Leptin-deficient mice (ob/ob) are an excellent murine model for
obesity,
insulin resistance, and diabetes, all of which are components of a multiple risk factor syndrome that, along with
hypercholesterolemia, precipitates a potential high risk for
atherosclerosis. In the current study, we show an unexpectedly severe
hyperlipidemia in ob/ob mice on a background of
low density lipoprotein receptor (LDLR) deficiency (-/-). Doubly mutant mice (LDLR-/-;ob/ob) exhibited striking elevations in both total plasma
cholesterol (TC) and
triglyceride (TG) levels (1715 +/- 87 and 1016 +/- 172 mg/dl, respectively), at age 3-4 months, resulting in extensive atherosclerotic lesions throughout the aorta by 6 months.
Lipoprotein analyses revealed the elevated TC and TG levels to be due to a large increase in an
apoB-containing broad-beta remnant
lipoprotein fraction. While fasting, diet restriction, and low level
leptin treatment significantly lowered TG levels, they caused only slight changes in TC levels. Hepatic
cholesterol and
triglyceride contents as well as
mRNA levels of cholesterologenic and lipogenic
enzymes suggest that
leptin deficiency increased hepatic
triglyceride production but did not change
cholesterol production in ob/ob mice regardless of their LDLR genotype. These data provide evidence that the
hypertriglyceridemia and
hypercholesterolemia in the doubly mutant mice are caused by distinct mechanisms and point to the possibility that
leptin might have some impact on plasma
cholesterol metabolism, possibly through an LDLR-independent pathway. This model will be an excellent tool for future studies on the relationship between impaired fuel metabolism, increased plasma remnant
lipoproteins, diabetes, and
atherosclerosis.