Mechanisms and genetic determinants regulating sterol absorption, circulating LDL levels, and sterol elimination: implications for classification and disease risk

Abstract

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 ( 1-4 ), the movement of diverse molecules through different membranebound compartments (5)(6)(7)(8), and multiple other cell functions (9)(10)(11), including myelination ( 12 ). The latter, Abstract This review integrates historical biochemical and modern genetic fi ndings 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 oldage. We particularly focus on the biological aspects of those gene mutations and variants that impact on sterol absorption and hepatobiliary excretion via specifi c 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 classifi cation 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. -Calandra, S., P. Tarugi Abbreviations: ABCG5, ATP-binding cassette, subfamily G, member 5; ABCG8, ATP-binding cassette, subfamily G, member 8; ABL, abetalipoproteinemia; ADH, autosomal dominant hypercholesterolemia; ANGPTL3, angiopoietin-like 3; ARH, autosomal recessive hypercholesterolemia; BMI, body mass index; CAC, coronary artery calcifi cation; CAD, coronary artery disease; CHD, coronary heart disease; CMRD, chylomicron retention disease; CYP7A1 , cholesterol 7 ␣ -hydroxylase; EGF, epidermal growth factor; ER, endoplasmic reticulum; FCHL, familial combined hyperlipidemia; FDB, familial defective apoB; FH, familial hypercholesterolemia; FHBL, familial hypobetalipoproteinemia; GWAS, genome-wide association study; HMGCR, HMGCoA reductase; IDOL, inducible degrader of LDLR; LD, linkage disequilibrium; LDL-C, LDL-cholesterol; LDLR, LDL receptor; LRP1, LDLRAP1, LDLR-associated protein 1; LDLR-related protein 1; LXR, liver X receptor; MI, myocardial infarction; MTP, m...

Potential Effects of NPC1L1 Polymorphisms in Protecting against Clinical Disease in a Chinese Family with Sitosterolaemia

“…The proband exhibited elevated plasma levels of sterols and LDL-C and tendon xanthomas, whereas her genetically affected sister displayed low LDL-C (e.g. cholesterol absorption and endogenous cholesterol synthesis) and its interaction with the disease process 4) . Therefore, a diagnosis of sitosterolaemia may be considered in patients with an elevated LDL-C level who exhibit an unusually large LDL-C response to ezetimibe.…”

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increased absorption and decreased biliary excretion of cholesterol (similar to plant sterols), usually have normal to moderately elevated plasma cholesterol levels, despite the downregulation of endogenous cholesterol synthesis in hepatocytes 4) . Intestinal sterol/cholesterol absorption is governed by three key transporter molecules, including the two ATP-binding cassette (ABC) half transporters, ABCG5 and ABCG8 (previously known as sterolin-1 and -2, respectively), which heterodimerise to form a sterol efflux transporter in the liver and intestine to transport sterols (cholesterol and plant sterols) and the Niemann-Pick C1-like 1 (NPC1L1) transporter, a polytopic transmembrane protein that mediates intestinal absorption of cholesterol and sterols 5) .

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Regulation of Intestinal Cholesterol Absorption: A Disease Perspective

“…The deletion of Npc1l1 in mice results in a reduction in fractional cholesterol absorption [32] (i.e., the percentage of cholesterol absorbed from the intestine, which is determined using a dual-isotope feeding technique). Various mechanisms have been suggested to impair NPC1L1 cholesterol uptake in twenty rare NCP1L1 alleles found in the low cholesterol absorbers [41].…”

Up-regulation of Cholesterol Absorption Is a Mechanism for Cholecystokinin-induced Hypercholesterolemia

“…The amount of intestinal cholesterol absorbed into the bloodstream varies from 20 to 80% among individuals (6). It has been shown that a change in the expression and/or activities of the aforementioned proteins alters the efficacy of enterocytes to absorb cholesterol (4).…”

“…Absorption of cholesterol from the intestine involves multiple processes (3,4). Specifically, free cholesterol in the intestinal lumen is transported into enterocytes by the cholesterol transporter NPC1L1 (Niemann-Pick C1-like 1) (5).…”