Identification of a novel mutation for phytosterolemia. Genetic analyses of 2 cases.

Background: Phytosterolemia is one of the genetic disorders causing hypercholesterolemia and atherosclerosis together with the accumulation of plant sterol in plasma and tissues. The mutations in ABCG5 and ABCG8 genes, encoding sterolin-1 and -2, respectively, are responsible for phytosterolemia.

Methods: We performed genetic analyses on 2 Japanese phytosterolemia patients.

Differential effects of apolipoprotein E isoforms on lipolysis of very low-density lipoprotein triglycerides.

Apolipoprotein (apo) E plays a key role in lipoprotein metabolism and has been proposed to modulate triglyceride (TG) lipolysis. However, no systematic investigation on lipolysis using all 3 isoforms of apoE has been performed. To clarify the role of common human apoE isoforms in the lipolysis of very low-density lipoprotein (VLDL) TGs, we overexpressed human apoE isoforms in apoE and low-density lipoprotein receptor-deficient mice using adenoviral-mediated gene transfer and used VLDL particles obtained from these mice for in vitro lipolysis assay.

Adenovirus-mediated gene transfer and lipoprotein-mediated protein delivery of plasma PAF-AH ameliorates proteinuria in rat model of glomerulosclerosis.

Oxidative stress has been proposed to play a crucial role in glomerulosclerosis, although its in vivo demonstration has proved taxing given the difficulty of inducing gene expression in specific renal cells. In this study, we examined whether the liver-directed expression of plasma platelet-activating factor acetylhydrolase (PAF-AH) would affect the glomerular pathophysiology in Imai rats, an animal model for glomerulosclerosis. Adenovirus-mediated liver-directed gene delivery of human PAF-AH resulted in a significant increase in plasma PAF-AH activity, which was detected almost exclusively on HDL.

Modulation of HDL metabolism by probucol in complete cholesteryl ester transfer protein deficiency.

Probucol, an antioxidative and hypolipidemic agent, has been postulated to increase reverse cholesterol transport by enhancing cholesteryl ester transfer protein (CETP) activity. However, its clinical implication in CETP deficient patients has not been fully defined. To characterize the effects of probucol in the absence of CETP, we evaluated the changes in lipid profile, lipid peroxidation, and paraoxonase 1 (PON1) activity in two complete CETP deficient patients, caused by treatment with probucol.

Human plasma platelet-activating factor acetylhydrolase binds to all the murine lipoproteins, conferring protection against oxidative stress.

Objective: Plasma platelet-activating factor (PAF) acetylhydrolase (AH) is an enzyme bound with lipoproteins that degrades not only PAF but also PAF-like oxidized phospholipids that are proposed to promote atherosclerosis. In this study, we investigated the distribution of PAF-AH protein among lipoprotein classes by using adenovirus-mediated gene transfer in mice, and we examined its effects on lipoprotein oxidation and foam cell formation of macrophages.

Methods And Results: Adenovirus-mediated overexpression of PAF-AH in mice resulted in a 76- to 140-fold increase in plasma PAF-AH activity.

Association between insulin resistance and carotid arteriosclerosis in subjects with normal fasting glucose and normal glucose tolerance.

Objective: We examined the possible association between insulin resistance and carotid arteriosclerosis in subjects who had both normal fasting glucose and normal glucose tolerance after intake of a glucose load.

Methods And Results: Our subjects were individuals who underwent general health screening at our institute, which included carotid ultrasound and oral glucose tolerance testing. Of the 1238 subjects enrolled in our study, 738 (60%) were classified as normal, defined as a normal fasting glucose level and normal glucose tolerance, and 334 (27%) and 166 (13%) were classified as borderline and diabetic, respectively, according to the criteria of the Japan Diabetes Society.

Isoform-dependent cholesterol efflux from macrophages by apolipoprotein E is modulated by cell surface proteoglycans.

Objective: Apolipoprotein E (apoE) mediates cellular cholesterol efflux and plays a crucial role in the inhibition of atherogenesis. We investigated whether there is an isoform-specific difference in its function for cholesterol efflux from cholesterol-loaded RAW264.7 cells, a murine macrophage cell line that lacks endogenous apoE expression.

Heme oxygenase-1 gene promoter polymorphism is associated with coronary artery disease in Japanese patients with coronary risk factors.

Objective: Heme oxygenase (HO) is important in the defense against oxidative stress and as a factor in an antiatherogenic mechanism. Compared with long (GT)(n) repeats, short (GT)(n) repeats in the human HO-1 gene promoter were shown to have higher transcriptional activity in response to oxidative stress. There is a strong link between oxidative stress and the pathogenesis of coronary artery disease (CAD).