Genetic factors at the enterocyte level account for variations in intestinal cholesterol absorption efficiency among inbred strains of mice.
Interindividual and interstrain variations in cholesterol absorption efficiency occur in humans and animals. We investigated physiological biliary and small intestinal factors that might determine variations in cholesterol absorption efficiency among inbred mouse strains. We found that there were significant differences in cholesterol absorption efficiency measured by plasma, fecal, and lymphatic methods: <25% in AKR/J, C3H/J, and A/J strains; 25-30% in SJL/J, DBA/2J, BALB/cJ, SWR/J, and SM/J strains; and 31-40% in C57L/J, C57BL/6J, FVB/J, and 129/SvJ strains. In (AKRxC57L)F1 mice, the cholesterol absorption efficiency (31 +/- 6%) mimicked that of the C57L parent (37 +/- 5%) and was significantly higher than in AKR mice (24 +/- 4%). Although biliary bile salt compositions and small intestinal transit times were similar, C57L mice displayed significantly greater bile salt secretion rates and pool sizes than AKR mice. In examining lymphatic cholesterol transport in the setting of a chronic biliary fistula, C57L mice displayed significantly higher cholesterol absorption rates compared with AKR mice. Because biliary and intestinal transit factors were accounted for, we conclude that genetic variations at the enterocyte level determine differences in murine cholesterol absorption efficiency, with high cholesterol absorption likely to be a dominant trait. This study provides baseline information for identifying candidate genes that regulate intestinal cholesterol absorption at the cellular level.
Wang
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Department of Medicine, Gastroenterology Division, Brigham and Women's Hospital, Harvard Medical School and Harvard Digestive Diseases Center, Boston, MA 02115, USA. dqwang@caregroup.harvard.edu
Paigen
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B
Carey
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D000818:Animals; D001646:Bile / Q000737:chemistry; D001647:Bile Acids and Salts / Q000032:analysis; D001658:Biliary Fistula; D002784:Cholesterol / Q000097:blood; D002791:Cholesterol, Dietary / Q000493:pharmacokinetics*; D003433:Crosses, Genetic; D020895:Enterocytes / Q000378:metabolism*; D005260:Female; D005704:Gallbladder / Q000378:metabolism; D005772:Gastrointestinal Transit; D007408:Intestinal Absorption / Q000235:genetics*; D008208:Lymphatic System / Q000378:metabolism; D008297:Male; D051379:Mice; D008805:Mice, Inbred A; D008806:Mice, Inbred AKR; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008815:Mice, Inbred Strains; D010743:Phospholipids / Q000378:metabolism
D001647:Bile Acids and Salts; D002791:Cholesterol, Dietary; D010743:Phospholipids; D002784:Cholesterol