Activated polyamine catabolism leads to low cholesterol levels by enhancing bile acid synthesis.
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.
Pirinen
Eija
E
Department of Medicine, University of Kuopio, P.O. Box 1777, 70211, Kuopio, Finland.
Gylling
Helena
H
Itkonen
Paula
P
Yaluri
Nagendra
N
Heikkinen
Sami
S
Pietilä
Marko
M
Kuulasmaa
Teemu
T
Tusa
Maija
M
Cerrada-Gimenez
Marc
M
Pihlajamäki
Jussi
J
Alhonen
Leena
L
Jänne
Juhani
J
Miettinen
Tatu A
TA
Laakso
Markku
M
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
D000123:Acetyltransferases; D001647:Bile Acids and Salts; D015317:Biogenic Polyamines; D002784:Cholesterol; D002790:Cholesterol 7-alpha-Hydroxylase; D000099228:Diamine N-Acetyltransferase