Aberrant oxidation of the cholesterol side chain in bile acid synthesis ofsterol carrier protein-2/sterol carrier protein-x knockout mice

Peroxisomal beta-oxidation plays an important role in the metabolism of a w ide range of substrates, including various fatty acids and the steroid side chain in bile acid synthesis. Two distinct thiolases have been implicated to function in peroxisomal beta-oxidation: the long known 41-kDa beta-ketot hiolase identified by Hashimoto and coworkers (Hijikata, M,, Ishii, N,, Kag amiyama, H., Osumi, T,, and Hashimoto, T, (1987) J, BioE, Chem, 262, 8151-8 158) and the recently discovered 60-kDa SCPx thiolase, that consists of an N-terminal domain with beta-ketothiolase activity and a C-terminal moiety o f sterol carrier protein-alpha (SCPS, a lipid carrier or transfer protein), Recently, gene targeting of the SCP2/SCPx gene has shown in mice that the SCPx beta-ketothiolase is involved in peroxisomal beta-oxidation of alpha-m ethyl-branched chain fatty acids like pristanic acid. In our present work w e have investigated bile acid synthesis in the SCP2/SCPx knockout mice. Spe cific inhibition of beta-oxidation at the thiolytic cleavage step in bile a cid synthesis is supported by our finding of pronounced accumulation in bil e and serum from the knockout mice of 3 alpha,7 alpha,12 alpha-trihydroxy-2 7-nor-5 beta-cholestane-24-one (which is known bile alcohol derivative of t he cholic acid synthetic intermediate 3 alpha,7 alpha,12 alpha-trihydroxy-2 4-keto-cholestanoyl-coenzyme A). Moreover, these mice have elevated concent rations of bile acids with shortened side chains (i,e, 23-norcholic acid an d 23-norchenodeoxycholic acid), which may be produced via alpha- rather tha n beta-oxidation, Our results demonstrate that the SCPx thiolase is critica l for beta-oxidation of the steroid side chain in conversion of cholesterol into bile acids.