Increased HDL Size and Enhanced Apo A‐I Catabolic Rates Are Associated With Doxorubicin‐Induced Proteinuria in New Zealand White Rabbits

Abstract

The catabolism and structure of high-density lipoproteins (HDL) may be the determining factor of their atheroprotective properties. To better understand the role of the kidney in HDL catabolism, here we characterized HDL subclasses and the catabolic rates of apo A-I in a rabbit model of proteinuria. Proteinuria was induced by intravenous administration of doxorubicin in New Zealand white rabbits (n = 10). HDL size and HDL subclass lipids were assessed by electrophoresis of the isolated lipoproteins. The catabolic rate of HDL-apo A-I was evaluated by exogenous radiolabelling with iodine-131. Doxorubicin induced significant proteinuria after 4 weeks (4.47 ± 0.55 vs. 0.30 ± 0.02 g/L of protein in urine, P < 0.001) associated with increased uremia, creatininemia, and cardiotoxicity. Large HDL2b augmented significantly during proteinuria, whereas small HDL3b and HDL3c decreased compared to basal conditions. HDL2b, HDL2a, and HDL3a subclasses were enriched with triacylglycerols in proteinuric animals as determined by the triacylglycerol-to-phospholipid ratio; the cholesterol content in HDL subclasses remained unchanged. The fractional catabolic rate (FCR) of [(131)I]-apo A-I in the proteinuric rabbits was faster (FCR = 0.036 h(-1)) compared to control rabbits group (FCR = 0.026 h(-1), P < 0.05). Apo E increased and apo A-I decreased in HDL, whereas PON-1 activity increased in proteinuric rabbits. Proteinuria was associated with an increased number of large HDL2b particles and a decreased number of small HDL3b and 3c. Proteinuria was also connected to an alteration in HDL subclass lipids, apolipoprotein content of HDL, high paraoxonase-1 activity, and a rise in the fractional catabolic rate of the [(131)I]-apo A-I.

Hyperuricemia is Associated with Increased Apo AI Fractional Catabolic Rates and Dysfunctional HDL in New Zealand Rabbits

“…In contrast, the triglyceridesto-phospholipids (Tg-to-PL) ratio remained comparable to basal values (Table 2). Since HDL size and composition are likely to be related to their metabolism [11,12,14], we also performed kinetic studies of HDL-apo AI during hyperuricemia in our animal model. Since HDL size and composition are likely to be related to their metabolism [11,12,14], we also performed kinetic studies of HDL-apo AI during hyperuricemia in our animal model.…”

“…Considering an expected apo AI-FCR difference of 0.01 pool/h between groups, and a maximal standard deviation of 0.006 pool/h [11,14], the statistical power of our study is 80% with seven animals. Comparisons before and after OA treatment were performed by paired Student's t test, whereas comparisons between treated and control groups were made using Student's t test for independent samples.…”

“…Therefore, this study aimed to explore the effect of oxonic acid (OA)-induced hyperuricemia on the HDL size distribution, lipid content of HDL subclasses, and apo AI turnover, as well as HDL functionality in New Zealand white rabbits. Hyperuricemia is almost always concurrent with the multiple risk factors of CAD, i.e., insulin resistance, renal disease, metabolic syndrome, and such risk factors are associated with an abnormal structure and metabolism of HDL [12][13][14][15][16]. The HDLapo AI fractional catabolic rate (FCR) was determined by exogenous labeling with 125 I, and HDL subclasses were determined by sequential ultracentrifugation and PAGE.…”

“…However, the demonstration of a cause-effect association between uric acid and impaired HDL metabolism and function has been elusive. Hyperuricemia is almost always concurrent with the multiple risk factors of CAD, i.e., insulin resistance, renal disease, metabolic syndrome, and such risk factors are associated with an abnormal structure and metabolism of HDL [12][13][14][15][16].…”

“…In this context, oxonic acid (OA) is an uricase inhibitor that has been used to induce hyperuricemia in rats [17,18]. However, the lipoprotein metabolism in rats and humans is very different, and the rabbit is as a better model to understand HDL metabolism [11,14,15].…”