Browsing by Author "Molina, Héctor"

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    Deficiency of Niemann-Pick C1 protein protects against diet-induced gallstone formation in mice
    (2010) Morales France, María Gabriela; Amigo Böker, Ludwig Peter; Balboa Castillo, Elisa Ivana; Acuña Aravena, Mariana Loreto; Castro, Juan; Molina, Héctor; Miquel P., Juan Francisco; Nervi, Flavio; Rigotti Rivera, Attilio; Zanlungo Matsuhiro, Silvana
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    Ezetimibe prevents cholesterol gallstone formation in mice
    (2008) Zuñiga, Silvia Eugenia; Molina, Héctor; Azócar, Lorena; Amigo Boker, Ludwig Peter; Nervi Oddone, Flavio; Pimentel Muller, Fernando Ernesto; Jarufe Cassis, Nicolas Patricio; Arrese Jimenez, Marco Antonio; Lammert, Frank; Miquel Poblete, Juan Francisco
    Background: Intestinal cholesterol absorption may influence gallstone formation and its modulation could be a useful therapeutic strategy for gallstone disease (GSD). Ezetimibe (EZET) is a cholesterol-lowering agent that specifically inhibits intestinal cholesterol absorption. Aims: To test whether EZET can prevent gallstone formation in mice. Methods/Results: Gallstone-susceptible C57BL/6 inbred mice were fed control and lithogenic diets with or without simultaneous EZET administration. Lithogenic diet increased biliary cholesterol content and secretion, and induced sludge or gallstone formation in 100% of the animals. EZET administration reduced intestinal cholesterol absorption by 90% in control animals and by 35% in mice receiving the lithogenic diet. EZET prevented the appearance of cholesterol crystals and gallstones. In addition, mice fed the lithogenic diet plus EZET exhibited a 60% reduction in biliary cholesterol saturation index. Of note, EZET treatment caused a significant increase in bile flow (+50%, P < 0.01) as well as bile salt, phospholipid and glutathione secretion rates (+60%, +44% and +100%, respectively, P < 0.01), which was associated with a moderately increased expression of hepatic bile salt transporters. In addition, relative expression levels of Nieman-Pick C1 like 1 (NPC1L1) in the enterohepatic axis in humans were assessed. Expression levels of NPC1L1 were 15-to 30-fold higher in the duodenum compared with the liver at transcript and protein levels, respectively, suggesting preferential action of EZET on intestinal cholesterol absorption in humans. Conclusions: In a murine model of GSD, EZET prevented gallstone formation by reducing intestinal cholesterol absorption and increasing bile salt-dependent and -independent bile flow. EZET could be useful in preventing GSD disease in susceptible patients.
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    Genetic and functional identification of the likely causative variant for cholesterol gallstone disease at the ABCG5/8 lithogenic locus
    (2013) Von Kampen, Oliver; Buch, Stephan; Nothnagel, Michael; Azócar, Lorena; Molina, Héctor; Brosch, Mario; Erhart, Wiebke; Von Schöenfels, Witigo; Egberts, Jan; Seeger, Marcus; Miquel P., Juan Francisco; Puschel Illanes, Klaus
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    Transcriptomic profiles reveal differences in zinc metabolism, inflammation, and tight junction proteins in duodenum from cholesterol gallstone subjects
    (2020) Riveras Hernández, Eleodoro Javier; Azócar, Lorena; Moyano, Tomás C.; Ocares, Marcia; Molina, Héctor; Romero, Diego; Roa Strauch, Juan Carlos Enrique; Valbuena Mora, José Rafael; Gutiérrez, Rodrigo A.; Miquel P., Juan Francisco
    Cholesterol Gallstone Disease (GSD) is a common multifactorial disorder characterized by crystallization and aggregation of biliary cholesterol in the gallbladder. The global prevalence of GSD is similar to 10-20% in the adult population but rises to 28% in Chile (17% among men and 30% among women). The small intestine may play a role in GSD pathogenesis, but the molecular mechanisms have not been clarified. Our aim was to identify the role of the small intestine in GSD pathogenesis. Duodenal biopsy samples were obtained from patients with GSD and healthy volunteers. GSD status was defined by abdominal ultrasonography. We performed a transcriptome study in a discovery cohort using Illumina HiSeq. 2500, and qPCR, immunohistochemistry and immunofluorescence were used to validate differentially expressed genes among additional case-control cohorts. 548 differentially expressed genes between GSD and control subjects were identified. Enriched biological processes related to cellular response to zinc, and immune and antimicrobial responses were observed in GSD patients. We validated lower transcript levels of metallothionein, NPC1L1 and tight junction genes and higher transcript levels of genes involved in immune and antimicrobial pathways in GSD patients. Interestingly, serum zinc and phytosterol to cholesterol precursor ratios were lower in GSD patients. A significant association was observed between serum zinc and phytosterol levels. Our results support a model where proximal small intestine plays a key role in GSD pathogenesis. Zinc supplementation, modulation of proximal microbiota and/or intestinal barrier may be novel targets for strategies to prevent GSD.