title: Mechanisms and genetic determinants regulating sterol absorption, circulating LDL levels, and sterol elimination: implications for classification and disease risk.
abstract: This review integrates historical biochemical and modern genetic findings that underpin our understanding of the low-density lipoprotein (LDL) dyslipidemias that bear on human disease. These range from life-threatening conditions of infancy through severe coronary heart disease of young adulthood, to indolent disorders of middle- and old-age. We particularly focus on the biological aspects of those gene mutations and variants that impact on sterol absorption and hepatobiliary excretion via specific membrane transporter systems (NPC1L1, ABCG5/8); the incorporation of dietary sterols (MTP) and of de novo synthesized lipids (HMGCR, TRIB1) into apoB-containing lipoproteins (APOB) and their release into the circulation (ANGPTL3, SARA2, SORT1); and receptor-mediated uptake of LDL and of intestinal and hepatic-derived lipoprotein remnants (LDLR, APOB, APOE, LDLRAP1, PCSK9, IDOL). The insights gained from integrating the wealth of genetic data with biological processes have important implications for the classification of clinical and presymptomatic diagnoses of traditional LDL dyslipidemias, sitosterolemia, and newly emerging phenotypes, as well as their management through both nutritional and pharmaceutical means.
authors.affiliation: Department of Biomedical Sciences, University of Modena and Reggio Emilia, Modena, Italy. c.shoulders@qmul.ac.uk
authors.forename: Sebastiano
authors.initials: S
authors.lastname: Calandra
authors.forename: Patrizia
authors.initials: P
authors.lastname: Tarugi
authors.forename: Helen E
authors.initials: HE
authors.lastname: Speedy
authors.forename: Andrew F
authors.initials: AF
authors.lastname: Dean
authors.forename: Stefano
authors.initials: S
authors.lastname: Bertolini
authors.forename: Carol C
authors.initials: CC
authors.lastname: Shoulders
mesh_terms: D000042:Absorption; D000595:Amino Acid Sequence; D000818:Animals; D001055:Apolipoproteins B / Q000235:genetics / Q000378:metabolism; D004194:Disease / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D006801:Humans; D008077:Lipoproteins, LDL / Q000097:blood*; D008969:Molecular Sequence Data; D013261:Sterols / Q000378:metabolism*
chemical_list: D001055:Apolipoproteins B; D008077:Lipoproteins, LDL; D013261:Sterols