Cholesterol synthesis inhibition distal to squalene upregulates biliary phospholipid secretion and counteracts cholelithiasis in the genetically prone C57L/J mouse.
OBJECTIVE
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.
Clarke
G A
GA
Department of Medicine, Harvard Medical School, Division of Gastroenterology, Brigham and Women's Hospital and Harvard Digestive Diseases Center, Boston, MA 02115, USA.
Bouchard
G
G
Paigen
B
B
Carey
M C
MC
D000818:Animals; D000924:Anticholesteremic Agents / Q000627:therapeutic use*; D001577:Benzophenones / Q000627:therapeutic use; D001646:Bile / Q000378:metabolism*; D001648:Bile Canaliculi / Q000378:metabolism; D002769:Cholelithiasis / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D002784:Cholesterol / Q000096:biosynthesis* / Q000097:blood; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D020022:Genetic Predisposition to Disease; D019751:Intramolecular Transferases / Q000037:antagonists & inhibitors; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008806:Mice, Inbred AKR; D008810:Mice, Inbred C57BL; D010105:Oxygenases / Q000037:antagonists & inhibitors; D010743:Phospholipids / Q000378:metabolism*; D050603:Squalene Monooxygenase; D013876:Thiophenes / Q000627:therapeutic use
D000924:Anticholesteremic Agents; D001577:Benzophenones; D004791:Enzyme Inhibitors; D010743:Phospholipids; D013876:Thiophenes; C481929:Tu 2208; C105726:Ro 48-8071; D002784:Cholesterol; D010105:Oxygenases; D050603:Squalene Monooxygenase; D019751:Intramolecular Transferases; C021924:lanosterol synthase