Increased apolipoprotein C3 drives cardiovascular risk in type 1 diabetes
Jenny E. Kanter, … , Jay W. Heinecke, Karin E. Bornfeldt
Jenny E. Kanter, … , Jay W. Heinecke, Karin E. Bornfeldt
Published July 11, 2019
Citation Information: J Clin Invest. 2019;129(10):4165-4179. https://doi.org/10.1172/JCI127308.
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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 examined 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 expression of Apoc3 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 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, inhibition of APOC3 might reduce CVD risk in patients with T1DM.

Authors

Jenny E. Kanter, Baohai Shao, Farah Kramer, Shelley Barnhart, Masami Shimizu-Albergine, Tomas Vaisar, Mark J. Graham, Rosanne M. Crooke, Clarence R. Manuel, Rebecca A. Haeusler, Daniel Mar, Karol Bomsztyk, John E. Hokanson, Gregory L. Kinney, Janet K. Snell-Bergeon, Jay W. Heinecke, Karin E. Bornfeldt

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Figure 3

Reducing APOC3 expression with an ASO normalizes TRL levels in diabetic mice.

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Reducing APOC3 expression with an ASO normalizes TRL levels in diabetic ...
Female Ldlr–/– GpTg mice were rendered diabetic using LCMV. Saline was used as a control in nondiabetic mice. The mice were maintained for 12 weeks. At the onset of diabetes, the animals were switched to a low-fat, semipurified diet. The mice were treated twice weekly with 25 mg/kg (i.p. injections) Apoc3 ASO or cASO starting 2 days after the onset of diabetes. Doses were adjusted every 2 weeks on the basis of body weight. Animals were bled every 4 weeks for glucose and lipid measurements. (A) Blood glucose levels. (B) Plasma cholesterol levels. Note that time point 0 is before animals were initiated on the low-fat, semipurified diet but after they had developed diabetes. (C) Plasma TGs (A–C; n = 16–20). (D) Hepatic mRNA was isolated, and Apoc3 mRNA was measured by real-time PCR (n = 6–18). (E and F) At the end of the study, cholesterol and TG lipoprotein profiles were analyzed in a subset (n = 4) of mice. (G) Plasma levels of APOC3, measured by ELISA (n = 12–16) at the end of the study. (H) The APOC3 ELISA was validated by targeted MS (n = 5–6). *P < 0.05, and ***P < 0.001, unless otherwise indicated, by 1-way ANOVA followed by Tukey’s multiple comparisons test (D, G, and H) or 2-way ANOVA followed by Bonferroni’s multiple comparisons test (E and F). #P < 0.01 compared with D cASO and §P < 0.01 compared with ND cASO, by 2-way ANOVA followed by Bonferroni’s multiple comparisons test (B and C).