Sexually dimorphic metabolism of branched-chain lipids in C57BL6/6J mice

doi:10.1194/jlr.M300408-JLR200

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Sexually dimorphic metabolism of branched-chain lipids in C57BL6/6J mice

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

Physiology and Pharmacology, Texas A&M University, College Station, Texas 77845

Corresponding Author: fschroeder{at}cvm.tamu.edu

Peroxisomal oxidation of branched-chain lipids (phytol, cholesterol) is essential to prevent accumulation of potentially toxic compounds (phytanic acid) and represents the major route for cholesterol elimination from the body. Despite the importance of branched-chain lipid oxidation in detoxification, almost nothing is known regarding factors that regulate their peroxisomal uptake, targeting, and metabolism. One peroxisomal protein, sterol carrier protein-x (SCP-x), is thought to catalyze exclusively the key 2/3-oxoacyl-CoA thiolytic step in branched-chain lipid oxidation. Since female mice have substantially lower hepatic levels of SCP-x than their male counterparts, it was postulated that female mice would be more susceptible to dietary stress with phytol, a phytanic acid precursor and peroxisome proliferator. In agreement with this and consistent with an inability to metabolize phytol metabolites, livers of phytol-fed female but not male mice accumulated elevated levels of phytanic acid, pristanic acid, and delta-2,3-pristanic acid. Phytol-fed females but not males also exhibited decreased fat (41%) and lean (12%) tissue mass, increased liver mass/body mass (74%), and histopathological lesions in the liver as compared to control-fed mice. Phytol-induced peroxisomal proliferation occurred in both male and female mice, as evidenced by liver morphology and up regulation of the peroxisomal protein catalase. Levels of the cytosolic fatty acid binding protein (L-FABP), along with sterol carrier protein 2 (SCP-2) and SCP-x increased, suggesting up regulation mediated by phytanic acid, a known ligand agonist of the peroxisomal proliferator-activated receptor $alpha$ (PPAR $alpha$ ). Significant alterations in hepatic and serum lipid distributions were also observed in the phytol-fed female mice, but not males. Similar effects were observed with mice fed a clofibric acid diet, another known ligand of PPAR $alpha$ . In summary, the present work investigated the role of SCP-x in branched chain lipid catabolism and demonstrated a sexual dimorphic response to phytol, a precursor of phytanic acid, on lipid parameters and hepatotoxicity.

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				B. P. Atshaves, A. L. McIntosh, D. Landrock, H. R. Payne, J. T. Mackie, N. Maeda, J. Ball, F. Schroeder, and A. B. Kier Effect of SCP-x gene ablation on branched-chain fatty acid metabolism Am J Physiol Gastrointest Liver Physiol, March 1, 2007; 292(3): G939 - G951. [Abstract] [Full Text] [PDF]

				J. Gloerich, D. M. van den Brink, J. P. N. Ruiter, N. van Vlies, F. M. Vaz, R. J. A. Wanders, and S. Ferdinandusse Metabolism of phytol to phytanic acid in the mouse, and the role of PPAR{alpha} in its regulation J. Lipid Res., January 1, 2007; 48(1): 77 - 85. [Abstract] [Full Text] [PDF]

				J. Gloerich, N. van Vlies, G. A. Jansen, S. Denis, J. P. N. Ruiter, M. A. van Werkhoven, M. Duran, F. M. Vaz, R. J. A. Wanders, and S. Ferdinandusse A phytol-enriched diet induces changes in fatty acid metabolism in mice both via PPAR{alpha}-dependent and -independent pathways J. Lipid Res., April 1, 2005; 46(4): 716 - 726. [Abstract] [Full Text] [PDF]

				B. P. Atshaves, A. L. McIntosh, H. R. Payne, J. Mackie, A. B. Kier, and F. Schroeder Effect of branched-chain fatty acid on lipid dynamics in mice lacking liver fatty acid binding protein gene Am J Physiol Cell Physiol, March 1, 2005; 288(3): C543 - C558. [Abstract] [Full Text] [PDF]