Abstract 173: Cathepsin B Is a Novel Gender-Dependent Modifier of Dietary Cholesterol and Fat Absorption from the Intestine
The absorption of dietary cholesterol and fat from the intestine is an important determinant of major risk factors for atherosclerotic cardiovascular diseases including hypercholesterolemia, obesity, metabolic syndrome, and type 2 diabetes. Nevertheless, the molecular mechanisms regulating the absorption process are only partially understood. We used two inbred mouse strains, C57BL/6J and CASA/Rk that differ in dietary cholesterol and fat absorption, to map a locus on chromosome 14 that modifies the absorption process. Studies in congenics of this locus revealed a complex effect of several genetic determinants. Fine mapping of one genetic determinant allowed identification of a critical 6.3Mb CASA/Rk interval (63.3-69.7 Mb) with gender dependent effect. Therefore, congenic females of the critical interval, but not congenic males, displayed a 30% decrease in dietary cholesterol absorption. RNA-seq studies in jejuna of congenic females found 50% suppression of Cathepsin B (Ctsb), a gene that maps within the critical congenic interval and encodes for a ubiquitously expressed lysosomal cysteine protease. Concordant with findings in congenic females, Ctsb knockout females, but not knockout males, displayed significantly (25%) decreased dietary cholesterol absorption rates and a large (80%) decrease in dietary fat absorption. These studies indicate that: (i) Cathepsin B is a novel gender-dependent determinant of cholesterol and fat absorption from the intestine, and (ii) the critical chromosome 14 interval is likely to harbor additional genetic determinants of cholesterol and fat absorption from the intestine.
- © 2012 by American Heart Association, Inc.