# APOC3

## Overview
The APOC3 gene encodes apolipoprotein C-III (ApoC-III), a small protein that plays a pivotal role in lipid metabolism. ApoC-III is primarily synthesized in the liver and is a component of several lipoproteins, including chylomicrons, very low-density lipoproteins (VLDL), and high-density lipoproteins (HDL) (Herron2006Associations; Maeda1994Targeted). As a key regulator of triglyceride metabolism, ApoC-III inhibits lipoprotein lipase (LPL), an enzyme crucial for the hydrolysis of triglycerides, thereby influencing plasma triglyceride levels (Borén2020The; Jong1999Role). The protein's structure, characterized by amphipathic helices, facilitates its interaction with lipid micelles and lipoproteins, impacting their metabolism and clearance (Gangabadage2008Structure). Variants in the APOC3 gene, particularly loss-of-function mutations, have been linked to altered lipid profiles and a reduced risk of cardiovascular diseases, underscoring its clinical significance (Jørgensen2014LossofFunction; Wulff2018APOC3).

## Structure
Human apolipoprotein CIII (apoCIII) is a protein encoded by the APOC3 gene, primarily involved in lipid metabolism. The molecular structure of apoCIII is characterized by a sequence of amphipathic helices, which are crucial for its function. The primary structure consists of a sequence of amino acids that form six amphipathic helices, connected by semiflexible hinges. These helices are arranged in a necklace-like fashion, wrapping around lipid micelles, such as SDS micelles, which mimic its natural lipid-bound state (Gangabadage2008Structure).

The secondary structure of apoCIII is predominantly α-helical, with specific helices identified as h1 (positions 8-18), h2 (positions 20/23-29), h3 (positions 34-43), h4 (positions 47-53), h5 (positions 55-64), and h6 (positions 74-79). The regions between these helices are less structured, allowing flexibility (Gangabadage2008Structure).

In terms of tertiary structure, the helices of apoCIII are curved to optimize interaction with the micelle surface, with hydrophobic residues interacting with the micelle interior and charged residues interacting with lipid head groups (Gangabadage2008Structure). The quaternary structure involves its interaction with lipoproteins, such as chylomicrons, VLDL, and HDL, where it plays a role in inhibiting lipoprotein lipase and receptor binding (Gangabadage2008Structure). The protein's charge distribution, with positive charges in the N-terminal region and negative charges in the C-terminal region, is conserved among mammals and is important for its lipid interaction (Gangabadage2008Structure).

## Function
The APOC3 gene encodes apolipoprotein C-III (ApoC-III), a protein that plays a crucial role in lipid metabolism. ApoC-III is primarily synthesized in the liver and, to a lesser extent, in the intestine. It is a component of plasma chylomicrons, very low-density lipoproteins (VLDL), and high-density lipoproteins (HDL) (Herron2006Associations; Maeda1994Targeted). ApoC-III inhibits the activity of lipoprotein lipase (LPL), an enzyme essential for the hydrolysis of triglycerides, thereby leading to increased plasma triglyceride levels (Borén2020The; Jong1999Role). It also interferes with the hepatic clearance of triglyceride-rich lipoprotein remnants by displacing apolipoprotein E (ApoE), which inhibits their uptake by liver cells (Herron2006Associations; Borén2020The).

ApoC-III is involved in the assembly and secretion of VLDL particles, particularly under lipid-rich conditions, by enhancing the activity of microsomal triglyceride transfer protein (MTP) and stimulating the secretion of apoB-100 (Sundaram2009Expression). It also affects the interaction of lipoproteins with artery wall proteoglycans, facilitating atherogenesis (Borén2020The). The protein's role in lipid metabolism is significant, as its overexpression is associated with hypertriglyceridemia, while its deficiency leads to increased catabolic rates of VLDL and efficient conversion to intermediate and low-density lipoproteins (Maeda1994Targeted; Borén2020The).

## Clinical Significance
Mutations in the APOC3 gene, particularly loss-of-function variants, have been associated with a reduced risk of cardiovascular diseases, including coronary heart disease and ischemic vascular disease. These mutations lead to lower levels of triglycerides and remnant cholesterol, which are significant factors in reducing cardiovascular risk (Jørgensen2014LossofFunction; Wulff2018APOC3). Carriers of APOC3 loss-of-function mutations exhibit a 40% lower risk of coronary heart disease compared to noncarriers (Unknownauthors2014LossofFunction).

APOC3 is also implicated in familial chylomicronemia syndrome, a genetic disorder characterized by severe hypertriglyceridemia and recurrent pancreatitis. This condition arises due to APOC3's role in inhibiting lipoprotein lipase, leading to elevated plasma triglyceride levels (Gaudet2014Targeting). Elevated APOC3 levels are linked to increased cardiovascular disease risk due to their effect on the atherogenicity of lipoprotein particles and their role in promoting atherosclerosis (Dib2021Apolipoprotein).

Therapeutic strategies targeting APOC3, such as antisense oligonucleotide therapy, have shown promise in reducing triglyceride levels and potentially lowering cardiovascular disease risk (Reeskamp2020The). These findings highlight the clinical significance of APOC3 in lipid metabolism and cardiovascular health.

## Interactions
Apolipoprotein C-III (APOC3) is involved in several interactions that influence lipid metabolism. It primarily inhibits lipoprotein lipase (LPL) activity by displacing the enzyme from lipid droplets, which affects the hydrolysis of triglycerides in lipoproteins (Larsson2013Apolipoproteins; Ginsberg1986Apolipoprotein). APOC3 also interacts with hepatic triglyceride lipase (HTGL), inhibiting its activity and thereby influencing the metabolism of very low-density lipoproteins (VLDL) and intermediate-density lipoproteins (IDL) (Ginsberg1986Apolipoprotein).

APOC3 affects the binding of apolipoprotein B (apoB) and apolipoprotein E (apoE) to hepatic receptors, which delays the catabolism of triglyceride-rich lipoprotein remnants (Norata2015Apolipoprotein). It also interacts with syndecan-1 (SDC1) in the clearance of triglyceride-rich lipoproteins (TRLs) (Ramms2019ApoCIII). The presence of APOC3 on lipoproteins can impair their clearance by interfering with the binding to hepatic receptors such as LDLR and LRP1 (Borén2020The).

Mutations in APOC3 can alter its interactions, affecting its ability to inhibit LPL and influence triglyceride levels. For instance, the A23T variant reduces LPL inhibition, leading to lower triglyceride levels (Vitali2020ApoCIII). These interactions highlight APOC3's role in regulating lipid metabolism and its potential impact on cardiovascular health.


## References


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[2. (Ramms2019ApoCIII) Bastian Ramms, Sohan Patel, Chelsea Nora, Ariane R. Pessentheiner, Max W. Chang, Courtney R. Green, Gregory J. Golden, Patrick Secrest, Ronald M. Krauss, Christian M. Metallo, Christopher Benner, Veronica J. Alexander, Joseph L. Witztum, Sotirios Tsimikas, Jeffrey D. Esko, and Philip L.S.M. Gordts. Apoc-iii aso promotes tissue lpl activity in the absence of apoe-mediated trl clearance. Journal of Lipid Research, 60(8):1379–1395, August 2019. URL: http://dx.doi.org/10.1194/jlr.m093740, doi:10.1194/jlr.m093740. This article has 53 citations and is from a peer-reviewed journal.](https://doi.org/10.1194/jlr.m093740)

[3. (Larsson2013Apolipoproteins) Mikael Larsson, Evelina Vorrsjö, Philippa Talmud, Aivar Lookene, and Gunilla Olivecrona. Apolipoproteins c-i and c-iii inhibit lipoprotein lipase activity by displacement of the enzyme from lipid droplets. Journal of Biological Chemistry, 288(47):33997–34008, November 2013. URL: http://dx.doi.org/10.1074/jbc.m113.495366, doi:10.1074/jbc.m113.495366. This article has 137 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1074/jbc.m113.495366)

[4. (Maeda1994Targeted) N. Maeda, H. Li, D. Lee, P. Oliver, S.H. Quarfordt, and J. Osada. Targeted disruption of the apolipoprotein c-iii gene in mice results in hypotriglyceridemia and protection from postprandial hypertriglyceridemia. Journal of Biological Chemistry, 269(38):23610–23616, September 1994. URL: http://dx.doi.org/10.1016/s0021-9258(17)31559-4, doi:10.1016/s0021-9258(17)31559-4. This article has 255 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1016/s0021-9258(17)31559-4)

[5. (Reeskamp2020The) Laurens F. Reeskamp, Tycho R. Tromp, and Erik S.G. Stroes. The next generation of triglyceride-lowering drugs: will reducing apolipoprotein c-iii or angiopoietin like protein 3 reduce cardiovascular disease? Current Opinion in Lipidology, 31(3):140–146, June 2020. URL: http://dx.doi.org/10.1097/mol.0000000000000679, doi:10.1097/mol.0000000000000679. This article has 31 citations and is from a peer-reviewed journal.](https://doi.org/10.1097/mol.0000000000000679)

[6. (Gangabadage2008Structure) Chinthaka Saneth Gangabadage, Janusz Zdunek, Marco Tessari, Solveig Nilsson, Gunilla Olivecrona, and Sybren Sipke Wijmenga. Structure and dynamics of human apolipoprotein ciii. Journal of Biological Chemistry, 283(25):17416–17427, June 2008. URL: http://dx.doi.org/10.1074/jbc.M800756200, doi:10.1074/jbc.m800756200. This article has 115 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1074/jbc.M800756200)

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[9. (Gaudet2014Targeting) Daniel Gaudet, Diane Brisson, Karine Tremblay, Veronica J. Alexander, Walter Singleton, Steven G. Hughes, Richard S. Geary, Brenda F. Baker, Mark J. Graham, Rosanne M. Crooke, and Joseph L. Witztum. Targeting apoc3 in the familial chylomicronemia syndrome. New England Journal of Medicine, 371(23):2200–2206, December 2014. URL: http://dx.doi.org/10.1056/nejmoa1400284, doi:10.1056/nejmoa1400284. This article has 381 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1056/nejmoa1400284)

[10. (Dib2021Apolipoprotein) Israa Dib, Alia Khalil, Racha Chouaib, Yolla El-Makhour, and Hiba Noureddine. Apolipoprotein c-iii and cardiovascular diseases: when genetics meet molecular pathologies. Molecular Biology Reports, 48(1):875–886, January 2021. URL: http://dx.doi.org/10.1007/s11033-020-06071-5, doi:10.1007/s11033-020-06071-5. This article has 20 citations and is from a peer-reviewed journal.](https://doi.org/10.1007/s11033-020-06071-5)

[11. (Borén2020The) Jan Borén, Chris J. Packard, and Marja-Riitta Taskinen. The roles of apoc-iii on the metabolism of triglyceride-rich lipoproteins in humans. Frontiers in Endocrinology, July 2020. URL: http://dx.doi.org/10.3389/fendo.2020.00474, doi:10.3389/fendo.2020.00474. This article has 95 citations and is from a peer-reviewed journal.](https://doi.org/10.3389/fendo.2020.00474)

[12. (Ginsberg1986Apolipoprotein) H N Ginsberg, N A Le, I J Goldberg, J C Gibson, A Rubinstein, P Wang-Iverson, R Norum, and W V Brown. Apolipoprotein b metabolism in subjects with deficiency of apolipoproteins ciii and ai. evidence that apolipoprotein ciii inhibits catabolism of triglyceride-rich lipoproteins by lipoprotein lipase in vivo. Journal of Clinical Investigation, 78(5):1287–1295, November 1986. URL: http://dx.doi.org/10.1172/jci112713, doi:10.1172/jci112713. This article has 344 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1172/jci112713)

[13. (Sundaram2009Expression) M. Sundaram, S. Zhong, M. B. Khalil, P. H. Links, Y. Zhao, J. Iqbal, M. M. Hussain, R. J. Parks, Y. Wang, and Z. Yao. Expression of apolipoprotein c-iii in mca-rh7777 cells enhances vldl assembly and secretion under lipid-rich conditions. The Journal of Lipid Research, 51(1):150–161, July 2009. URL: http://dx.doi.org/10.1194/m900346-jlr200, doi:10.1194/m900346-jlr200. This article has 50 citations.](https://doi.org/10.1194/m900346-jlr200)

[14. (Jørgensen2014LossofFunction) Anders Berg Jørgensen, Ruth Frikke-Schmidt, Børge G. Nordestgaard, and Anne Tybjærg-Hansen. Loss-of-function mutations inapoc3and risk of ischemic vascular disease. New England Journal of Medicine, 371(1):32–41, July 2014. URL: http://dx.doi.org/10.1056/NEJMoa1308027, doi:10.1056/nejmoa1308027. This article has 1030 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1056/NEJMoa1308027)

[15. (Norata2015Apolipoprotein) Giuseppe Danilo Norata, Sotirios Tsimikas, Angela Pirillo, and Alberico L. Catapano. Apolipoprotein c-iii: from pathophysiology to pharmacology. Trends in Pharmacological Sciences, 36(10):675–687, October 2015. URL: http://dx.doi.org/10.1016/j.tips.2015.07.001, doi:10.1016/j.tips.2015.07.001. This article has 148 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1016/j.tips.2015.07.001)

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[17. (Wulff2018APOC3) Anders B. Wulff, Børge G. Nordestgaard, and Anne Tybjærg-Hansen. Apoc3 loss-of-function mutations, remnant cholesterol, low-density lipoprotein cholesterol, and cardiovascular risk: mediation- and meta-analyses of 137 895 individuals. Arteriosclerosis, Thrombosis, and Vascular Biology, 38(3):660–668, March 2018. URL: http://dx.doi.org/10.1161/atvbaha.117.310473, doi:10.1161/atvbaha.117.310473. This article has 75 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1161/atvbaha.117.310473)