ApoC-III levels associated with triglycerides and CAC in diabetic CHD-free subjectsLiterature - Qamar A et al., ATVB 2015
Plasma Apolipoprotein C-III Levels, Triglycerides, and Coronary Artery Calcification in Type 2 Diabetics
Qamar A, Khetarpal SA, Khera AV., et al.
Arteriosclerosis, Thrombosis, and Vascular Biology. 2015; 35: 1880-1888
BackgroundAlthough statins greatly lower LDL-c and vascular risk, considerable residual risk remains for many. Plasma triglyceride (TG) levels have been shown to be an independent predictor of cardiovascular (CV) risk in multiple prospective epidemiological studies [1,2]. Data of recent human genetics studies also suggest that TG-rich lipoproteins (TRLs) may be causally related to CV risk [3,4]. For instance, the APOC3 gene, which encodes for apolipoprotein C-III (ApoC-III) appears related to TG levels and CHD risk [3,5,6].
ApoC-III is a small protein that circulates in the blood, on VLDL, chylomicrons and HDL. ApoC-III inhibits the turnover of plasma TGs, through various pathways including inhibition of lipoprotein lipase activity, delay of hepatic clearance of TRLs and promotion of VLDL secretion. Various lines of evidence suggest that inhibition of ApoC-III may reduce vascular risk.
The molecular regulation of ApoC-III expression and circulating levels in metabolic disease states is complex, involving several nutrient- and metabolite-activated hepatic transcription factors. In mice, ApoC3 gene expression increases in response to glucose, and decreases upon insulin stimulation. However, in humans plasma ApoC-III levels do not correlate with plasma insulin [12,14]. It has been hypothesised that a disturbed TRL metabolism may modulate insulin resistance and CV risk via multiple pathways.
To shed more light on the relationship between ApoC-III and TRL metabolism and CHD in the context of type 2 diabetes (T2DM), this study examined the relationship of plasma ApoC-III levels with TGs, related metabolic biomarkers, and coronary artery calcification, in 1422 subjects with T2DM but without clinical CHD.
- A significant association between ApoC-III levels and TGs was seen, after adjusting for age, sex, race, BMI, alcohol use, GFR, exercise, use of lipid-lowering and hypoglycemic medication (β=0.57, P<0.0001) in a linear regression model. When stratifying by sex, a significant β=0.53 was seen for women, and β=0.60 for men.
- Positive associations were also seen between plasma ApoC-III and total cholesterol, ApoB and ApoE levels, and a negative relation with HDL-c and APoA-I levels.
- Plasma ApoC-III levels were positively correlated with glycosylated haemoglobin (Spearman’s rho: 0.12, P<0.00001) and fasting glucose levels (Spearman’s rho: 0.16, P<0.00001), also after adjustment for age, sex and race.
When stratifying the association of fasting glucose and haemoglobin A1c (HbA1c) by plasma TG levels, it was found to only significantly associate in subjects with elevated TGs (>150 mg/dL), and not in those with normal TG levels.
When adjusting for TG levels, the associations of HbA1c and fasting glucose were not statistically significant in men and women.
- In Tobit conditional regression analysis, higher plasma ApoC-III was significantly associated with increasing CAC scores, after adjusting for smoking, GFR, BMI, alcohol, C-reactive protein, SBP, history of hypertension, use of lipid-lowering and hypoglycaemic medication (Tobit regression ratio: 1.91, 95%CI: 1.32-2.74, P<0.01). Including TGs into the model attenuated the association to a non-significant relation (ratio: 1.43, 95%CI: 0.94-2.18, P=0.086).
- Tobit regression showed that subjects in the highest ApoC-III quartiles had a greater likelihood of increased CAC in comparison with those in the lowest ApoC-III quartile.
DiscussionThis study found a positive relationship between plasma ApoC-III and TGs and other plasma lipids, in diabetic subjects without pre-existing CHD. ApoC-III also significantly correlated to fasting glucose and HbA1c; these relationships appeared dependent on TGs. Furthermore, an association between ApoC-III levels and CAC score was revealed, which also seemed to be partially explained by TG levels.
These data support evidence from other lines of research that ApoC-III is a key regulator of plasma TGs and CHD. Thus, these data suggest that in a T2DM population, therapeutic targeting of ApoC-III may be useful to reduce cardiovascular risk factors, and thereby the residual risk of atherosclerotic CHD.
Find this article online at ATVB
1. Nordestgaard BG, Benn M, Schnohr P, et al. Nonfasting triglycerides and risk of myocardial infarction, ischemic heart disease, and death in men and women. JAMA. 2007;298:299–308. doi: 10.1001/jama.298.3.299.
2. Sarwar N, Danesh J, Eiriksdottir G, et al. Triglycerides and the risk of coronary heart disease: 10,158 incident cases among 262,525 participants in 29 Western prospective studies. Circulation. 2007;115:450–458. doi:10.1161/CIRCULATIONAHA.106.637793.
3. Do R, Willer CJ, Schmidt EM, et al. Common variants associated with plasma triglycerides and risk for coronary artery disease. Nat Genet. 2013;45:1345–1352. doi: 10.1038/ng.2795.
4. Rosenson RS, Davidson MH, Hirsh BJ, et al. Genetics and causality of triglyceride-rich lipoproteins in atherosclerotic cardiovascular disease. J Am Coll Cardiol. 2014;64:2525–2540. doi: 10.1016/j.jacc.2014.09.042.
5. Blood I, Crosby J, Peloso GM, et al; Tg, Hdl Working Group of the Exome Sequencing Project NHL. Loss-of-function mutations in apoc3, triglycerides, and coronary disease. New Engl J Med. 2014;371:22–31.
7. Jørgensen AB, Frikke-Schmidt R, Nordestgaard BG, et al. Loss-of-function mutations in APOC3 and risk of ischemic vascular disease. N Engl J Med. 2014;371:32–41. doi: 10.1056/NEJMoa1308027
8. Eisenberg S, Patsch JR, Sparrow JT, et al. Very low density lipoprotein. Removal of Apolipoproteins C-II and C-III-1 during lipolysis in vitro. J Biol Chem. 1979;254:12603–12608.
9. Aalto-Setälä K, Fisher EA, Chen X, et al. Mechanism of hypertriglyceridemia in human apolipoprotein (apo) CIII transgenic mice. Diminished very low density lipoprotein fractional catabolic rate associated with increased apo CIII and reduced apo E on the particles. J Clin Invest. 1992;90:1889–1900. doi: 10.1172/JCI116066.
10. Aalto-Setälä K, Weinstock PH, Bisgaier CL, et al. Further characterization of the metabolic properties of triglyceriderich lipoproteins from human and mouse apoC-III transgenic mice. J Lipid Res. 1996;37:1802–1811.
11. Ebara T, Ramakrishnan R, Steiner G et al. Chylomicronemia due to apolipoprotein CIII overexpression in apolipoprotein E-null mice. Apolipoprotein CIII-induced hypertriglyceridemia is not mediated by effects on apolipoprotein E. J Clin Invest. 1997;99:2672–2681. doi:10.1172/JCI119456.
12. Liu H, Talmud PJ, Lins L, et al. Characterization of recombinant wild type and site-directed mutations of apolipoprotein C-III: lipid binding, displacement of ApoE, and inhibition of lipoprotein lipase. Biochemistry. 2000;39:9201–9212.
13. Ginsberg HN, Brown WV. Apolipoprotein CIII: 42 years old and even more interesting. Arterioscler Thromb Vasc Biol. 2011;31:471–473. doi: 10.1161/ATVBAHA.110.221846.
14. Larsson M, Vorrsjö E, Talmud P, et al. Apolipoproteins C-I and C-III inhibit lipoprotein lipase activity by displacement of the enzyme from lipid droplets. J Biol Chem. 2013;288:33997–34008. doi: 10.1074/jbc.M113.495366.
15. Li WW, Dammerman MM, Smith JD et al. Common genetic variation in the promoter of the human apo CIII gene abolishes regulation by insulin and may contribute to hypertriglyceridemia. J Clin Invest. 1995;96:2601–2605. doi: 10.1172/JCI118324.