The human ATP-binding cassette (ABC) transporter superfamily

The ATP-binding cassette (ABC) transporter superfamily contains membrane proteins that translocate a variety of substrates across extra- and intra-cellular membranes. Genetic variation in these genes is the cause of or contributor to a wide variety of human disorders with Mendelian and complex inheritance, including cystic fibrosis, neurological disease, retinal degeneration, cholesterol and bile transport defects, anemia, and drug response. Conservation of the ATP-binding domains of these genes has allowed the identification of new members of the superfamily based on nucleotide and protein sequence homology. Phylogenetic analysis is used to divide all 48 known ABC transporters into seven distinct subfamilies of proteins. For each gene, the precise map location on human chromosomes, expression data, and localization within the superfamily has been determined. These data allow predictions to be made as to potential functions or disease phenotypes associated with each protein. In this paper, we review the current state of knowledge on all human ABC genes in inherited disease and drug resistance. In addition, the availability of the complete Drosophila genome sequence allows the comparison of the known human ABC genes with those in the fly genome. The combined data enable an evolutionary analysis of the superfamily. Complete characterization of all ABC from the human genome and from model organisms will lead to important insights into the physiology and the molecular basis of many human disorders.

The Human ATP-Binding Cassette (ABC) Transporter Superfamily

https://www.cell.com/cell-metabolism/pdf/S1550-4131(05)00029-X.pdf

ABCG1 has a critical role in mediating cholesterol efflux to HDL and preventing cellular lipid accumulation.

The liver X receptors α and β (LXRα and LXRβ) are members of the nuclear receptor family of proteins that are critical for the control of lipid homeostasis in vertebrates. The endogenous activators of these receptors are oxysterols and intermediates in the cholesterol biosynthetic pathway. LXRs serve as cholesterol sensors that regulate the expression of multiple genes involved in the efflux, transport, and excretion of cholesterol. Recent studies have outlined the importance of LXR signaling pathways in the development of metabolic disorders such as hyperlipidemia and atherosclerosis. Synthetic LXR agonists inhibit the development of atherosclerosis in murine models, an effect that is likely to result from the modulation of both metabolic and inflammatory gene expression. These observations identify the LXR pathway as a potential target for therapeutic intervention in human cardiovascular disease.

/pdf/liver-x-receptor-signaling-pathways-in-cardiovascular-566jfdnyfl.pdf

Liver X Receptor Signaling Pathways in Cardiovascular Disease

SIRT1 Deacetylates and Positively Regulates the Nuclear Receptor LXR

https://biochem.wisc.edu/sites/default/files/labs/attie/publications/attie_etal.pdf

Pivotal role of ABCA1 in reverse cholesterol transport influencing HDL levels and susceptibility to atherosclerosis

A missense mutation (Asp250----Asn) in exon 6 of the human lipoprotein lipase gene causes chylomicronemia in patients of different ancestries.

The invention provides for the use of a therapeutic derived from a truncated lipoprotein lipase protein (LPL S447X), including nucleic acids encoding such proteins, for the treatment of conditions including LPL responsive conditions, such as cardiovascular disease, hypertension, LPL deficiency, high triglyceride levels, low HDL-cholesterol levels or atherosclerosis.

Lpl variant therapeutics

Of the three major Afrikaner founder mutations, responsible for more than 95% of Familial Hypercholesterolemia cases among South African Afrikaners, one mutation called V408M or FHAfrikaner-2 was identified in the Netherlands. Subsequent analysis of a group of Canadian patients of Dutch origin with Familial Hypercholesterolemia revealed the presence of this mutation in western Canada. The founder of the Canadian family, suffering from Familial Hypercholesterolemia caused by V408M, was traced back to Andijk, a small village in the northwestern part of the Netherlands, a region from where the first settlers to South Africa departed in the 17th and 18th century. Further genealogical investigation demonstrated that the mutation must have been introduced in the Netherlands by an individual from northern Germany. Haplotype analysis resulted in the identification of the common haplotypes TaqI-, StuI+, AvaII+, NcoI+ in Canadian as well as Dutch patients with V408M. The results of this study further support the hypothesis that Dutch settlers introduced this Afrikaner founder mutation in the Afrikaner population in South Africa. After a recombinational event in the mutated gene, the mutation was also introduced in western Canada.

Kastelein John J P

Papers

Pivotal role of ABCA1 in reverse cholesterol transport influencing HDL levels and susceptibility to atherosclerosis

A missense mutation (Asp250----Asn) in exon 6 of the human lipoprotein lipase gene causes chylomicronemia in patients of different ancestries.

Lpl variant therapeutics

Origin and migration of an Afrikaner founder mutation FHAfrikaner-2 (V408M) causing familial hypercholesterolemia.

Lipoprotein lipase (lpl) variant therapeutics