We triggered acute hyperlipidemia in aged and young mice by inducing liver-specific degradation of the LDL receptor combined with a 10-week western diet and found that atherogenesis was enhanced in aged WT mice.
LDLR KO along with LDLR/apoE double KO rabbits should provide a novel means for translational investigations of human hyperlipidemia and atherosclerosis.
Biological samples refining: Collection 1 (primary hypercholesterolemia suspected) included unrelated individuals with hyperlipidaemia and without LDLR, APOB and PCSK9 gene mutations (Set 1), and Collection 2 (LSD suspected) included individuals without definitive LSD diagnosis (Set 2).
Familial hypercholesterolemia (FH) is a severe genetic hyperlipidemia characterized by increased levels of low-density lipoprotein cholesterol (LDL-C), leading to premature atherosclerosis.
LDL-associated LPA was increased in plasma from high-fat Western diet-fed mice that are genetically prone to hyperlipidemia (LDL receptor knockout or activated proprotein convertase subtilisin/kexin type 9-overexpressing C57Bl6).
However, most of the experimental animal models with LDLR deficiency could not fully recapitulate FH because they develop hyperlipidemia and atherosclerosis only in homozygous, but not in heterozygous, form.
These results implied that the enhanced effect of the combination of berberine with resveratrol on lipid-lowering may be associated with upregulation of low-density-lipoprotein receptor, and could be an effective therapy for hyperlipidemia in some obese-associated disease, such as type II diabetes and metabolic syndrome.
The current study revealed that M3 and its structurally modified analog, A8, could regulate hepatic LDLR and PCSK9 expression to exert lipid-lowering effects via the ERK signal pathway, while A8 showed a stronger effect and might be a promising drug candidate against hyperlipidemia.
Our findings demonstrate that the Ldlr KO hamster is an animal model of choice for human FH and has great potential in translational research of hyperlipidemia and coronary heart disease.
We further obtained NOD mice deficient in both LDLR and ApoE, and assessed the severity of atherosclerosis and immune response to hyperlipidemia in comparison to ApoE-deficient C57BL/6 mice.
We describe two novel immunodeficient mouse models of hyperlipidemia (Rag1<sup>-/</sup><sup>-</sup>/LDLR<sup>-/</sup><sup>-</sup> and Rag1<sup>-/</sup><sup>-</sup>/ApoE (apolipoprotein E)<sup>-/</sup><sup>-</sup> mice) in addition to established immunocompetent LDLR<sup>-/</sup><sup>-</sup> and ApoE<sup>-/</sup><sup>-</sup> mice.
The strongest associations for lipid levels change were detected at LPL, TRIB1, APOA1-C3-A4-A5, LIPC, CETP, and LDLR (P range from 4.84×10(-4) to 4.62×10(-18)), whereas LPL, TRIB1, ABCA1, APOA1-C3-A4-A5, CETP, and APOE displayed significant strongest associations for incident hyperlipidemia (P range from 1.20×10(-3) to 4.67×10(-16)).
Several novel therapies have been introduced for the treatment of people with genetic defects that result in loss of function within the LDL receptor, a major determinant of inherited hyperlipidaemias.
In experimental animal models of FH, LDLr overexpression following viral vector-based gene transfer has been shown to be associated with long-term stable correction of hyperlipidemia, with attenuation of atherosclerosis progression, and in certain cases even with lesion regression.
Recent studies on LDL receptor-deficient mice that are hyperglycemic, but exhibit no marked dyslipidemia compared with nondiabetic controls, show that diabetes in the absence of diabetes-induced hyperlipidemia is associated with an accelerated formation of atherosclerotic lesions, similar to what is seen in fat-fed nondiabetic mice.