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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.
Highlights
This review covers the dietary and biochemical origins and fates of key classes of sterol molecules in humans, namely, cholesterol and the relatively under-recognized and often unappreciated noncholesterol sterols and stanols; the intra- and intercellular systems that govern their transport; and the contribution of innate genetic programs to the biochemically observed levels of plasma low-density lipoprotein (LDL)-cholesterol (LDL-C)
We found that heterozygote autosomal dominant hypercholesterolemia (ADH)-1 patients with the rare allele at singlenucleotide polymorphism (SNP) site rs934197 (-516 C>T), which is in strong linkage disequilibrium (LD) with the T71I variant (Table 5), had higher LDL-C levels than noncarriers; 11 mg/dl in the heterozygous apoB ADH-1 patients and a staggering 71 mg/dl hike in the apoB homozygotes (Table 8), a result that warrants further clinical and laboratory investigations
We focus on correlations between proprotein convertase subtilisin-like/kexin type 9 (PCSK9), de novo cholesterol biosynthesis, and LDL-C levels in humans [328, 329], as well as the growing consensus that PCSK9 participates in VLDL production/net secretion [330]
Summary
This review covers the dietary and biochemical origins and fates of key classes of sterol molecules in humans, namely, cholesterol and the relatively under-recognized and often unappreciated noncholesterol sterols and stanols; the intra- and intercellular systems that govern their transport; and the contribution of innate genetic programs to the biochemically observed levels of plasma LDL-cholesterol (LDL-C) The reasons for these foci are both biological and medical. The former is the burgeoning knowledge of the normal physiological roles that cholesterol performs within cell membranes in supporting receptor-mediated signaling activities [1,2,3,4], the movement of diverse molecules through different membranebound compartments [5,6,7,8], and multiple other cell functions [9,10,11], including myelination [12]. Implicit in this approach is the view that the pathological consequences of deranged LDL levels can arise from the type, properties, and amounts of individual lipid classes conveyed by LDL particles [21,22,23,24]
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