Overall cholesterol fluxes through the body cannot be derived from these data, because then different pool sizes of cholesterol are important and would have to be taken into account. selleck products Besides mediating RCT, HDL particles have additional anti-atherosclerotic properties such as inhibiting endothelial inflammation (33), promoting vascular nitric oxide generation (34) as well as protecting LDL against oxidative modification (35, 36). Increasing evidence suggests that also these atheroprotective functions of HDL particles are impaired in T1DM. The anti-oxidative properties of HDL appear to be diminished in T1DM (37, 38) and the ability of HDL from T1DM patients to counteract the inhibitory effects of oxidized LDL on endothelium-dependent vasorelaxation is also reduced (39).

In addition, glycation of apoA-I was recently shown to decrease the potency of HDL to inhibit neutrophil infiltration and adhesion molecule expression using the carotid artery collar model in rabbits (40). In addition to decreased RCT, these alterations are expected to contribute to an overall reduced capacity of diabetic HDL to protect against atherosclerotic CVD. Figure 7 summarizes our current working model on the effects of T1DM on sterol metabolism and RCT. Biliary secretion of BAs and cholesterol is significantly increased, whereas hepatic cholesterol synthesis remains largely unaffected. Nevertheless, hepatic cholesterol levels do not decrease, because the liver cholesterol pool in diabetic mice receives more input via increased food intake and higher intestinal cholesterol absorption.

These events result in an enhanced cycling of cholesterol between the liver and the intestine without having a net effect on fecal neutral sterol excretion. To compensate for increased fecal BA loss, also hepatic BA synthesis from cholesterol is up-regulated. With respect to RCT, less cholesterol originating from macrophages enters the hepatic cholesterol pool because SR-BI-mediated selective uptake from diabetic HDL is impaired. Thereby, a smaller fraction of this cholesterol is then used for BA synthesis. These changes are reflected by decreased overall RCT, primarily due to reduced tracer excretion within the fecal BA fraction. Fig. 7. Working model summarizing the impact of T1DM on sterol metabolism and RCT. Compared with controls (A), biliary secretion of bile acids and cholesterol is significantly increased in T1DM (B).

Whereas hepatic cholesterol synthesis remains unaltered, bile … In conclusion, insulin-deficient T1DM Dacomitinib mice exhibit decreased RCT despite increased biliary sterol secretion. These unfavorable changes are conceivably due to decreased properties of glycated HDL to function in hepatic selective uptake. Impaired RCT is expected to contribute to the increased risk for atherosclerotic CVD morbidity and mortality in patients with T1DM. Acknowledgments The authors are grateful to Dr. Monty Krieger (Dept.