Proteomic Analysis of Liver from Transgenic Mice Overexpressing Small Heterodimer Partner

The small heterodimer partner (SHP) is a key regulator of genes involved in cholesterol-bile acid homeostasis and functions as a specific transcription repressor. Differential protein expression in the liver of transgenic mice expressing the human SHP gene was compared with wild-type animals. Liver protein extracts were analyzed by two-dimensional electrophoresis and the proteins were identified by MALDI-TOF-MS. Approximately 30 proteins were differentially-expressed in the livers of transgenic mice, compared to the control mice. Major effects were evident in lipid accumulation, including a fatty acid-binding protein. Overexpression of SHP also triggered alterations in key enzymes involved in the metabolism of amino acids, nucleic acids and urea and was associated with changes in cellular proteins involved in calcium homeostasis, detoxification and protein folding and repair. Cholesterol is essential for a number of cellular functions, including membrane biogenesis, steroid hormone and bile acid biosynthesis. Excess of cholesterol contributes to diseases such as atherosclerosis and gallstone formation. Cholesterol degradation to bile acids in the liver is initiated by either cholesterol 7·-hydroxylase (CYP7A1) of the classic (neutral) pathway, or by mitochondrial sterol 27-hydroxylase (CYP27A1) of the alternative (or acidic) pathway (1). Bile acids, the end-products of cholesterol catabolism in the liver, regulate signaling pathways in hepatocytes.The importance of bile acids as ligands for transcriptional regulators of cholesterol homeostasis is becoming increasingly evident. Bile acids are natural ligands of the nuclear hormone receptors, farnesoid X receptor (FXR) and pregnane X receptor (PXR) (2, 3).