Role of intestinal sterol transporters Abcg5, Abcg8, and Npc1l1 in cholesterol absorption in mice: gender and age effects

Abstract

Recent studies have indicated that intestinal cholesterol absorption is a multistep process, which is regulated by multiple genes at the enterocyte level. However, the molecular mechanisms whereby there are gender differences in intestinal cholesterol absorption efficiency and the efficiency of cholesterol absorption increases with age have not yet been fully understood. To explore whether aging increases cholesterol absorption via intestinal sterol transporters, we studied the higher cholesterol-absorbing C57L/J vs. the lower cholesterol-absorbing AKR/J mice at 8 (young adult), 36 (older adult), and 50 (aged) wk of age. To test the hypothesis that estrogen receptor (ER )alpha plays an important regulatory role in cholesterol absorption, we investigated the gonadectomized mice of both genders treated with 17beta-estradiol-releasing pellets at 0, 3, or 6 mug/day and antiestrogenic ICI 182,780 at 125 microg/day. We found that hepatic outputs of biliary cholesterol were significantly increased with age and in response to high levels of estrogen. Aging significantly enhances cholesterol absorption by suppressing expression of the jejunal and ileal sterol efflux transporters [ATP-binding cassette (Abc)g5 and Abcg8] and upregulating expression of the putative duodenal and jejunal sterol influx transporter Npc1l1. Estrogen significantly augmented cholesterol absorption mostly due to an upregulated expression of intestinal Npc1l1, Abcg5, and Abcg8 via the intestinal ERalpha pathway, which can be fully abolished by the antagonist. We conclude that ERalpha activated by estrogen and aging enhances cholesterol absorption by increasing biliary lipid output and mediating intestinal sterol transporters favoring influx of intraluminal cholesterol molecules across the apical membrane of the enterocyte.

Fatty Acid- and Cholesterol Transporter Protein Expression along the Human Intestinal Tract

“…Duan et al [67] showed that estrogens may influence cholesterol uptake through up-regulation of NPC1L1 and possibly by down-regulation of the sterol efflux transporters ABCG5 and ABCG8. It was suggested that estrogen acts as transcription modulator for the target genes through effects on estrogen receptor (ER) a or ER b, two subtypes of the steroid hormone receptor superfamily.…”

“…It was suggested that estrogen acts as transcription modulator for the target genes through effects on estrogen receptor (ER) a or ER b, two subtypes of the steroid hormone receptor superfamily. Furthermore, a significant positive effect of aging on cholesterol uptake through inhibition of the sterol efflux transporters ABCG5 and ABCG8 has been reported [67]. In contrast, fat uptake was suggested to decline with ageing [68,69,70] and also more recently decreased ileal uptake of palmitic, stearic, oleic and linoleic acid was found with ageing in rats [71].…”

Age may determine the effect of hypolipidemic agents on plasma adipokine levels in patients with elevated low-density lipoprotein cholesterol levels

“…Ezetimibe is an inhibitor of Niemann-Pick C1-Like 1 transporter (NPC1L1) in the jejunal brush border, thus decreasing intestinal cholesterol absorption and reducing total and LDL-cholesterol levels [27,28]. Although, to the best of our knowledge, no data are available in humans, aging was associated with up-regulated expression of NPC1L1 in mice [29]. However, the lack of correlation between ezetimibeinduced changes in plasma lipids and the impact of this drug on plasma hsCRP, leptin, and adiponectin suggests that non-lipid-related effects of ezetimibe are responsible for its different effect on systemic inflammation and adipose disuse in various age groups.…”

La Respuesta Terapéutica a Ezetimiba en Ratones C57BL/6 es Mediada por Cambios en la Expresión de NPC1L1, ABCG5 y ABCG8 en el Enterocito

“…Lally et al en ratas Sprague -Dawley, a las que se indujo diabetes mediante estreptozotocina, investigaron el efecto de una dieta estándar de laboratorio a la que se adicionó un 40% de grasa y 0,5% de colesterol, en la expresión de NPC1L1, ABCG5 y ABCG8, demostrando un incremento neto en la absorción de colesterol a través de la sobrerregulación de NPC1L1 y una represión de ABCG5 y G8 en el hígado e intestino. Duan et al (2006), estudiaron el efecto de la edad en la absorción de colesterol en ratones C57L/J (caracterizados por su alta absorción de colesterol) y ratones AKR/J (caracterizados por absorber poco colesterol). Los animales fueron mantenidos consumiendo una dieta estándar de laboratorio y estudiados a las 8 semanas (adultos jóvenes), 36 semanas (adultos mayores) y 50 semanas (ancianos) de edad, respectivamente.…”

“…15 ratones machos C57BL/6 fueron divididos en grupos de cinco, sometidos a 15 días de adaptación con ciclos de 12 horas de luz y oscuridad y alimentados a libre acceso con la dieta rata de laboratorio (Champion S.A.). Luego, a cinco de los animales se les extrajo sangre para medir los lípidos plasmáticos y extirpó el intestino delgado, para evaluar la expresión basal génica y proteica de NPC1L1, ABCG5 y ABCG8 (Duan et al, 2006). A los 10 animales restantes se les indujo hipercolesterolemia, alimentándolos por 4 semanas, a libre acceso con la dieta tipo Paigen; D12336 (Paigen et al, 1985).…”