogenous and pathogen-derived lipid antigens to a specific set of natural killer T lymphocytes. CD1s associate with phosphatidylinositolcontaining molecules in the endoplasmic reticulum (ER) (Park et al. 2004), which may be important for their folding and transport, and also display endosomally derived endogenous and exogenous glycolipid antigens at the cell surface (Kang and Cresswell 2004; Zhou et al. 2004). Brozovic et al. (Brozovic et al. 2004) recently demonstrated in mouse hepatocytes that CD1d physically associates with MTP in the ER, and that MTP deficiency interferes with CD1d anterograde trafficking. Furthermore, MTP-deficient hepatocytes were incapable of activating natural killer T cells in vitro, and MTP-deficient mice were resistant to natural killer Tcell-mediated hepatitis and colitis in vivo. It appears, therefore, that in addition to its role in bulk lipid transport, MTP may regulate CD1-dependent antigenic lipid presentation. The connection between MTP and CD1d could explain the relatively ubiquitous low-level expression of MTP observed in many non-lipoprotein-producing cells (Shoulders et al. 1993; Sellers and Shelness 2001)
[Figure 82: Evolutionary relationships among large lipid transfer protein family members Large lipid transfer protein (LLTP) family members, diagrammed against the light blue background, share a conserved N-terminal bsheet and a-helical domain. The lipid binding domains of each protein are more divergent, as indicated. Microsomal triglyceride transfer protein (MTP) appears to be the oldest member of the family based on its presence in nematodes and its ability to act on other LLTP family members (continuous blue arrow) to create various lipidated proteins (black horizontal arrows). Note, that MTP’s ability to form high density lipophorins has not been demonstrated experimentally, and the possible existence of an MTP-containing ‘progenitor LLTP’ is hypothetical. The red arrows indicate the predicted order of evolutionary appearance of each protein. The approximate number of amino acids in each LLTP family member is indicated; however, the diagram is not drawn to scale. CD1d, shown with its lower molecular weight b2m subunit is also an MTP substrate,although it is clearly not a member of the LLTP family. HDLp, High density lipophorins; LV, lipovitellin; Vtg, vitellogenin (Shelness and Ledford 2005).]
Based on recent published and preliminary evidence (Avramoglu and Adeli 2004), it is hypothesized (Fig. 83) that diet-induced insulin resistance results from perturbations in key
molecules of the insulin signaling pathway, including overexpression of phosphatases, PTP- 1B and PTEN, downregulation of the PI-3 kinase pathway and basal activation of the MAP
kinase cascade. These signaling changes in turn cause an increased expression of SREBP- 1c, induction of de novo lipogenesis and higher activity of MTP, which together with high
exogenous free fatty acid flux collectively stimulate the hepatic production of apoB-containing VLDL particles.
[Figure 83. Molecular mechanisms linking insulin resistance and metabolic dyslipidemia. Binding of insulin to the insulin receptor triggers signalling mechanisms that negatively regulate VLDL assembly and secretion principally via the PI-3 kinase pathway. This negative regulation appears to be lost in insulin resistant states leading to stimulation of VLDL production. Upregulation of key phosphatases, including PTP-1B and PTEN, may play an important role in downregulation of PI-3 kinase signaling. Conversely, inflammatory and stress mechanisms result in stimulation of the MAP kinase pathway which in turn can upregulate MTP, SREBP-1c, and apoB, leading to increased de novo lipogenesis and enhanced VLDL secretion. Increased free fatty acid flux into the liver in the insulin resistant state also plays an important role in MTP activation and enhanced triglyceride synthesis that contribute to VLDL production and thus exacerbate elevated circulating VLDL (Avramoglu and Adeli 2004).]
