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Increased apolipoprotein C3 drives cardiovascular risk in type 1 diabetes.

ABSTRACT: Type 1 diabetes mellitus (T1DM) increases the risk of atherosclerotic cardiovascular disease (CVD) in humans by poorly understood mechanisms. Using mouse models of T1DM-accelerated atherosclerosis, we found that relative insulin deficiency rather than hyperglycemia elevated levels of apolipoprotein C3 (APOC3), an apolipoprotein that prevents clearance of triglyceride-rich lipoproteins (TRLs) and their remnants. We then showed that serum APOC3 levels predict incident CVD events in subjects with T1DM in the Coronary Artery Calcification in Type 1 Diabetes (CACTI) study. To explore underlying mechanisms, we investigated the impact of Apoc3 antisense oligonucleotides (ASOs) on lipoprotein metabolism and atherosclerosis in a mouse model of T1DM. Apoc3 ASO treatment abolished the increased hepatic Apoc3 expression in diabetic mice - resulting in lower levels of TRLs - without improving glycemic control. APOC3 suppression also prevented arterial accumulation of APOC3-containing lipoprotein particles, macrophage foam cell formation, and the accelerated atherosclerosis in diabetic mice. Our observations demonstrate that relative insulin deficiency increases APOC3 and that this results in elevated levels of TRLs and accelerated atherosclerosis in a mouse model of T1DM. Because serum levels of APOC3 predicted incident CVD events in the CACTI study, inhibiting APOC3 might reduce CVD risk in T1DM patients.

SUBMITTER: Kanter JE

PROVIDER: S-EPMC6763229 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Increased apolipoprotein C3 drives cardiovascular risk in type 1 diabetes.

Kanter Jenny E JE Shao Baohai B Kramer Farah F Barnhart Shelley S Shimizu-Albergine Masami M Vaisar Tomas T Graham Mark J MJ Crooke Rosanne M RM Manuel Clarence R CR Haeusler Rebecca A RA Mar Daniel D Bomsztyk Karol K Hokanson John E JE Kinney Gregory L GL Snell-Bergeon Janet K JK Heinecke Jay W JW Bornfeldt Karin E KE

The Journal of clinical investigation 20190711 10

Type 1 diabetes mellitus (T1DM) increases the risk of atherosclerotic cardiovascular disease (CVD) in humans by poorly understood mechanisms. Using mouse models of T1DM-accelerated atherosclerosis, we found that relative insulin deficiency rather than hyperglycemia elevated levels of apolipoprotein C3 (APOC3), an apolipoprotein that prevents clearance of triglyceride-rich lipoproteins (TRLs) and their remnants. We then showed that serum APOC3 levels predict incident CVD events in subjects with T ...[more]

PMID: 31295146

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Project description:Lipoprotein-related mechanisms have been associated with damage to the cardiovascular system in diabetic patients. Apolipoprotein E gene which affects the clearance of lipoproteins and consequently the lipid profile in our body is one of the most studied candidate genes and recently has been reported to be associated with T2DM and CAD. In this work, we studied the association of apoE gene polymorphism with T2DM and CVD and its effect on plasma lipids profile.Our study was conducted on 284 subjects categorized into 100 patients with T2DM, 100 patients with T2DM complicated with CVD and 84 normal control subjects. ApoE gene polymorphism was genotyped by real-time PCR using TaqMan(®) SNP Genotyping Assay.ApoE E3/E3 genotype was the most common in our subjects. The frequencies of E3/E4 genotype and ?4 allele were increased in both T2DM patients and CVD patients as compared with controls, but were significant only in CVD patients (p = 0.004 and 0.007, respectively). Diabetic patients who carried E3/E4 genotype were at 2.4-fold increased risk to develop CVD (95 % CI 1.14-5.19, P = 0.02) and the ?4 allele associated with 2.23-fold higher CVD risk (95 % CI 1.09-4.59, P = 0.02). After adjustment for other established risk factors, E3/E4 genotype was an independent risk factor for CVD (OR = 2.3, p = 0.009) but not for T2DM (OR = 1.7, p = 0.28), while ?4 allele was an independent risk factor for both T2DM (OR = 2.2, p = 0.04) and CVD (OR = 3.0, p = 0.018) with 5.9-fold increased risk to develop CVD in T2DM patients (p = 0.019). E3/E4 genotype associated with significantly higher levels of TC and non HDL-C in all groups and with significantly higher levels of LDL-C in both T2DM and CVD patients.ApoE gene polymorphisms associate with CVD and affect the lipid profile. The ?4 allele is an independent risk factor for both T2DM and CVD. Further genetic studies to add information beyond the traditional cardiovascular risk factors in T2DM and to identify risk genotypes will help in early prediction and identification of at risk patients.

Project description:BackgroundTriglycerides (TGs) are proatherogenic lipoproteins involving the risk of coronary heart disease (CHD), while apolipoprotein A5 (APOA5) and apolipoprotein C3 (APOC3) are main lipoproteins composing TG-rich lipoproteins. In this study, we aim to explore the correlation of CHD with APOA5 -1131 T > C and APOC3 -455 T > C single nucleotide polymorphisms (SNPs).MethodsA sum of 210 CHD patients, hospitalized between Jan. 2013 and Mar. 2015 at China-Japan Union Hospital, Jilin University, were selected as our case group and 223 healthy individuals who had physical examination at same hospital at the same period were selected as control group. The frequency distribution of genotypes of APOA5 -1131 T > C and APOC3 -455 T > C SNPs were measured by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The Stata 12.0 software was utilized for statistical analyses.ResultsThere was no significant difference on age and sex between case and control group (P > 0.05). History of smoking, drinking, hypertension and diabetes mellitus, body mass index and levels of TG and fasting blood sugar in case group were shown to be higher than control group (P < 0.05), while levels of total cholesterol, high-density lipoprotein cholesterol and low-density lipoprotein cholesterol in case group were lower than control group (P < 0.05). Both CC and TC' + CC frequencies of APOA5 -1131 T > C and APOC3 -455 T > C in case group were higher compared to control group (both P < 0.05). Additionally, T allele frequencies of the two SNPs in case group were lower than control group, while C allele in case group has higher frequencies compared to control group (both P < 0.05). The results of meta-analysis under allele and dominant models showed that APOA5 -1131 T > C and APOC3 -455 T > C SNPs are likely to increase the risk of CHD (both P < 0.05).ConclusionAPOA5 -1131 T > C and APOC3 -455 T > C SNPs may play potent roles in the development and progression of CHD.

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Increased apolipoprotein C3 drives cardiovascular risk in type 1 diabetes.

Publications

Increased apolipoprotein C3 drives cardiovascular risk in type 1 diabetes.

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