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.
View: Text | PDF
Research Article Metabolism Article has an altmetric score of 7

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

×

Figure 7

Apoc3 ASO treatment reduces necrotic cores in preexisting lesions in diabetic mice.

Options: View larger image (or click on image) Download as PowerPoint
Apoc3 ASO treatment reduces necrotic cores in preexisting lesions in dia...
Female Ldlr–/– GpTg mice were fed a high-fat diet containing 1.25% cholesterol for 12 weeks, switched to chow for 2 weeks, and then injected with LCMV to induce diabetes (D) or with saline (ND). Once diabetic, the mice were maintained for 4 weeks on 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. (A) Blood glucose. (B) Plasma cholesterol. (C) Plasma TGs. (D) Plasma APOC3. (E) IHC images of aortic sinus lesions stained with Movat’s pentachrome, Mac-2, and APOC3. Arrow indicates the necrotic core. Scale bar: 100 μm. (F) Quantification of aortic sinus lesion size at +180 μm (largest lesion) after the appearance of all 3 aortic valve leaflets. There were no differences in lesion size at 0 or +90 μm. (G) Quantification of aortic lesion Mac-2 staining at +180 μm. (H and I) Quantification of APOC3 IHC staining at +180 μm. (J and K) Quantification of aortic lesion necrotic cores at +180 μm. Similar results were observed at +90 μm. n = 9–10. *P < 0.05, and ***P < 0.001, by 2-tailed, unpaired Student’s t test.