Rabbit Anti-Human ABCG8 (a.a. 566-673) Polyclonal antibody

The liver X receptor (LXR) signaling pathway is an important modulator of atherosclerosis, but the relative importance of the two LXRs in atheroprotection is incompletely understood. We show here that LXR alpha, the dominant LXR isotype expressed in liver, plays a particularly important role in whole-body sterol homeostasis. In the context of the ApoE(-/-) background, deletion of LXR alpha, but not LXR beta, led to prominent increases in atherosclerosis and peripheral cholesterol accumulation. However, combined loss of LXR alpha and LXR beta on the ApoE(-/-) background led to an even more severe cholesterol accumulation phenotype compared to LXR alpha(-/-)ApoE(-/-) mice, indicating that LXR beta does contribute to reverse cholesterol transport (RCT) but that this contribution is quantitatively less important than that of LXR alpha. Unexpectedly, macrophages did not appear to underlie the differential phenotype of LXR alpha(-/-)ApoE(-/-) and LXR beta(-/-)ApoE(-/-) mice, as in vitro assays revealed no difference in the efficiency of cholesterol efflux from isolated macrophages. By contrast, in vivo assays of RCT using exogenously labeled macrophages revealed a marked defect in fecal sterol efflux in LXR alpha(-/-)ApoE(-/-) mice. Mechanistically, this defect was linked to a specific requirement for LXR alpha(-/-) in the expression of hepatic LXR target genes involved in sterol transport and metabolism. These studies reveal a previously unrecognized requirement for hepatic LXR alpha for optimal reverse cholesterol transport in mice. Hong, C., M. N. Bradley, X. Rong, X. Wang, A. Wagner, V. Grijalva, L. W. Castellani, J. Salazar, S. Realegeno, R. Boyadjian, A. M. Fogelman, B. J. Van Lenten, S. T. Reddy, A. J. Lusis, R. K. Tangirala, and P. Tontonoz. LXR alpha is uniquely required for maximal reverse cholesterol transport and atheroprotection in ApoE-deficient mice. J. Lipid Res. 2012. 53: 1126-1133.

BACKGROUND: The genetic background of severe familial hypercholesterolemia (FH) has yet to be determined. OBJECTIVE: We tested if genetic variants associated with low-density lipoprotein (LDL)-altering autosomal recessive diseases influenced LDL cholesterol levels and the odds for coronary artery disease in patients with high LDL cholesterol. METHODS: We recruited 500 individuals with elevated LDL cholesterol levels (>= 180 mg/dL or >= 140 mg/dL for subjects <15 years). We sequenced the exons of 3 FH genes (LDLR, apolipoprotein B, and proprotein convertase subtilisin/kexin type 9) and 4 LDL-altering accessory genes (ABCG5, ABCG8, APOE, and LDL receptor adaptor protein 1). In addition, 4 single nucleotide polymorphisms associated with polygenic FH in East Asian subjects were genotyped. Oligogenic FH patients were defined as those who harbored damaging variants of both conventional FH genes and LDL-altering accessory genes. RESULTS: We identified damaging variants of conventional FH genes in 248 participants (50%). We also detected damaging variants in accessory genes in 57 patients (11%) and identified oligogenic FH in 27 of these patients (5%). Polygenic score in the subjects without any FH mutations was significantly higher than those in any other groups. Compared with monogenic FH, oligogenic FH exhibited significantly higher LDL cholesterol (265 mg/dL, 95% confidence interval [CI] 216-312, and 210 mg/dL, 95% CI 189-243; P = .04). Oligogenic FH exhibited higher odds for coronary artery disease when compared with monogenic FH, although it did not reach statistical significance (odds ratio 1.41, 95% CI 0.68-2.21, P = .24). CONCLUSIONS: Among patients with elevated LDL cholesterol, those with oligogenic FH had higher LDL cholesterol than monogenic FH. (C) 2018 National Lipid Association. All rights reserved.