Atshaves Barbara P, Payne H Ross, McIntosh Avery L, Tichy Shane E, Russell David, Kier Ann B, Schroeder Friedhelm
Departments of Physiology and Pharmacology, Texas A&M University, College Station, TX 77843-4466, USA.
J Lipid Res. 2004 May;45(5):812-30. doi: 10.1194/jlr.M300408-JLR200. Epub 2004 Mar 1.
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 Delta-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 alpha. 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.
尽管支链脂质氧化在解毒过程中十分重要，但关于调节过氧化物酶体摄取、靶向和代谢的因素却几乎一无所知。一种过氧化物酶体蛋白，即固醇载体蛋白-x（SCP-x），被认为在支链脂质氧化过程中催化关键的硫解步骤。当对肝脏中SCP-x水平显著降低的小鼠进行植醇（一种植烷酸前体和过氧化物酶体增殖剂）饮食应激敏感性测试时，喂食植醇的雌性小鼠（而非雄性小鼠）的肝脏：i）积累了植醇代谢产物（植烷酸、降植烷酸和Δ2,3-降植烷酸）；ii）脂肪组织质量减少，肝脏质量/体重增加；iii）呈现出肝脏组织病理学损伤的迹象；iv）肝脏脂质分布出现显著改变。此外，雄性和雌性小鼠均表现出植醇诱导的过氧化物酶体增殖，这通过肝脏形态学和过氧化物酶体蛋白过氧化氢酶的上调得以证明。另外，肝脏脂肪酸结合蛋白以及SCP-2和SCP-x的水平升高，表明这是由植烷酸介导的上调，植烷酸是过氧化物酶体增殖物激活受体α的已知配体激动剂。总之，本研究确定了SCP-x在支链脂质分解代谢中的作用，并证明了在脂质参数和肝毒性方面，对植烷酸前体植醇存在性别差异反应。
