Obesity causes very low density lipoprotein clearance defects in low-density lipoprotein receptor-deficient mice
- 作者：Kimberly R. Coenen ; Marnie L. Gruen ; Alyssa H. Hasty
- 关键词：Leptin ; Hyperlipidemia ; Lipoprotein clearance ; Hepatic triglyceride production
- 刊名：Journal of Nutritional Biochemistry
- 出版年：2007
- 期刊代码：70_09552863
- 类别：abs
- 出版时间：November 2007
- 卷：18
- 期：11
- 页码：727-735
- 文件大小：549 K
摘要
We have reported that obese leptin-deficient mice (ob/ob) lacking the low-density lipoprotein receptor (LDLR−/−) develop severe hyperlipidemia and spontaneous atherosclerosis. In the present study, we show that obese leptin receptor-deficient mice (db/db) lacking LDLR have a similar phenotype, even in the presence of elevated plasma leptin levels. We investigated the mechanism for the hyperlipidemia in obese LDLR−/− mice by comparing lipoprotein production and clearance rates in C57BL/6, ob/ob, LDLR−/− and ob/ob;LDLR−/− mice. Hepatic triglyceride production rates were equally increased (
1.4-fold, P<.05) in both LDLR−/− and ob/ob;LDLR−/− mice compared to C57BL/6 and ob/ob mice. LDL clearance was decreased (1.3- fold, P<.01) to a similar extent in LDLR−/− and ob/ob;LDLR−/− mice compared to C57BL/6 and ob/ob controls. While VLDL clearance was delayed in LDLR−/− compared to C57BL/6 and ob/ob mice (2-fold, P<.001), this delay was exaggerated in ob/ob;LDLR−/− mice (3.8-fold, P<001). The VLDL clearance defects were due to decreased hepatic uptake compared to C57BL/6 (54%and 26%for LDLR−/− and ob/ob;LDLR−/−, respectively, P<.001). When VLDL was collected from C57BL/6, ob/ob, LDLR−/−, and ob/ob;LDLR−/− donors and injected into LDLR−/− recipient mice, counts remaining in the liver were 1.4-fold elevated in mice receiving LDLR−/− VLDL and 2-fold increased in mice receiving ob/ob;LDLR−/− VLDL compared to controls receiving C57BL/6 VLDL (P<.01). Thus, the increase in plasma lipoproteins in ob/ob;LDLR−/− mice is caused by delayed VLDL clearance. This appears to be due to defects in both the liver and the lipoproteins themselves in these obese mice.
1.4-fold, P<.05) in both LDLR−/− and ob/ob;LDLR−/− mice compared to C57BL/6 and ob/ob mice. LDL clearance was decreased (1.3- fold, P<.01) to a similar extent in LDLR−/− and ob/ob;LDLR−/− mice compared to C57BL/6 and ob/ob controls. While VLDL clearance was delayed in LDLR−/− compared to C57BL/6 and ob/ob mice (2-fold, P<.001), this delay was exaggerated in ob/ob;LDLR−/− mice (3.8-fold, P<001). The VLDL clearance defects were due to decreased hepatic uptake compared to C57BL/6 (54%and 26%for LDLR−/− and ob/ob;LDLR−/−, respectively, P<.001). When VLDL was collected from C57BL/6, ob/ob, LDLR−/−, and ob/ob;LDLR−/− donors and injected into LDLR−/− recipient mice, counts remaining in the liver were 1.4-fold elevated in mice receiving LDLR−/− VLDL and 2-fold increased in mice receiving ob/ob;LDLR−/− VLDL compared to controls receiving C57BL/6 VLDL (P<.01). Thus, the increase in plasma lipoproteins in ob/ob;LDLR−/− mice is caused by delayed VLDL clearance. This appears to be due to defects in both the liver and the lipoproteins themselves in these obese mice.