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Journal of Lipid Research, Vol. 45, 812-830, May 2004
Copyright © 2004 by American Society for Biochemistry and Molecular Biology

Sexually dimorphic metabolism of branched-chain lipids in C57BL/6J mice

Barbara P. Atshaves^*, H. Ross Payne, Avery L. McIntosh^*, Shane E. Tichy, David Russell, Ann B. Kier and Friedhelm Schroeder^1,*,

^* Departments of Physiology and Pharmacology, Texas A&M University, College Station, TX 77843-4466
Pathobiology, Texas A&M University, College Station, TX 77843-4466
Chemistry, Texas A&M University, College Station, TX 77843-4466

¹ To whom correspondence should be addressed. e-mail: fschroeder{at}cvm.tamu.edu

Despite the importance of branched chain lipid oxidation in detoxification, almost nothing is known regarding factors regulating peroxisomal uptake, targeting, and metabolism. One peroxisomal protein, sterol carrier protein-x (SCP-x), is thought to catalyze a key thiolytic step in branched chain lipid oxidation. When mice with substantially lower hepatic levels of SCP-x were tested for susceptibility to dietary stress with phytol (a phytanic acid precursor and peroxisome proliferator), livers of phytol-fed female but not male mice i) accumulated phytol metabolites (phytanic acid, pristanic acid, and -2,3-pristanic acid); ii) exhibited decreased fat tissue mass and increased liver mass/body mass; iii) displayed signs of histopathological lesions in the liver; and iv) demonstrated significant alterations in hepatic lipid distributions. Moreover, both male and female mice exhibited phytol-induced peroxisomal proliferation, as demonstrated by liver morphology and upregulation of the peroxisomal protein catalase. In addition, levels of liver fatty acid binding protein, along with SCP-2 and SCP-x, increased, suggesting upregulation mediated by phytanic acid, a known ligand agonist of the peroxisomal proliferator-activated receptor .

In summary, the present work establishes a role for SCP-x in branched chain lipid catabolism and demonstrates a sexual dimorphic response to phytol, a precursor of phytanic acid, in lipid parameters and hepatotoxicity.

Abbreviations: CCD, charge coupled device; DAB, 3,3'-diaminobenzidine; DEXA, dual-energy X-ray absorptiometry; FAME, fatty acid methyl ester; FAT, fatty acid translocase; L-FABP, liver fatty acid binding protein; PAS, periodic acid-Schiff; PPAR, peroxisome proliferator-activated receptor; SCP-2, sterol carrier protein-2; SCP-x, sterol carrier protein-x; TEM, transmission electron microscopy

Supplementary key words sterol carrier protein-2 • sterol carrier protein-x • liver fatty acid binding protein • peroxisome proliferator-activated receptor • peroxisome • phytanic acid • hepatocellular toxicity • sexual dimorphism

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