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Cholesterol synthesis inhibition distal to squalene upregulates biliary phospholipid secretion and counteracts cholelithiasis in the genetically prone C57L/J mouse
  1. G A Clarke1,
  2. G Bouchard1,
  3. B Paigen2,
  4. M C Carey1
  1. 1Department of Medicine, Harvard Medical School, Division of Gastroenterology, Brigham and Women’s Hospital and Harvard Digestive Diseases Center, Boston, MA 02115, USA
  2. 2The Jackson Laboratory, Bar Harbor, ME 04609, USA
  1. Correspondence to:
    Dr M C Carey
    Department of Medicine, Thorn 1430, Brigham and Women’s Hospital, 75 Francis Street, Boston, MA 02115, USA;


Background and aims: Newly synthesised cholesterol contributes poorly to biliary lipid secretion but may assume greater importance when the rate limiting enzyme 3-hydroxy-3-methylglutaryl-CoA reductase (HMGR) is upregulated. As this occurs in the gall stone susceptible C57L/J inbred mouse, we employed two cholesterol biosynthesis inhibitors, Tu 2208 and Ro 48-8071, potent inhibitors of squalene epoxidase and oxidosqualene-lanosterol cyclase, respectively, to assess their potential in preventing cholesterol cholelithiasis in the C57L/J mouse strain. Mice were fed a lithogenic diet comprising a balanced nutrient intake with 15% dairy fat, 1% cholesterol, and 0.5% cholic acid added.

Methods: We determined gall stone phenotype, HMGR activity, biliary lipid secretion rates, and counterregulatory events in male C57L/J mice and gall stone resistant AKR treated with Tu 2208 (30–60 mg/kg/day) or Ro 48-8071 (30–100 mg/kg/day), while ingesting chow or the lithogenic diet.

Results: Both agents reduced the gall stone prevalence rate from 73% to 17% in C57L/J mice, inhibited HMGR activity, and decreased hepatic cholesterol concentrations without appreciably influencing biliary cholesterol secretion. In C57L as well as AKR mice, both agents increased biliary phospholipid (which is mostly phosphatidylcholine) secretion rates and at the highest doses effectively reduced the biliary cholesterol saturation index.

Conclusions: Cholesterol biosynthesis inhibitors acting distally to squalene do not reduce biliary cholesterol secretion rates despite reductions in cholesterol biosynthesis and hepatocellular levels. However, they effectively prevent gall stone formation through stimulation of pathways that lead to enhanced biliary phospholipid secretion.

  • holesterol synthesis
  • holesterol inhibition
  • phospholipid
  • cholelithiasis
  • mouse
  • mdr2
  • LD, lithogenic diet
  • Mdr2, multidrug resistance protein, isoform 2 (where italicised in lowercase indicates the corresponding murine gene)
  • bsep, bile salt export protein
  • ABC, ATP binding cassette (class and number are suffixed for official designations—that is, B4 and B11 for mdr2 and bsep, respectively)
  • Lith, murine cholesterol gall stone alleles
  • HMGR, 3-hydroxy-3-methylglutaryl-CoA reductase
  • SREBP, sterol regulatory element binding proteins
  • PC, phosphatidylcholine (biliary phospholipid)
  • CSI, cholesterol saturation index

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