title: Severe hypercholesterolemia, hypertriglyceridemia, and atherosclerosis in mice lacking both leptin and the low density lipoprotein receptor.
abstract: 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.
authors.affiliation: Department of Metabolic Diseases, University of Tokyo, Tokyo, 113-8655, Japan.
authors.forename: A H
authors.initials: AH
authors.lastname: Hasty
authors.forename: H
authors.initials: H
authors.lastname: Shimano
authors.forename: J
authors.initials: J
authors.lastname: Osuga
authors.forename: I
authors.initials: I
authors.lastname: Namatame
authors.forename: A
authors.initials: A
authors.lastname: Takahashi
authors.forename: N
authors.initials: N
authors.lastname: Yahagi
authors.forename: S
authors.initials: S
authors.lastname: Perrey
authors.forename: Y
authors.initials: Y
authors.lastname: Iizuka
authors.forename: Y
authors.initials: Y
authors.lastname: Tamura
authors.forename: M
authors.initials: M
authors.lastname: Amemiya-Kudo
authors.forename: T
authors.initials: T
authors.lastname: Yoshikawa
authors.forename: H
authors.initials: H
authors.lastname: Okazaki
authors.forename: K
authors.initials: K
authors.lastname: Ohashi
authors.forename: K
authors.initials: K
authors.lastname: Harada
authors.forename: T
authors.initials: T
authors.lastname: Matsuzaka
authors.forename: H
authors.initials: H
authors.lastname: Sone
authors.forename: T
authors.initials: T
authors.lastname: Gotoda
authors.forename: R
authors.initials: R
authors.lastname: Nagai
authors.forename: S
authors.initials: S
authors.lastname: Ishibashi
authors.forename: N
authors.initials: N
authors.lastname: Yamada
mesh_terms: D000818:Animals; D001161:Arteriosclerosis / Q000097:blood*; D004032:Diet; D004195:Disease Models, Animal; D006937:Hypercholesterolemia / Q000097:blood*; D015228:Hypertriglyceridemia / Q000097:blood*; D020738:Leptin / Q000172:deficiency / Q000378:metabolism*; D008074:Lipoproteins / Q000097:blood; D051379:Mice; D008810:Mice, Inbred C57BL; D011973:Receptors, LDL / Q000172:deficiency / Q000378:metabolism*; D054411:Receptors, Leptin
chemical_list: D020738:Leptin; D008074:Lipoproteins; D011973:Receptors, LDL; D054411:Receptors, Leptin; C515447:leptin receptor, mouse