{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n Apolipoprotein C‐III (APOC3) is emerging as a critical regulator of triglyceride metabolism and an important mediator of cardiovascular and metabolic risk. Several large-scale genetic studies have shown that loss‐of‐function mutations in APOC3 are associated with markedly lower circulating triglyceride levels and significant protection against coronary heart disease."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "3"}]}, {"type": "t", "text": " Conversely, common promoter variants and haplotypes that increase APOC3 expression lead to elevated plasma APOC3, impaired lipoprotein clearance, and are linked with dyslipidemia as well as an increased risk for nonalcoholic fatty liver disease."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Functionally, APOC3 acts by inhibiting lipoprotein lipase–mediated hydrolysis of triglyceride‐rich lipoproteins, thereby attenuating their clearance from plasma; heightened production of APOC3 in overweight individuals with insulin resistance further accentuates this effect and contributes to hypertriglyceridemia."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": " In addition, APOC3-containing lipoproteins have been shown to directly promote vascular inflammation. Specifically, APOC3 can activate the NLRP3 inflammasome in human monocytes via a caspase-8–dependent mechanism that involves the dimerization of Toll-like receptors, ultimately impairing endothelial regeneration and promoting organ injury"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": ", while also enhancing monocyte adhesion through activation of PKCα and RhoA signaling pathways."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Notably, genetic studies have also identified beneficial APOC3 variants, such as the −641C allele, which are associated with reduced APOC3 levels, a favorable lipoprotein profile, improved insulin sensitivity, lower blood pressure, and even increased longevity."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": " Together, these findings support the view that APOC3 plays a central role not only in controlling plasma triglyceride concentrations but also in modulating inflammatory processes that contribute to atherosclerosis and metabolic disease. Consequently, therapeutic strategies aimed at reducing APOC3 production or function may offer substantial benefits in reducing cardiovascular risk.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Jacy Crosby, Gina M Peloso, Paul L Auer, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Loss-of-function mutations in APOC3, triglycerides, and coronary disease."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "N Engl J Med (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1056/NEJMoa1307095"}], "href": "https://doi.org/10.1056/NEJMoa1307095"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24941081"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24941081"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Anders Berg Jørgensen, Ruth Frikke-Schmidt, Børge G Nordestgaard, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Loss-of-function mutations in APOC3 and risk of ischemic vascular disease."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "N Engl J Med (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1056/NEJMoa1308027"}], "href": "https://doi.org/10.1056/NEJMoa1308027"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24941082"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24941082"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Toni I Pollin, Coleen M Damcott, Haiqing Shen, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A null mutation in human APOC3 confers a favorable plasma lipid profile and apparent cardioprotection."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Science (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1126/science.1161524"}], "href": "https://doi.org/10.1126/science.1161524"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19074352"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19074352"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Kitt Falk Petersen, Sylvie Dufour, Ali Hariri, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Apolipoprotein C3 gene variants in nonalcoholic fatty liver disease."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "N Engl J Med (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1056/NEJMoa0907295"}], "href": "https://doi.org/10.1056/NEJMoa0907295"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20335584"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20335584"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Philippa J Talmud, Emma Hawe, Steve Martin, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Relative contribution of variation within the APOC3/A4/A5 gene cluster in determining plasma triglycerides."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hum Mol Genet (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/hmg/11.24.3039"}], "href": "https://doi.org/10.1093/hmg/11.24.3039"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12417525"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12417525"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Jeffrey S Cohn, Bruce W Patterson, Kris D Uffelman, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Rate of production of plasma and very-low-density lipoprotein (VLDL) apolipoprotein C-III is strongly related to the concentration and level of production of VLDL triglyceride in male subjects with different body weights and levels of insulin sensitivity."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Clin Endocrinol Metab (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1210/jc.2003-032056"}], "href": "https://doi.org/10.1210/jc.2003-032056"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15292332"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15292332"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Stephen Zewinger, Jochen Reiser, Vera Jankowski, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Apolipoprotein C3 induces inflammation and organ damage by alternative inflammasome activation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Immunol (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41590-019-0548-1"}], "href": "https://doi.org/10.1038/s41590-019-0548-1"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31819254"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31819254"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Akio Kawakami, Masanori Aikawa, Peter Libby, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Apolipoprotein CIII in apolipoprotein B lipoproteins enhances the adhesion of human monocytic cells to endothelial cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Circulation (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1161/CIRCULATIONAHA.105.591743"}], "href": "https://doi.org/10.1161/CIRCULATIONAHA.105.591743"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16461842"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16461842"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Christina Christoffersen, Lars Bo Nielsen, Olof Axler, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Isolation and characterization of human apolipoprotein M-containing lipoproteins."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Lipid Res (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1194/jlr.M600055-JLR200"}], "href": "https://doi.org/10.1194/jlr.M600055-JLR200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16682745"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16682745"}]}]}]}