Department of Pediatrics, Center for Liver, Digestive, and Metabolic Diseases, University Medical Center Groningen, Groningen, The Netherlands.
Department of Pediatrics, Center for Liver, Digestive, and Metabolic Diseases, University Medical Center Groningen, Groningen, The Netherlands; Top Institute Food and Nutrition, Wageningen, The Netherlands.
J Lipid Res. 2012 Mar;53(3):348-357. doi: 10.1194/jlr.M018671. Epub 2011 Dec 18.
Type I diabetes mellitus (T1DM) increases atherosclerotic cardiovascular disease; however, the underlying pathophysiology is still incompletely understood. We investigated whether experimental T1DM impacts HDL-mediated reverse cholesterol transport (RCT). C57BL/6J mice with alloxan-induced T1DM had higher plasma cholesterol levels (P < 0.05), particularly within HDL, and increased hepatic cholesterol content (P < 0.001). T1DM resulted in increased bile flow (2.1-fold; P < 0.05) and biliary secretion of bile acids (BA, 10.5-fold; P < 0.001), phospholipids (4.5-fold; P < 0.001), and cholesterol (5.5-fold; P < 0.05). Hepatic cholesterol synthesis was unaltered, whereas BA synthesis was increased in T1DM (P < 0.001). Mass fecal BA output was significantly higher in T1DM mice (1.5-fold; P < 0.05), fecal neutral sterol excretion did not change due to increased intestinal cholesterol absorption (2.1-fold; P < 0.05). Overall in vivo macrophage-to-feces RCT, using [(3)H]cholesterol-loaded primary mouse macrophage foam cells, was 20% lower in T1DM (P < 0.05), mainly due to reduced tracer excretion within BA (P < 0.05). In vitro experiments revealed unchanged cholesterol efflux toward T1DM HDL, whereas scavenger receptor class BI-mediated selective uptake from T1DM HDL was lower in vitro and in vivo (HDL kinetic experiments) (P < 0.05), conceivably due to increased glycation of HDL-associated proteins (+65%, P < 0.01). In summary, despite higher mass biliary sterol secretion T1DM impairs macrophage-to-feces RCT, mainly by decreasing hepatic selective uptake, a mechanism conceivably contributing to increased cardiovascular disease in T1DM.
1 型糖尿病（T1DM）会增加动脉粥样硬化性心血管疾病；然而，其潜在的病理生理学仍不完全清楚。我们研究了实验性 T1DM 是否会影响高密度脂蛋白（HDL）介导的胆固醇逆向转运（RCT）。用链脲佐菌素诱导的 T1DM C57BL/6J 小鼠的血浆胆固醇水平更高（P<0.05），尤其是在 HDL 中，肝内胆固醇含量也增加（P<0.001）。T1DM 导致胆汁流量增加（2.1 倍；P<0.05）和胆汁中胆汁酸（BA）、磷脂（4.5 倍；P<0.001）和胆固醇（5.5 倍；P<0.05）的分泌增加。肝内胆固醇合成未改变，但 T1DM 中 BA 合成增加（P<0.001）。T1DM 小鼠的粪便 BA 总排泄量显著增加（1.5 倍；P<0.05），由于肠道胆固醇吸收增加（2.1 倍；P<0.05），粪便中性固醇排泄没有变化。用[(3)H]胆固醇负载的原代鼠巨噬细胞泡沫细胞进行的体内整体巨噬细胞向粪便的 RCT 减少了 20%（P<0.05），主要是由于 BA 内示踪剂排泄减少（P<0.05）。体外实验显示，T1DM HDL 向胆固醇的外流没有变化，而 T1DM HDL 中清道夫受体 B 类 I 介导的选择性摄取在体外和体内（HDL 动力学实验）均较低（P<0.05），这可能是由于 HDL 相关蛋白的糖化增加（+65%，P<0.01）。总之，尽管胆汁中胆固醇的分泌量增加，但 T1DM 仍会损害巨噬细胞向粪便的 RCT，主要是通过减少肝内的选择性摄取，这一机制可能导致 T1DM 中心血管疾病的增加。
