Severe hypercholesterolemia, hypertriglyceridemia, and atherosclerosis in mice lacking both leptin and the low density lipoprotein receptor

Leptin-deficient mice (ob/ob) are an excellent murine model for obesity, in sulin resistance, and diabetes, all of which are components of a multiple r isk factor syndrome that, along with hypercholesterolemia, precipitates a p otential high risk for atherosclerosis. In the current study, we show an un expectedly severe hyperlipidemia in ob/ob mice on a background of low densi ty lipoprotein receptor (LDLR) deficiency (-/-). Doubly mutant mice (LDLR-/ -; ob/ob) exhibited striking elevations in both total plasma cholesterol (T C) and triglyceride (TG) levels (1715 +/- 87 and 1016 +/- 172 mg/dl, respec tively), at age 3-4 months, resulting in extensive atherosclerotic lesions throughout the aorta by 6 months. Lipoprotein analyses revealed the elevate d TC and TG levels to be due to a large increase in an apoB-containing broa d-beta remnant lipoprotein fraction. While fasting, diet restriction, and l ow 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 no t change cholesterol production in ob/ob mice regardless of their LDLR geno type. These data provide evidence that the hypertriglyceridemia and hyperch olesterolemia in the doubly mutant mice are caused by distinct mechanisms a nd point to the possibility that leptin might have some impact on plasma ch olesterol metabolism, possibly through an LDLR-independent pathway. This mo del will be an excellent tool for future studies on the relationship betwee n impaired fuel metabolism, increased plasma remnant lipoproteins, diabetes , and atherosclerosis.