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

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Abstract

Transgenic mice with activated polyamine catabolism due to overexpression of spermidine/spermine N1-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 7α-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 γ co-activator 1α, 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.

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Abbreviations

HMGCR:

3-Hydroxy-3-methylglutaryl-CoA reductase

NPC1L1:

Niemann–Pick C1-like 1 protein

CYP7A1:

Cholesterol 7α-hydroxylase

PGC-1α:

Peroxisome proliferator-activated receptor γ co-activator 1α

SSAT:

Spermidine/spermine N¹-acetyltransferase

HDL:

High-density lipoprotein

GLC:

Gas–liquid chromatography

AMPK:

5′-AMP-activated protein kinase

HNF-4α:

Hepatocyte nuclear factor 4α

LXRα:

Liver X receptor α

FXR:

Farnesoid X receptor

SIRT1:

Sirtuin 1

MAPK:

Mitogen-activated protein kinase

PRMT1:

Protein arginine methyltransferase 1

PI3K:

Phosphatidylinositol 3-kinase

GSK-3β:

Glycogen synthase kinase 3β

PPARδ:

Peroxisome proliferator-activated receptor δ

DENSPM:

N1, N11-diethylnorspermine

NTCP:

Na+-taurocholate cotransporting polypeptide

OATP1:

Na+-independent organic anion transporting polypeptide

BSEP:

Bile salt export pump

FDFT1:

Squalene synthase

DHCR7:

7-Dehydrocholesterol reductase

SREBP:

Sterol regulatory element binding protein

ABCA1:

ATP binding cassette protein A1

ACAT2:

Acyl CoA: cholesterol acyltransferase 2

SR-BI:

Class B type 1 scavenger receptor

ABCG5:

ATP binding cassette protein G5

ABCG8:

ATP binding cassette protein G8

PXR:

Pregnane X receptor

CAR:

Constitutive androstane receptor

PPARα:

Peroxisome proliferator-activated receptor α

HDAC7:

Histone deacetylase 7

ASBT:

Apical Na+-dependent bile acid transporter

I-BABP:

Ileal bile acid binding protein

LDL:

Low-density lipoprotein

VLDL:

Very-low-density lipoprotein

IDL:

Intermediate-density lipoprotein

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Acknowledgments

We thank warmly Leena Kaipiainen, Sisko Juutinen, Anne Karppinen, Arja Korhonen, Marita Heikkinen, Teija Oinonen, Eveliina Kiriloff, and Riikka Frilander-Keinänen for technical assistance. We also thank Professor Johan Auwerx (Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland) for comments and critical reading of the manuscript. This research was supported by grants to E. Pirinen from Finnish Cultural Foundation of Northern Savo, Finnish Cultural Foundation, Research and Science Foundation of Farmos, Foundation of Kuopio University and Finnish Diabetes Research Foundation, to J. Jänne from the Academy of Finland and to M. Laakso from the Academy of Finland and the European Union (LSHM-CT-2004-512013).

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Authors and Affiliations

  1. Department of Medicine, University of Kuopio, P.O. Box 1777, 70211, Kuopio, Finland

    Eija Pirinen, Paula Itkonen, Nagendra Yaluri, Sami Heikkinen, Teemu Kuulasmaa, Maija Tusa, Jussi Pihlajamäki & Markku Laakso

  2. Department of Biotechnology and Molecular Medicine, Biocenter Kuopio, A.I.Virtanen Institute for Molecular Sciences, University of Kuopio, P.O. Box 1627, 70211, Kuopio, Finland

    Eija Pirinen, Sami Heikkinen, Marko Pietilä, Maija Tusa, Marc Cerrada-Gimenez, Leena Alhonen & Juhani Jänne

  3. Department of Clinical Nutrition, University of Kuopio, P.O. Box 1627, 70211, Kuopio, Finland

    Helena Gylling

  4. Division of Internal Medicine, Department of Medicine, University of Helsinki, 700, 00029, Helsinki, Finland

    Tatu A. Miettinen

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  1. Eija Pirinen
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  2. Helena Gylling
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  3. Paula Itkonen
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  4. Nagendra Yaluri
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  13. Tatu A. Miettinen
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  14. Markku Laakso
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Correspondence to Markku Laakso.

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Pirinen, E., Gylling, H., Itkonen, P. et al. Activated polyamine catabolism leads to low cholesterol levels by enhancing bile acid synthesis. Amino Acids 38, 549–560 (2010). https://doi.org/10.1007/s00726-009-0416-7

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