Familial hypercholesterolemia is an inherited disease in humans that is caused by a defect in the receptor for low density lipoproteins (LDLR). The existence of an animal model for this disease, the Watanabe heritable hyperlipidemic (WHHL) rabbit, makes it an attractive candidate for developing new therapies that involve gene transfer into liver. As a first step toward the development of these ...

The LDLR family of proteins is involved in lipoproteins trafficking. While the role of LDLR in cardiovascular disease has been widely studied, only recently the role of other members of the LDLR proteins in lipoprotein homeostasis and atherosclerosis has emerged. LDLR, VLDLR, and LRPs bind and internalize apoE- and apoB-containing lipoprotein, including LDL and VLDL, and regulate their cellular...

Cholesterol-core nanoparticles (LDE) have been shown to be recognized by low-density lipoprotein receptors (LDLR) after administration; therefore, LDE is an ideal vehicle to deliver drug with targeting property. Paclitaxel, when incorporated into LDE, promotes atherosclerosis regression with reduced drug toxicity in rabbits through LDLR. Here, we tested whether LDE-paclitaxel could still be eff...

OBJECTIVE Our recent studies identified berberine (BBR) as a novel cholesterol-lowering drug that upregulates low-density lipoprotein (LDL) receptor expression through mRNA stabilization. Here, we investigated mechanisms underlying regulatory effects of BBR on LDL receptor (LDLR) messenger. METHODS AND RESULTS We show that the extracellular signal-regulated kinase (ERK) signaling pathway is u...

It has been shown that natural killer T (NKT) cell activation accelerates atherosclerosis in apoE(-/-) mice. ApoE is, however, an important mediator in the presentation of lipids which may complicate conclusions on the role of NKT cells in atherosclerosis. Treatment of LDLr(-/-) mice with alpha-GalCer during Western-type diet feeding is therefore of interest. Atherosclerosis was induced by West...

OBJECTIVE Calcification and fibrosis reduce vascular compliance in arteriosclerosis. To better understand the role of osteopontin (OPN), a multifunctional protein upregulated in diabetic arteries, we evaluated contributions of OPN in male low-density lipoprotein receptor (LDLR)-/- mice fed a high-fat diet. METHODS AND RESULTS OPN had no impact on high-fat diet-induced hyperglycemia, dyslipide...

Proprotein convertase subtilisin kexin type 9 (PCSK9), the last member of the family of Proprotein Convertases related to Subtilisin and Kexin, regulates LDL-cholesterol by promoting the endosomal/lysosomal degradation of the LDL receptor (LDLR). Herein, we show that the LDLR cell surface levels dramatically increase in the liver and pancreatic islets of PCSK9 KO male but not female mice. In co...

OBJECTIVE We investigated atheroprotective properties of apolipoprotein (apo) E beyond its ability to lower plasma cholesterol. We hypothesized that apoE reduces atherosclerosis by decreasing lipid accumulation in circulating monocytes and the inflammatory state of monocytes and the vascular endothelium. METHODS AND RESULTS We developed mice with spontaneous hyperlipidemia with and without pl...

The final step of triacylglycerol synthesis is catalyzed by acyl-CoA:diacylglycerol acyltransferases (DGATs). We have previously shown that ApoE-/-Dgat1-/- mice are protected from developing atherosclerosis in association with reduced foam cell formation. However, the role of DGAT1, specifically in myeloid and other hematopoietic cell types, in determining this protective phenotype is unknown. ...

OBJECTIVES The aim of this study was to combine clinical criteria and next-generation sequencing (pyrosequencing) to establish a diagnosis of familial hypercholesterolaemia (FH). DESIGN, SETTING AND SUBJECTS A total of 77 subjects with a Dutch Lipid Clinic Network score of ≥ 3 (possible, probable or definite FH clinical diagnosis) were recruited from the Lipid Clinic at Sahlgrenska Hospital, ...