title: ATP-binding cassette G5/G8 deficiency causes hypertriglyceridemia by affecting multiple metabolic pathways.
abstract: Mutations in ABCG5 or ABCG8 transporters are responsible for sitosterolemia, an autosomal recessive disease characterized by the accumulation of plant sterols. The aim of this study was to investigate the effects of ABCG5 and ABCG8 deficiency on TG metabolism in mice. Experiments were carried out in wild-type (G5/G8+/+) mice, mice heterozygous for ABCG5 and ABCG8 deficiency (G5/G8+/-) and ABCG5/G8-deficient (G5/G8-/-) mice fed a chow diet. Plasma TG were 2.6 and 4.3-fold higher in fasted G5/G8+/- and G5/G8-/- mice, respectively, than in G5/G8+/+ mice. Postprandial TG were 5-fold higher in G5/G8-/- mice. TG metabolism studies indicate that: first, the fractional catabolic rate was significantly lower in G5/G8+/- (1.3-fold) and G5/G8-/- mice (1.5-fold) compared to G5/G8+/+ and postheparin plasma lipoprotein lipase activities were significantly lower in G5/G8+/- (1.8-fold) and G5/G8-/- mice (5.4-fold) than in G5/G8+/+. Second, liver TG secretion was 1.3-fold higher in G5/G8+/- and G5/G8-/- than in G5/G8+/+ mice and this was associated with an increase in liver LXR, FAS, ACAC and CD36 gene expression. Third, TG intestinal secretion, determined after an oral fat gavage of glycerol tri[9,10(n)-(3)H] oleate, was 5.8-fold higher in G5/G8-/- than in G5/G8+/+ mice. Also, the HOMA index was 2.6-fold higher in G5/G8-/- than in G5/G8+/+ mice, reflecting a degree of insulin resistance. In conclusion, ABCG5/G8 deficiency in mice fed a chow diet markedly raises TG levels by impairing TG catabolism and by increasing liver and intestinal TG secretion.
authors.affiliation: IIB Sant Pau, Barcelona, Spain.
authors.forename: Jesús
authors.initials: J
authors.lastname: Méndez-González
authors.forename: Josep
authors.initials: J
authors.lastname: Julve
authors.forename: Noemí
authors.initials: N
authors.lastname: Rotllan
authors.forename: Gemma
authors.initials: G
authors.lastname: Llaverias
authors.forename: Francisco
authors.initials: F
authors.lastname: Blanco-Vaca
authors.forename: Joan Carles
authors.initials: JC
authors.lastname: Escolà-Gil
mesh_terms: D000071018:ATP Binding Cassette Transporter, Subfamily G, Member 5; D000071019:ATP Binding Cassette Transporter, Subfamily G, Member 8; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000818:Animals; D001692:Biological Transport; D018955:CD36 Antigens / Q000235:genetics / Q000378:metabolism; D005215:Fasting; D015870:Gene Expression; D006579:Heterozygote; D006720:Homozygote; D006937:Hypercholesterolemia / Q000150:complications / Q000235:genetics / Q000378:metabolism*; D015228:Hypertriglyceridemia / Q000150:complications / Q000235:genetics / Q000378:metabolism*; D007410:Intestinal Diseases / Q000150:complications / Q000235:genetics / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000378:metabolism*; D007422:Intestines / Q000473:pathology; D008052:Lipid Metabolism, Inborn Errors / Q000150:complications / Q000235:genetics / Q000378:metabolism*; D008074:Lipoproteins / Q000172:deficiency* / Q000235:genetics; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D000071518:Liver X Receptors; D053858:Metabolic Networks and Pathways; D051379:Mice; D018345:Mice, Knockout; D057093:Orphan Nuclear Receptors / Q000235:genetics / Q000378:metabolism; D010840:Phytosterols / Q000009:adverse effects / Q000235:genetics / Q000378:metabolism; D019518:Postprandial Period; D014280:Triglycerides / Q000235:genetics / Q000378:metabolism*; D019014:fas Receptor / Q000235:genetics / Q000378:metabolism
chemical_list: C462600:ABCG5 protein, mouse; C462601:ABCG8 protein, mouse; D000071018:ATP Binding Cassette Transporter, Subfamily G, Member 5; D000071019:ATP Binding Cassette Transporter, Subfamily G, Member 8; D018528:ATP-Binding Cassette Transporters; D018955:CD36 Antigens; D008074:Lipoproteins; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D010840:Phytosterols; D014280:Triglycerides; D019014:fas Receptor