Adipose tissue deficiency results in severe hyperlipidemia and atherosclerosis in the low-density lipoprotein receptor knockout mice

Adipose tissue can store over 50% of whole-body cholesterol; however, the physiological role of adipose tissue in cholesterol metabolism and atherogenesis has not been directly assessed. Here, we examined lipoprotein metabolism and atherogenesis in a unique mouse model of severe lipodystrophy: the Seipin−/− mice, and also in mice deficient in both low-density lipoprotein receptor (Ldlr) and Seipin: the Ldlr−/− Seipin−/− mice. Plasma cholesterol was moderately increased in the Seipin−/− mice when fed an atherogenic diet. Strikingly, plasma cholesterol reached ~ 6000 mg/dl in the Seipin−/− Ldlr−/− mice on an atherogenic diet, as compared to ~ 1000 mg/dl in the Ldlr−/− mice on the same diet. The Seipin−/− Ldlr−/− mice also developed spontaneous atherosclerosis on chow diet and severe atherosclerosis on an atherogenic diet. Rosiglitazone treatment significantly reduced the hypercholesterolemia of the Seipin−/− Ldlr−/− mice, and also alleviated the severity of atherosclerosis. Our results provide direct evidence, for the first time, that the adipose tissue plays a critical role in the clearance of plasma cholesterol. Our results also reveal a previously unappreciated strong link between adipose tissue and LDLR in plasma cholesterol metabolism.