Activated polyamine catabolism leads to low cholesterol levels by enhancing bile acid synthesis

作者：Pirinen Eija; Gylling Helena; Itkonen Paula; Yaluri Nagendra; Heikkinen Sami; Pietila Marko; Kuulasmaa Teemu; Tusa Maija; Cerrada Gimenez Marc; Pihlajamaki Jussi; Alhonen Leena; Janne Juhani; Miettinen Tatu A; Laakso Markku^*

来源：Amino Acids, 2010, 38(2): 549-560.

DOI：10.1007/s00726-009-0416-7

• Spermidine/spermine N(1)-acetyltransferase
• Cholesterol
• Bile acids
• Cholesterol 7 alpha-hydroxylase
• Peroxisome proliferator-activated receptor gamma co-activator 1 alpha
• Akt

Transgenic mice with activated polyamine catabolism due to overexpression of spermidine/spermine N(1)-acetyltransferase (SSAT) have significantly reduced plasma total cholesterol levels. In our study, we show that low cholesterol levels were attributable to enhanced bile acid synthesis in combination with reduced cholesterol absorption. Hepatic cholesterol 7 alpha-hydroxylase (CYP7A1), the rate-limiting enzyme catalyzing the conversion of cholesterol to bile acids, plays an important role in the removal of excess cholesterol from the body. We suggest that by reducing activity of Akt activated polyamine catabolism increased the stability and activity of peroxisome proliferator-activated receptor gamma co-activator 1 alpha, the critical activator of CYP7A1. This is supported by our finding that the treatment with SSAT activator, N (1),N (11)-diethylnorspermine, reduced significantly the amount of phosphorylated (active) Akt in HepG2 cells. In summary, activated-polyamine catabolism is a novel mechanism to regulate bile acid synthesis. Therefore, polyamine catabolism could be a potential therapeutic target to control hepatic CYP7A1 expression.

• 出版日期2010-2