Obesity causes very low density lipoprotein clearance defects in low-density lipoprotein receptor-deficient mice

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 C5713L/6, ob/ob, LDLR-/- and ob/ob;LDLR-/- mice. Hepatic triglyceride production rates were equally increased (similar to 1.4-fold, P<.05) in both LDLR-/- and ob/ob;LDLR-/- mice compared to C5713L/6 and ob/ob mice. LDL clearance was decreased (similar to 1.3- fold, P<.01) to a similar extent in LDLR-/- and ob/ob;LDLR-/- mice compared to C5713L/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 C5713L/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 C5713L/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 lipoprotems themselves in these obese mice. (C) 2007 Elsevier Inc. All rights reserved.