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Micellar solubilisation of cholesterol is essential for absorption in humans
  1. L A Woollett1,
  2. Y Wang2,
  3. D D Buckley3,
  4. L Yao1,
  5. S Chin1,
  6. N Granholm1,
  7. P J H Jones4,
  8. K D R Setchell5,
  9. P Tso1,
  10. J E Heubi6
  1. 1Department of Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
  2. 2Institute for Nutrisciences and Health, National Research Council, Charlottetown, Prince Edward Island, Canada
  3. 3Department of Pediatrics, Clinical Research Center, Children’s Hospital Medical Center, Cincinnati, Ohio, USA
  4. 4School of Dietetics, and Human Nutrition McGill University, Quebec, Montreal, Canada
  5. 5Division of Pediatrics and Pathology, Department of Pediatrics, Children’s Hospital Medical Center, Cincinnati, Ohio, USA
  6. 6Department of Pediatrics, Clinical Research Center, Children’s Hospital Medical Center, Cincinnati, Ohio, USA, and Division of Pediatric Gastroenterology/Hepatology and Nutrition, Department of Pediatrics, Children’s Hospital Medical Center, Cincinnati, Ohio, USA
  1. Correspondence to:
    Dr J E Heubi
    General Clinical Research Center, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Ave, Cincinnati, OH 45229, USA; james.heubi{at}cchmc.org

Abstract

Background and aims: 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 3β hydroxy-C27 steroid dehydrogenase isomerase deficiency (3-HSD), two with Δ4-3-oxosteroid 5β reductase deficiency (5β 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 ≈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.

  • FSR, fractional synthetic rate
  • BA, bile acids
  • 3-HSD, 3β hydroxy-C27-steroid dehydrogenase/isomerase
  • 5β reductase, Δ4-3-oxosteroid 5β reductase
  • racemase, 2-methylacyl CoA racemase
  • CMC, critical micellar concentration
  • CA, cholic acid (3α,7α 12α-trihydroxy-5β-cholanoic acid)
  • CDCA, chenodeoxycholic acid (3α,7α-dihydroxy-5β-cholanoic acid)
  • UDCA, ursodeoxycholic acid (3α,7β-dihydroxy-5β-cholanoic acid)
  • GCA, glycocholic acid
  • RBC, red blood cells
  • LDL, low density lipoprotein
  • HDL, high density lipoprotein
  • ALT, alanine aminotransferase
  • GC, gas chromatography
  • AUC, areas under the curve
  • cholesterol synthesis
  • low density lipoprotein receptor
  • lumenal contents
  • bile acid

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Footnotes

  • Conflict of interest: None declared.

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