LDL receptor deficiency unmasks altered VLDL triglyceride metabolism in VLDL receptor transgenic and knockout mice

The very low density lipoprotein receptor (VLDLR) has been proposed to play a role in the delivery of fatty acids to peripheral tissues. However, desp ite reduced adipose tissue mass in VLDLR-deficient (VLDLR-/-) mice, this ha s been difficult to substantiate. In the present study, VLDLR-deficient and VLDLR-overexpressing (PVL) mice were cross-bred onto a low density Lipopro tein receptor knockout (LDLR-/-) background to study the VLDLR under condit ions of relatively high serum VLDL and triglyceride levels. Absence of the VLDLR resulted in a significant increase in serum triglyceride levels (1.9- fold) when mice were fed a high fat diet. In contrast, overexpression of th e VLDLR resulted in a significant decrease in serum triglyceride levels (2. 0-fold) under similar conditions. When kept on a chow diet, a period of pro longed fasting revealed a significant increase in serum triglyceride levels in VLDLR-/-; LDLR-/- mice (2.3-fold) as compared with LDLR-/- controls. Th is could not be attributed to altered apolipoprotein B and VLDL triglycerid e production rates. Furthermore, no major differences in nascent VLDL trigl yceride content were found between VLDLR-/-; LDLR-/- mice and LDLR-/- contr ols. However, the triglyceride content of circulating VLDL of VLDLR-/-; LDL R-/- mice (63%) was relatively high as compared with LDLR-/- controls (49%) . These observations suggest that the VLDLR affects peripheral uptake of VL DL triglycerides. In conclusion, under conditions of LDLR deficiency in com bination with high fat feeding or prolonged fasting, the effect of the VLDL R on VLDL triglyceride metabolism was revealed.