The ratio of serum plant sterols to cholesterol is positively correlated with the fractional cholesterol absorption, whereas serum precursors of cholesterol synthesis are positively correlated with cholesterol synthesis. Recently, two ABC (ATP-binding cassette) transporters, ABCG5 and ABCG8, have been described as playing an important role in the absorption and excretion of sterols. In the present study, we tested the hypothesis that genetic variation in ABCG5/ABCG8 influences the levels of serum plant sterol (sitosterol) and cholesterol precursor (lathosterol) in Japanese primary hypercholesterolaemic patients (n = 100). We identified a novel mutation [859T/C (C287R)] and a novel polymorphism [1285A/G (M429V)] at the ABCG5/ABCG8 loci, as well as four polymorphisms reported previously [1810C/G (Q604E), 161G/A (C54Y), 1199C/A (T400K) and 1895C/T (A632V)]. In carriers of the novel M429V variant, the serum level of sitosterol and the sitosterol/cholesterol ratio were significantly higher than those in non-carriers (3.64 compared with 2.56 microg/ml, and 1.45 microg/mg compared with 1.00 microg/mg respectively; P < 0.01 for both), and serum lathosterol tended to be lower (1.95 microg/ml compared with 3.03 microg/ml; P = 0.08), whereas no significant difference was observed in other lipid profiles. These four polymorphisms (1810C/G, 161G/A, 1199C/A and 1285A/G) generated six haplotypes, and the C/G/C/G haplotype was significantly associated with a higher sitosterol level and sitosterol/cholesterol ratio compared with the other five haplotypes (P < 0.05 for both). We conclude that, in 8% of patients with hypercholesterolaemia, the novel ABCG8 M429V variant was associated with higher cholesterol absorption efficiency. Future studies should investigate whether these findings have implications for the optimal cholesterol-lowering drug treatment in hypercholesterolaemic patients.

There was a co-linearity between insulin sensitivity and adiponectin as well as insulin sensitivity and LPL/HTGL activity.

Background-Autosomal recessive hypercholesterolemia (ARH) exhibits different responsiveness to statins compared with that in homozygous familial hypercholesterolemia (FH). However, few data exist regarding lipoprotein metabolism of ARH. Therefore, we aimed to clarify lipoprotein metabolism, especially the remnant lipoprotein fractions of ARH before and after statin therapy. Methods and Results-We performed a lipoprotein kinetic study in an ARH patient and 7 normal control subjects, using stable isotope methodology (10 mg/kg of [ 2 H 3 ]-leucine). These studies were performed at baseline and after the 20 mg daily dose of atorvastatin. Tracer/tracee ratio of apolipoprotein B (apoB) was determined by gas chromatography/mass spectrometry and fractional catabolic rates (FCR) were determined by multicompartmental modeling, including remnant lipoprotein fractions. FCR of low-density lipoprotein (LDL) apoB of ARH was significantly lower than those of control subjects (0.109 versus 0.450Ϯ0.122 1/day). In contrast, the direct removal of very-low-density lipoprotein remnant was significantly greater in ARH than those in control subjects (47.5 versus 2Ϯ2%). Interestingly, FCR of LDL apoB in ARH dramatically increased to 0.464 1/day, accompanying reduction of LDL cholesterol levels from 8.63 to 4.22 mmol/L after treatment with atorvastatin of 20 mg/d for 3 months.Conclusions-These results demonstrate that ARH exhibits decreased LDL clearance associated with decreased FCR of LDL apoB and increased clearance for very-low-density lipoprotein remnant. We suggest that increased clearance of remnant lipoprotein fractions could contribute to the great responsiveness to statins, providing new insights into the lipoprotein metabolism of ARH and the novel pharmacological target for LDLRAP1. (Circ Cardiovasc Genet. 2012;5:35-41.)Key Words: lipoproteins Ⅲ ARH Ⅲ genetics Ⅲ metabolism Ⅲ LDLRAP1 F amilial hypercholesterolemia (FH) is a common inherited disorder of plasma lipoprotein metabolism, characterized by an elevated level of low-density lipoprotein cholesterol (LDL-C), tendon xanthomas, and premature coronary artery disease. 1 Genetic causes of FH involve gene mutations such as LDL receptor (LDLR), apolipoprotein B-100 (apoB-100), and proprotein convertase subtilisin/kexin type 9 (PCSK9). 2 In contrast, there was a report of autosomal recessive inherited cases, who showed elevation of LDL-C, large xanthomas, and premature coronary artery disease typical of homozygous FH but in whom the fibroblasts had normal LDLR function. 3 Subsequently, Garcia et al 4 showed that this disorder was caused by a recessive form of null mutations in the LDLR adaptor protein 1 (LDLRAP1). Clinical Perspective on p 41Since then, evidence has been accumulating that it was not linked to mutations in the LDLR gene. 5,6 The N-terminal domain of LDLRAP1 contains a phosphotyrosine-binding (PTB) domain, which binds to the internalization sequence (FDNPVY) in the cytoplasmic tail of the LDLR. 7 LDLRAP1 protein serves as an adaptor for LDLR endocytosis in the live...