Arterial Retention of Remnant Lipoproteins Ex Vivo Is Increased in Insulin Resistance Because of Increased Arterial Biglycan and Production of Cholesterol‐Rich Atherogenic Particles That Can Be Improved by Ezetimibe in the JCR:LA‐ cp Rat

Abstract

BackgroundLiterature supports the “response-to-retention” hypothesis—that during insulin resistance, impaired metabolism of remnant lipoproteins can contribute to accelerated cardiovascular disease progression. We used the JCR:LA-cp rat model of metabolic syndrome (MetS) to determine the extent of arterial accumulation of intestinal-derived remnants ex vivo and potential mechanisms that contribute to exacerbated cholesterol deposition in insulin resistance.Methods and ResultsArteries from control and MetS (insulin-resistant) JCR:LA-cp rats were perfused ex vivo with Cy5-labeled remnant lipoproteins, and their arterial retention was quantified by confocal microscopy. Arterial proteoglycans were isolated from control and MetS rats at 6, 12, and 32 weeks of age. There was a significant increase in the arterial retention of remnants and in associated cholesterol accumulation in MetS rats as compared to control rats. Mechanistic studies reveal that increased cholesterol deposition is a result of greater arterial biglycan content; longer glycosaminoglycans and increased production of cholesterol-rich intestinal-derived remnants, as compared to controls. Additionally, perfusion of vessels treated with ezetimibe, alone or in combination with simvastatin, with remnants isolated from the respective treatment group reduced ex vivo arterial retention of remnant-derived cholesterol ex vivo as compared to untreated controls.ConclusionsIncreased progression of atherosclerotic cardiovascular disease in MetS and type 2 diabetes mellitus might be explained in part by an increase in the arterial retention of cholesterol-rich remnants. Furthermore, ezetimibe alone or in combination treatment with simvastatin could be beneficial in ameliorating atherosclerotic cardiovascular disease in insulin resistance and MetS.

Elevated remnant lipoproteins may increase subclinical CVD risk in pre‐pubertal children with obesity: a case‐control study

“…We propose that chronic overnutrition and imbalance between energy consumption and expenditure can lead to the early onset of obesity in children by increased lipid storage in adipocytes. Further, we suggest that anatomical adaptations by the obese intestine to increase nutrient absorption rates including net length of the intestine, height and width of villi will also encourage increased lipid secretion (42,43). Similarly, metabolic abnormalities associated with obesity including chronic low-grade inflammation (e.g.…”

Molecular Biology of Atherosclerosis

“…The measure of atherosclerosis was unconventional and consisted of the sum of reported myocardial ischemic lesions. Increased binding and retention of intestinal lipoproteins due to increased biglycan content of the arterial wall seemed to be the major differences in this unusual model of severe metabolic syndrome with high insulin levels (1133).…”

“…In carotid arteries perfused ex vivo with test remnant lipoproteins, the corpulent rats' arteries retained 2.5-fold more cholesterol. These differences were accompanied by a nearly fourfold increase in total ischemic myocardial lesions by 32 wk of cholesterol feeding (1133). Fasting plasma insulin strongly correlated with arterial wall biglycan.…”

Degenerative aortic valve disease and diabetes: Implications for a link between proteoglycans and diabetic disorders in the aortic valve

“…[18][19][20] Moreover, only sparse data exist on decorin and lumican with somewhat controversial results regarding the regulation of these SLRPs along DAVD. 15,18,21 In connection with diabetic disorders, previous research on SLRP has so far focused on atherosclerosis, 22,23 nephropathies, 24 obesity and fatty tissue, 25 as well as on monocytes. 26 Hyperglycaemia and its influence on SLRP turnover are assumed to be part of the clinically accelerated degeneration of the cardiovascular system in T2D.…”