Increased apolipoprotein C3 drives cardiovascular risk in type 1 diabetes
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
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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Research Article Metabolism

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 5

Diabetes-accelerated atherosclerosis is prevented by Apoc3 ASO treatment.

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Diabetes-accelerated atherosclerosis is prevented by Apoc3 ASO treatment...
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 mice were switched to a low-fat, semipurified diet. Animals were treated twice weekly with 25 mg/kg (i.p. injections) of Apoc3 ASO or cASO starting 2 days after the onset of diabetes. (A and D) En face aortic atherosclerosis (n = 15–19). (B and C) Examples of early lesions in the BCA. Inset in B shows Mac-2 staining at magnified 2-fold from the image above. The internal elastic lamina is indicated by arrows. (E) Quantification of the maximal lesion area in the BCA (n = 9–11). (F) Mac-2+ lesion area in BCA cross sections (n = 7–11). (G) Quantification of APOC3 immunoreactivity in the BCA (n = 3–8). (H) Quantification of APOE immunoreactivity in the BCA (n = 6–11). (I) Quantification of APOB immunoreactivity in the BCA (n = 7–11) *P < 0.05, **P < 0.01, and ***P < 0.001, by 1-way ANOVA followed by Tukey’s multiple comparisons test. Scale bar: 0.5 cm (A) and 100 μm (B and C).