Cathepsin B is a novel gender-dependent determinant of cholesterol absorption from the intestine[S]

• Published in: Journal of lipid research Vol. 54; no. 3; pp. 816 - 822
• Main Authors: Wong, Winifred P.S., Altemus, Jessica B., Hester, James F., Chan, Ernest R., Côté, Jean-François, Serre, David, Sehayek, Ephraim
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.03.2013; The American Society for Biochemistry and Molecular Biology; Elsevier
• Subjects: Animals; Cathepsin B - genetics; Cathepsin B - metabolism; Cholesterol - metabolism; Dock5; Female; genetics; Genotype; Gulo; Intestinal Mucosa - metabolism; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; RNA-Seq; Dock5; genetics; Gulo; RNA-Seq
• ISSN: 0022-2275; 1539-7262
• DOI: 10.1194/jlr.M034579

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.