Addition of dietary fat to cholesterol in the diets of LDL receptor knockout mice: effects on plasma insulin, lipoproteins, and atherosclerosis

Abstract

The factors underlying cardiovascular risk in patients with diabetes have not been clearly elucidated. Efforts to study this in mice have been hindered because the usual atherogenic diets that contain fat and cholesterol also lead to obesity and insulin resistance. We compared plasma glucose, insulin, and atherosclerotic lesion formation in LDL receptor knockout (Ldlr 2/2 ) mice fed diets with varying fat and cholesterol content that induced similar lipoprotein profiles. Ldlr 2/2 mice fed a high-fat diet developed obesity, mild hyperglycemia, hyperinsulinemia, and hypertriglyceridemia. Quantitative and qualitative assessments of atherosclerosis were unchanged in diabetic Ldlr 2/2 mice fed a high-fat diet compared with lean nondiabetic control mice after 20 weeks of diet. Although one group of mice fed diets for 40 weeks had larger lesions at the aortic root, this was associated with a more atherogenic lipoprotein profile. The presence of a human aldose reductase transgene had no effect on atherosclerosis in fat-fed Ldlr 2/2 mice with mild diabetes. Our data suggest that when lipoprotein profiles are similar, addition of fat to a cholesterol-rich diet does not increase atherosclerotic lesion formation in Ldlr 2/2

Mechanisms by which diabetes increases cardiovascular disease

“…Interestingly, atherosclerotic lesions in normoglycemic LDLR −/− did not differ significantly between AR overexpressing mice and mice with normal AR expression. AR overexpression also had no effect on atherosclerotic lesions in LDLR −/− mice with only mild diabetes [12]. These results suggest a pathological role for the polyol pathway depending on hyperglycemic conditions.…”

Mouse models of the metabolic syndrome

“…On a high-fat/highcholesterol 'Western-type' diet containing 21% fat and 0.15% added cholesterol, LDLR -/-mice develop severe hyperlipidemia and extensive atherosclerosis (Ishibashi et al, 1993). Furthermore, when LDLR -/-mice are placed on a diet with greater than 20% fat content they also become obese and display IR (Wu et al, 2006). Thus, the LDLR -/-mouse model can be particularly useful when studying diet-induced obesity and IR in the presence of hyperlipidemia.…”

“…In addition, these models have been useful in testing various agents for their therapeutic potential. One disappointment in the studies of these models is that the presence of IR does not appear to impact atherosclerotic lesion formation in most models unless there are concomitant changes in plasma lipid levels (Merat et al, 1999;Wu et al, 2006;Coenen and Hasty, 2007;and reviewed in Goldberg and Dansky, 2006).…”

Distinct metabolic and vascular effects of dietary triglycerides and cholesterol in atherosclerotic and diabetic mouse models

“…Indeed, cholesterol at Ͼ0.15% in a low-fat diet could worsen lesion size (27). Dietary triglycerides, despite promoting insulin resistance, also made little difference in aortic root lesion size and only in very old mice (31). On the other hand, the diabetogenic potential of dietary cholesterol is less clear.…”