SEVERE HYPERCHOLESTEROLEMIA, HYPERTRIGLYCERIDEMIA AND ATHEROSCLEROSIS IN MICE LACKING BOTH LEPTIN AND THE LOW DENSITY LIPOPROTEIN RECEPTOR
島野仁, Alyssa H Hasty, 山田信博
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 syndrome that, along with hypercholesterolemia, precipitates a potential high risk for atherosclerosis. However, they show only a modest increase in plasma triglyceride (TG) levels and almost normal plasma cholesterol (TC) levels, and thus, do not develop atherosclerosis on a regular chow diet. In the current study, we show an unexpectedly severe hyperlipidemia in ob/ob mice on a background of low density lipoprotein receptor (LDLR) deficiency (-/-). Double knockout mice (LDLR-/-/ob/ob) exhibited striking elevations in both TC and TG levels (1570 and 900 mg/dl, respectively), primarily due to the accumulation of apoB-containing remnant lipoproteins. Interestingly, dietary manipulations such as short-term fasting and long-term caloric restriction as well as low-dose leptin treatment, reduced TG levels but did not significantly reduce TC levels. Hepatic cholesterol and triglyceride content as well as mRNA levels of cholesterogenic and lipogenic enzymes suggest that leptin deficiency increased triglyceride production, through activation of SREBP-1c, but did not change cholesterol production in ob/ob mice regardless of their LDLR genotype.
These data indicate that the hypertriglyceridemia and hypercholesterolemia in the double knockout mice were caused by distinct mechanisms. The increased hepatic synthesis of TG results in over-production and secretion of TG-rich plasma remnant lipoproteins, which became prominent in plasma on the background of LDL receptor deficiency. These mice also spontaneously developed severe atherosclerotic regions throughout the aorta when on regular chow diet. This model will be an excellent tool for future studies on the relationship between impaired fuel metabolism, increased plasma remnant lipoproteins, diabetes and atherosclerosis.