The lipid components of lipoproteins are insoluble in water. However, because of their detergent-like (amphipathic) properties, apolipoproteins and other amphipathic molecules (such as phospholipids) can surround the lipids, creating a lipoprotein particle that is itself water-soluble, and can thus be carried through body fluids (i.e., blood, lymph).
In addition to stabilizing lipoprotein structure and solubilizing the lipid component, apolipoproteins interact with lipoprotein receptors and lipid transport proteins, thereby participating in lipoprotein uptake and clearance. They also serve as enzymecofactors for specific enzymes involved in the metabolism of lipoproteins.[1]
Apolipoproteins are also exploited by hepatitis C virus (HCV) to enable virus entry, assembly, and transmission. They play a role in viral pathogenesis and viral evasion from neutralizing antibodies.[2]
Apolipoprotein B plays a particularly important role in lipoprotein transport being the primary organizing protein of many lipoproteins.[1]
Apolipoprotein C-III (apoC3) plays an important role in lipid metabolism specific in regulating the metabolism of triglyceride-rich lipoproteins (TRLs).[6]
Apolipoprotein D (apoD) is a soluble carrier protein of lipophilic molecules in neurons and glial cells within the central and peripheral nervous system and apoD can also modulate the stability and oxidation status of these molecules.[7]
Apolipoprotein E (apoE) plays an important role in the transport and uptake of cholesterol by way of its high affinity interaction with lipoprotein receptors, including the low-density lipoprotein (LDL) receptor. ApoE is the major lipoprotein in the central nervous system. Recent findings with apoA1 and apoE suggest that the tertiary structures of these two members of the human exchangeable apolipoprotein gene family are related.[8] The three-dimensional structure of the LDL receptor-binding domain of apoE indicates that the protein forms an unusually elongated four-helix bundle that may be stabilised by a tightly packed hydrophobic core that includes leucine zipper-type interactions and by numerous salt bridges on the mostly charged surface. Basicamino acids important for LDL receptorbinding are clustered into a surface patch on one long helix.[9]
Apolipoprotein F (apoF) is one of the minor apolipoprotein in blood plasma and it is a lipid transfer inhibit protein to inhibit cholesteryl ester transfer protein-mediated transfers of cholesteryl esters and triglycerides.[10][11]
Apolipoprotein M (apoM) participates in the lipid metabolism and exhibit anti‑atherosclerotic functions and it is presented in high-density lipoprotein (HDL), low-density lipoprotein (LDL) and very low-density lipoprotein (VLDL).[12]
Classes
There are multiple classes of apolipoproteins and several sub-classes:
Exchangeable apolipoproteins (apoA, apoC, and apoE) have the same genomic structure and are members of a multi-gene family that probably evolved from a common ancestral gene. Apo-AI and ApoA4 are part of the APOA1/C3/A4/A5 gene cluster on chromosome 11.[14]
Hundreds of genetic polymorphisms of the apolipoproteins have been described, and many of them alter their structure and function.
Evolution
The cluster of exchangeable apoliproteins is well conserved in vertebrates.[15] The family diversified by duplication, with the ancestral gene most similar to ApoC1.[16]
Beyond vertebrates, proteins similar to the exchangeable ApoA/C/E and the nonexchangable Apo-B are found in a wide range of animals and choanoflagellates. This suggests that the ancestral animal already has both kinds of apolipoproteins. In arthropods in particular, diacylglycerol-carrying apolipoproteins are known as apolipophorins, with the ApoA/C/E-like one known as apolipophorin III and the Apo-B like one known as apolipophorin I/II.[16]
Synthesis and regulation
Apolipoprotein synthesis in the intestine is regulated principally by the fat content of the diet.
Apolipoprotein synthesis such as ApoA4 in hypothalamus involves in the integration of signals for regulation of food intake[5] which is regulated by vagal nerve and cholecystokinin.[17]
Disease
Apolipoprotein has been suggested to be implicated in several types of diseases and dysfunction.
ApoC1 level increases in neuropathic pain and fibromyalgia patients which suggest it plays an important role in occurrence of these conditions.[18]
ApoC3 is a risk factor of cardiovascular disease. Accumulation of plasma TRLs caused by elevated apoC-III leading to hypertriglyceridaemia.[19]
ApoD level increases in nervous system with a large number of neurologic disorders inclusive of Alzheimer's disease, schizophrenia, and stroke.[7]
Apo(a) is a component of lipoprotein(a) (Lp(a)) and elevated plasma Lp(a) level is a heritable, independent, and possibly causal risk factor for Atherosclerotic Cardiovascular Disease (ASCVD).[21] The cholesterol-rich apoB-containing lipoproteins also participate in the pathogenesis of ASCVD.
References
^ abEither roman numerals or arabic numbers may be used for gene family members. For example, apoA5 is also known as apo A-V.
^von Zychlinski A, Williams M, McCormick S, Kleffmann T (June 2014). "Absolute quantification of apolipoproteins and associated proteins on human plasma lipoproteins". Journal of Proteomics. 106: 181–90. doi:10.1016/j.jprot.2014.04.030. PMID24780726.
^ abLiu M, Doi T, Shen L, Woods SC, Seeley RJ, Zheng S, et al. (May 2001). "Intestinal satiety protein apolipoprotein AIV is synthesized and regulated in rat hypothalamus". American Journal of Physiology. Regulatory, Integrative and Comparative Physiology. 280 (5): R1382-7. doi:10.1152/ajpregu.2001.280.5.R1382. PMID11294757.
^Saito H, Lund-Katz S, Phillips MC (July 2004). "Contributions of domain structure and lipid interaction to the functionality of exchangeable human apolipoproteins". Progress in Lipid Research. 43 (4): 350–80. doi:10.1016/j.plipres.2004.05.002. PMID15234552.
^Wilson C, Wardell MR, Weisgraber KH, Mahley RW, Agard DA (June 1991). "Three-dimensional structure of the LDL receptor-binding domain of human apolipoprotein E". Science. 252 (5014): 1817–22. Bibcode:1991Sci...252.1817W. doi:10.1126/science.2063194. PMID2063194.
^Koren E, McConathy WJ, Alaupovic P (October 1982). "Isolation and characterization of simple and complex lipoproteins containing apolipoprotein F from human plasma". Biochemistry. 21 (21): 5347–51. doi:10.1021/bi00264a035. PMID6816269.
^Fullerton SM, Buchanan AV, Sonpar VA, Taylor SL, Smith JD, Carlson CS, et al. (June 2004). "The effects of scale: variation in the APOA1/C3/A4/A5 gene cluster". Human Genetics. 115 (1): 36–56. doi:10.1007/s00439-004-1106-x. PMID15108119. S2CID24857340.
^ abHuebbe P, Rimbach G (August 2017). "Evolution of human apolipoprotein E (APOE) isoforms: Gene structure, protein function and interaction with dietary factors". Ageing Research Reviews. 37: 146–161. doi:10.1016/j.arr.2017.06.002. PMID28647612. S2CID3758905.
