Micellar solubilisation of cholesterol is essential for absorption in humans.
OBJECTIVE
Intralumenal bile acid (BA) concentrations have a profound effect on cholesterol absorption. We performed studies to assess the effects of markedly reduced lumenal BA on cholesterol absorption in children with inborn errors in BA synthesis and the role of micellar solubilisation of cholesterol on its absorption in an animal model using human intestinal contents.


METHODS
We studied five subjects: two with 3beta hydroxy-C27 steroid dehydrogenase isomerase deficiency (3-HSD), two with Delta(4)-3-oxosteroid 5beta reductase deficiency (5beta reductase), and one with 2-methylacyl CoA racemase deficiency (racemase). Subjects were studied on supplemental BA therapy and three weeks after withdrawal of supplements. During each treatment period a liquid meal was consumed. Duodenal samples were collected and analysed, and cholesterol absorption and cholesterol fractional synthetic rates were measured. Human intralumenal contents were infused in a bile diverted rat lymph fistula model to assess micellar versus vesicular absorption of cholesterol.


RESULTS
Without BA supplementation, intralumenal BA concentrations were below the critical micellar concentration (CMC) whereas intralumenal BAs increased to above the CMC in all subjects on BA supplementation. Lumenal cholesterol was carried primarily as vesicles in untreated subjects whereas it was carried as both micelles and vesicles in treated subjects. Cholesterol absorption increased approximately 55% in treated compared with untreated subjects (p=0.041), with a simultaneous 70% decrease in synthesis rates (p=0.029). In the rat lymph fistula model, minimal vesicular cholesterol was absorbed whereas vesicular and micellar fatty acid and phospholipid were comparably absorbed.


CONCLUSIONS
Increasing micellar cholesterol solubilisation by supplemental BA in subjects with inborn errors of BA synthesis leads to an improvement in cholesterol absorption and reduction in cholesterol synthesis due to improved micellar solubilisation of cholesterol.
Woollett
L A
LA
Department of Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, and Department of Pediatrics, Clinical Research Center, Children's Hospital Medical Center, OH 45229, USA.
Wang
Y
Y
Buckley
D D
DD
Yao
L
L
Chin
S
S
Granholm
N
N
Jones
P J H
PJ
Setchell
K D R
KD
Tso
P
P
Heubi
J E
JE
D015096:3-Hydroxysteroid Dehydrogenases / Q000172:deficiency; D000293:Adolescent; D000328:Adult; D000818:Animals; D001647:Bile Acids and Salts / Q000096:biosynthesis* / Q000378:metabolism / Q000627:therapeutic use; D002648:Child; D002784:Cholesterol / Q000008:administration & dosage / Q000096:biosynthesis / Q000493:pharmacokinetics*; D004386:Duodenum / Q000378:metabolism; D005260:Female; D006801:Humans; D007408:Intestinal Absorption; D008196:Lymph / Q000378:metabolism; D008297:Male; D008823:Micelles; D010088:Oxidoreductases / Q000172:deficiency; D019998:Racemases and Epimerases / Q000172:deficiency; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility; D043202:Steroid Metabolism, Inborn Errors / Q000378:metabolism* / Q000503:physiopathology / Q000628:therapy
D001647:Bile Acids and Salts; D008823:Micelles; D002784:Cholesterol; D010088:Oxidoreductases; D015096:3-Hydroxysteroid Dehydrogenases; C051860:cholestenone 5 beta-reductase; D019998:Racemases and Epimerases; C108352:alpha-methylacyl-CoA racemase