Apolipoprotein

Apolipoproteins are proteins that bind lipids (oil-soluble substances such as fat and cholesterol) to form lipoproteins. They transport lipids (and fat soluble vitamins) in blood, cerebrospinal fluid and lymph.

Apolipoprotein
apolipoprotein e3 (apoe3)
Identifiers
SymbolApolipoprotein
PfamPF01442
InterProIPR000074
SCOPe1oef / SUPFAM
OPM superfamily172
OPM protein3r2p

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 water-based circulation (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 enzyme cofactors 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]

Functions

In lipid transport, apolipoproteins function as structural components of lipoprotein particles, ligands for cell-surface receptors and lipid transport proteins, and cofactors for enzymes (e.g. apolipoprotein C-II for lipoprotein lipase and apolipoprotein A-I (apoA1) for lecithin-cholesterol acyltransferase).

Different lipoproteins contain different classes of apolipoproteins, which influence their function. Apolipoprotein A-I (apoA1) is the major structural protein component of high-density lipoproteins (HDL), although it is present in other lipoproteins in smaller amounts.[3] Apolipoprotein A-IV (apoA4) is present in chylomicrons, very-low-density lipoproteins (VLDL), and HDL. It is thought to act primarily in reverse cholesterol transport[4] and intestinal lipid absorption via chylomicron assembly and secretion. ApoA-IV synthesized in hypothalamus is suggested to be a satiating factor which regulate the food intake of the rodent[5]. [6] Apoplipoprotein B plays a particularly important role in lipoprotein transport being the primary organizing protein of many lipoproteins.[6] Apolipoprotien C-III (apoC3) plays an important role in lipid metabolism specific in regulating the metabolism of triglyceride-rich lipoproteins (TRLs).[7] 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.[8]

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.[9] 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. Basic amino acids important for LDL receptor binding are clustered into a surface patch on one long helix.[10]

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.[11][12] 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).[13]

Classes

There are multiple classes of apolipoproteins and several sub-classes:

  • apolipoprotein A (apoA1, apoA2, apoA4, and apolipoprotein A-V (apoA5))
  • apolipoprotein B (apo B48 and apo B100)
  • apolipoprotein C (apo C-I, apo C-II, apo C-III, and apo C-IV)
  • apolipoprotein D
  • apolipoprotein E
  • apolipoprotein F
  • apolipoprotein H
  • apolipoprotein L
  • apolipoprotein M
  • apolipoprotein(a)

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. ApoA1 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.

Synthesis and regulation

Apolipoprotein synthesis in the intestine is regulated principally by the fat content of the diet.

Apolipoprotein synthesis in the liver is controlled by a host of factors, including dietary composition, hormones (insulin, glucagon, thyroxin, estrogens, androgens), alcohol intake, and various drugs (statins, niacin, and fibric acids). ApoB is an integral apoprotein whereas the others are peripheral apoproteins.

Apolipoprotein synthesis such as apoA4 in hypothalamus involves in the integration of signals for regulation of food intake[15] which is regulated by vagal nerve and cholecystokinin[16].

Disease

Apolipoprotein has been suggested to be implicated in several types of diseases and dysfunction in individual.

Apolipoprotein C-I (apoC1) level increases in neuropathic pain and fibromyalgia patients which suggest it play an important role in occurrence of these conditions.[17]

Apolipoprotein C-III (apoC3) is a risk factor of cardiovascular disease. Accumulation of plasma TRLs caused by elevated apoC-III leading to hypertriglyceridaemia.[18]

Apolipoprotein D (apoD) level increases in nervous system with a large number of neurologic disorders inclusive of Alzheimer's disease, schizophrenia, and stroke.[19]

Apolipoprotein E (apoE) has been implicated in dementia and Alzheimer's disease.[20]

Apolipoprtoein(a) (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 are also participate in the pathogenesis of ASCVD.

References

  1. Ramasamy I (December 2014). "Recent advances in physiological lipoprotein metabolism". Clinical Chemistry and Laboratory Medicine. 52 (12): 1695–727. doi:10.1515/cclm-2013-0358. PMID 23940067.
  2. Wrensch F, Crouchet E, Ligat G, Zeisel MB, Keck ZY, Foung SK, et al. (2018). "Hepatitis C Virus (HCV)-Apolipoprotein Interactions and Immune Evasion and Their Impact on HCV Vaccine Design". Frontiers in Immunology. 9: 1436. doi:10.3389/fimmu.2018.01436. PMC 6021501. PMID 29977246.
  3. 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. PMID 24780726.
  4. Steinmetz A, Barbaras R, Ghalim N, Clavey V, Fruchart JC, Ailhaud G (May 1990). "Human apolipoprotein A-IV binds to apolipoprotein A-I/A-II receptor sites and promotes cholesterol efflux from adipose cells". The Journal of Biological Chemistry. 265 (14): 7859–63. PMID 2159462.
  5. Liu 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. PMID 11294757.
  6. Ramasamy I (December 2014). "Recent advances in physiological lipoprotein metabolism". Clinical Chemistry and Laboratory Medicine. 52 (12): 1695–727. doi:10.1515/cclm-2013-0358. PMID 23940067.
  7. Ooi EM, Barrett PH, Chan DC, Watts GF (May 2008). "Apolipoprotein C-III: understanding an emerging cardiovascular risk factor". Clinical Science. 114 (10): 611–24. doi:10.1042/CS20070308. PMID 18399797.
  8. Dassati S, Waldner A, Schweigreiter R (July 2014). "Apolipoprotein D takes center stage in the stress response of the aging and degenerative brain". Neurobiology of Aging. 35 (7): 1632–42. doi:10.1016/j.neurobiolaging.2014.01.148. PMC 3988949. PMID 24612673.
  9. 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. PMID 15234552.
  10. 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. PMID 2063194.
  11. Wang X, Driscoll DM, Morton RE (January 1999). "Molecular cloning and expression of lipid transfer inhibitor protein reveals its identity with apolipoprotein F". The Journal of Biological Chemistry. 274 (3): 1814–20. doi:10.1074/jbc.274.3.1814. PMID 9880564.
  12. 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. PMID 6816269.
  13. Huang LZ, Gao JL, Pu C, Zhang PH, Wang LZ, Feng G, Zhang Y (August 2015). "Apolipoprotein M: Research progress, regulation and metabolic functions (Review)". Molecular Medicine Reports. 12 (2): 1617–24. doi:10.3892/mmr.2015.3658. PMID 25901639.
  14. 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. PMID 15108119.
  15. Liu 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. PMID 11294757.
  16. Lo CC, Langhans W, Georgievsky M, Arnold M, Caldwell JL, Cheng S, et al. (December 2012). "Apolipoprotein AIV requires cholecystokinin and vagal nerves to suppress food intake". Endocrinology. 153 (12): 5857–65. doi:10.1210/en.2012-1427. PMC 3512075. PMID 23027805.
  17. Lind, Anne-Li; Just, David; Mikus, Maria; Fredolini, Claudia; Ioannou, Marina; Gerdle, Björn; Ghafouri, Bijar; Bäckryd, Emmanuel; Tanum, Lars (2019-10-15). "CSF levels of apolipoprotein C1 and autotaxin found to associate with neuropathic pain and fibromyalgia". Journal of Pain Research. 12: 2875–2889. doi:10.2147/jpr.s215348. PMC 6800548. PMID 31686904.
  18. Chan DC, Chen MM, Ooi EM, Watts GF (May 2008). "An ABC of apolipoprotein C-III: a clinically useful new cardiovascular risk factor?". International Journal of Clinical Practice. 62 (5): 799–809. doi:10.1111/j.1742-1241.2007.01678.x. PMID 18201179.
  19. Dassati S, Waldner A, Schweigreiter R (July 2014). "Apolipoprotein D takes center stage in the stress response of the aging and degenerative brain". Neurobiology of Aging. 35 (7): 1632–42. doi:10.1016/j.neurobiolaging.2014.01.148. PMC 3988949. PMID 24612673.
  20. Chang TY, Yamauchi Y, Hasan MT, Chang C (December 2017). "Cellular cholesterol homeostasis and Alzheimer's disease". Journal of Lipid Research. 58 (12): 2239–2254. doi:10.1194/jlr.R075630. PMC 5711498. PMID 28298292.
  21. Wu MF, Xu KZ, Guo YG, Yu J, Wu Y, Lin LM (October 2019). "Lipoprotein(a) and Atherosclerotic Cardiovascular Disease: Current Understanding and Future Perspectives". Cardiovascular Drugs and Therapy. doi:10.1007/s10557-019-06906-9. PMID 31655942.
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