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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:2191.)
© 2007 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Studies on the Cholesterol-Free Mouse

Strong Activation of LXR-Regulated Hepatic Genes When Replacing Cholesterol With Desmosterol

Maura Heverin; Steve Meaney; Anat Brafman; Millicent Shafir; Maria Olin; Marjan Shafaati; Sara von Bahr; Lilian Larsson; Anita Lövgren-Sandblom; Ulf Diczfalusy; Paolo Parini; Elena Feinstein; Ingemar Björkhem

From the Division of Clinical Chemistry (M.H., S.M., M.O., M.S., S.v.B., L.L., A.L.-S., U.D., P.P., I.B.), Karolinska Institute, Huddinge University Hospital, Sweden; and Quark Biotech Inc (A.B., M.S., E.F.), Fremont, Calif.

Correspondence to Dr Ingemar Björkhem, Division of Clinical Chemistry, Karolinska University Hospital, Huddinge, S-14186, Sweden. E-mail ingemar.bjorkhem{at}karolinska.se

Objective— Characterization of cholesterol homeostasis in male mice with a genetic inactivation of 3β-hydroxysteroid-²⁴-reductase, causing replacement of almost all cholesterol with desmosterol.

Methods and Results— There was an increase in hepatic sterol synthesis and markedly increased fecal loss of neutral sterols. Fecal excretion of bile acids was similar in knockout mice and in controls. The composition of bile acids was changed, with reduced formation of cholic acid. It was shown that both Cyp7a1 and Cyp27a1 are active toward desmosterol, consistent with the formation of normal bile acids from this steroid. The levels of plant sterols were markedly reduced. Hepatic mRNA levels of 3-hydroxy-3-methylglutaryl (HMG) coenzyme A (CoA) reductase, Srebp-1c, Srebp-2, Cyp7a1, Abcg5, Abcg8, and Fas were all significantly increased.

Conclusions— The changes in hepatic mRNA levels in combination with increased biliary and fecal excretion of neutral steroids, reduced tissue levels of plant sterols, increased plasma levels of triglyceride-rich VLDL, are consistent with a strong activation of LXR-targeted genes. The markedly increased fecal loss of neutral sterols may explain the fact that the Dhcr24^–/– mice do not accumulate dietary cholesterol. The study illustrates the importance of the integrity of the cholesterol structure—presence of a double bond in the steroid side-chain is compatible with life but is associated with serious disturbances in sterol homeostasis.

Disruption of the 3β-hydroxysteroid-²⁴-reductase gene in mouse results in replacement of cholesterol with desmosterol. This inactivation leads to a markedly increased fecal loss of neutral sterols, a compensatory increase in hepatic sterol synthesis, and activation of LXR-targeted genes.

Key Words: desmosterol • sterol deficiency • sterol malabsorption • LXR-activation • Abcg5

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