title: Activated polyamine catabolism leads to low cholesterol levels by enhancing bile acid synthesis.
abstract: 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 7alpha-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 1alpha, 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.
authors: Department of Medicine, University of Kuopio, P.O. Box 1777, 70211, Kuopio, Finland.
authors: Eija
authors: E
authors: Pirinen
authors: Helena
authors: H
authors: Gylling
authors: Paula
authors: P
authors: Itkonen
authors: Nagendra
authors: N
authors: Yaluri
authors: Sami
authors: S
authors: Heikkinen
authors: Marko
authors: M
authors: Pietilä
authors: Teemu
authors: T
authors: Kuulasmaa
authors: Maija
authors: M
authors: Tusa
authors: Marc
authors: M
authors: Cerrada-Gimenez
authors: Jussi
authors: J
authors: Pihlajamäki
authors: Leena
authors: L
authors: Alhonen
authors: Juhani
authors: J
authors: Jänne
authors: Tatu A
authors: TA
authors: Miettinen
authors: Markku
authors: M
authors: Laakso
mesh_terms: D000123:Acetyltransferases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001647:Bile Acids and Salts / Q000096:biosynthesis*; D015317:Biogenic Polyamines / Q000096:biosynthesis*; D002784:Cholesterol / Q000097:blood*; D002790:Cholesterol 7-alpha-Hydroxylase / Q000235:genetics / Q000378:metabolism; D005260:Female; D056945:Hep G2 Cells; D008099:Liver / Q000201:enzymology / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D008822:Mice, Transgenic; D000099228:Diamine N-Acetyltransferase
chemical_list: D000123:Acetyltransferases; D001647:Bile Acids and Salts; D015317:Biogenic Polyamines; D002784:Cholesterol; D002790:Cholesterol 7-alpha-Hydroxylase; D000099228:Diamine N-Acetyltransferase