title: Cathepsin B is a novel gender-dependent determinant of cholesterol absorption from the intestine.
abstract: We used a mouse C57BL/6J×CASA/Rk intercross to map a locus on chromosome 14 that displayed a gender-dependent effect on cholesterol absorption from the intestine. Studies in congenic animals revealed a complex locus with multiple operating genetic determinants resulting in alternating gender-dependent phenotypic effects. Fine-mapping narrowed the locus to a critical 6.3 Mb interval. Female subcongenics, but not males, of the critical interval displayed a decrease of 33% in cholesterol absorption. RNA-Seq analysis of female subcongenic jejunum revealed that cysteine protease cathepsin B (Ctsb) is a candidate to explain the interval effect. Consistent with the phenotype in critical interval subcongenics, female Ctsb knockout mice, but not males, displayed a decrease of 31% in cholesterol absorption. Although studies in Ctsb knockouts revealed a gender-dependent effect on cholesterol absorption, further fine-mapping dismissed a role for Ctsb in determining the effect of the critical 6.3 Mb interval on cholesterol absorption.
authors.affiliation: Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH.
authors.forename: Winifred P S
authors.initials: WPS
authors.lastname: Wong
authors.affiliation: Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH.
authors.forename: Jessica B
authors.initials: JB
authors.lastname: Altemus
authors.affiliation: Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH.
authors.forename: James F
authors.initials: JF
authors.lastname: Hester
authors.affiliation: Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH.
authors.forename: Ernest R
authors.initials: ER
authors.lastname: Chan
authors.affiliation: Institut de Recherches Cliniques de Montreal, Montreal, Canada.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Côté
authors.affiliation: Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH.
authors.forename: David
authors.initials: D
authors.lastname: Serre
authors.affiliation: Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH.
authors.forename: Ephraim
authors.initials: E
authors.lastname: Sehayek
mesh_terms: D000818:Animals; D002401:Cathepsin B / Q000235:genetics / Q000378:metabolism*; D002784:Cholesterol / Q000378:metabolism*; D005260:Female; D005838:Genotype; D007413:Intestinal Mucosa / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout
chemical_list: D002784:Cholesterol; D002401:Cathepsin B