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J. Biol. Chem., Vol. 276, Issue 51, 48058-48065, December 21, 2001
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From the Hepatic up-regulation of sterol carrier protein 2 (Scp2) in mice promotes hypersecretion of cholesterol into bile and
gallstone formation in response to a lithogenic diet. We hypothesized
that Scp2 deficiency may alter biliary lipid secretion and hepatic cholesterol metabolism. Male gallstone-susceptible C57BL/6 and C57BL/6Scp2(
Disruption of the Sterol Carrier Protein 2 Gene in Mice Impairs
Biliary Lipid and Hepatic Cholesterol Metabolism*
§,,,,,, and Division of Gastroenterology, Department of
Medicine I, Medical University of Lübeck, D-23538 Lübeck,
Germany and the ¶ Institute for Arteriosclerosis Research and
Institute for Clinical Chemistry and Laboratory Medicine, University of
Münster, D-48129 Münster, Germany
/) knockout mice were fed a
standard chow or lithogenic diet. Hepatic biles were collected to
determine biliary lipid secretion rates, bile flow, and bile salt pool
size. Plasma lipoprotein distribution was investigated, and gene
expression of cytosolic lipid-binding proteins, lipoprotein receptors,
hepatic regulatory enzymes, and intestinal cholesterol absorption was
measured. Compared with chow-fed wild-type animals,
C57BL/6Scp2(/) mice had higher bile flow
and lower bile salt secretion rates, decreased hepatic apolipoprotein
expression, increased hepatic cholesterol synthesis, and up-regulation
of liver fatty acid-binding protein. In addition, the bile salt pool
size was reduced and intestinal cholesterol absorption was unaltered in
C57BL/6Scp2(/) mice. When
C57BL/6Scp2(/) mice were challenged with
a lithogenic diet, a smaller increase of hepatic free cholesterol
failed to suppress cholesterol synthesis and biliary cholesterol
secretion increased to a much smaller extent than phospholipid and bile
salt secretion. Scp2 deficiency did not prevent gallstone formation and
may be compensated in part by hepatic up-regulation of liver fatty
acid-binding protein. These results support a role of Scp2 in hepatic
cholesterol metabolism, biliary lipid secretion, and
intracellular cholesterol distribution.
*
This work was supported in part by Deutsche
Forschungsgemeinschaft Grant Fu 288/2; by Medical Faculty Project N10,
Medical University of Lübeck; and by the
"Interdisziplinäres Klinisches Forschungszentrum" of the
Medical Faculty, University of Münster (Project A4).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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