Studies on the regulatory roles of cholesterol and bile acids
Author: Murphy, Charlotte
Date: 2007-05-25
Location: Föreläsingssal B64, Karolinska Universitetssjukhuset, Huddinge
Time: 09.00
Department: Institutionen för laboratoriemedicin / Department of Laboratory Medicine
View/ Open:
thesis.pdf (395.2Kb)
Abstract
Cholesterol is essential for normal growth and development in mammals.
However, excess cholesterol can be harmful leading to diseases such as
atherosclerosis and gallstones. Once formed the ring structure of
cholesterol cannot be catabolised by the body and must therefore be
converted to other compounds for excretion. In most vertebrates the
faecal route of cholesterol excretion is through the formation of bile
acids (BA) and the solubilisation of free cholesterol in bile.
Cholesterol is converted into the primary bile acids cholic acid (CA) and
chenodeoxycholic acid, the ratio of which is determined by the enzyme
sterol 12 a -hydroxylase (CYP8B1). Both cholesterol and BAs regulate
their own synthesis, and other biological processes, through the actions
of transcription factors such as the sterol regulatory element binding
proteins (SREBP), the liver X receptor and the farnesoid X receptor.
A Cyp8b1 knockout mouse model has been created, which lacks the ability
to synthesize CA. Using this model we investigated the regulatory effects
of CA and cholesterol on metabolism and found that a reduction in CA
resulted in decreased cholesterol absorption, increased cholesterol
synthesis and was protective against large increases in hepatic
cholesterol levels. Our results suggest an inhibitor of CYP8B1 may reduce
cholesterol levels and thereby reduce the development of cardiovascular
disease.
The gene involved in cholesterol synthesis most responsive to regulation
by CA and cholesterol treatment was squalene epoxidase (Sqle). Therefore
the promoter of this gene was investigated further. In analogy to the
human SQLE promoter the murine promoter was activated by SREBPs. A 205bp
region of the promoter, containing three novel sterol regulatory
elements, was found to be responsible for SREBP-2 regulation.
While investigating the promoters of other genes involved in cholesterol
synthesis mevalonate kinase was found to share a short common promoter
with the cob(I)alamin adenotransferase gene (MMAB) catalysing the
synthesis of AdoCbl, a cofactor for methylmalonyl CoA mutase. In mice the
expression of Mmab was increased by statin treatment. Therefore, statins
may represent a novel treatment for patients with methylmalonic aciduria
type B, resulting from mutations in this gene.
List of papers:
I. Murphy C, Parini P, Wang J, Bjorkhem I, Eggertsen G, Gafvels M (2005). "Cholic acid as key regulator of cholesterol synthesis, intestinal absorption and hepatic storage in mice." Biochim Biophys Acta 1735(3): 167-75
Pubmed
II. Wang J, Einarsson C, Murphy C, Parini P, Bjorkhem I, Gafvels M, Eggertsen G (2006). "Studies on LXR- and FXR-mediated effects on cholesterol homeostasis in normal and cholic acid-depleted mice." J Lipid Res 47(2): 421-30. Epub 2005 Nov 1
Pubmed
III. Murphy C, Ledmyr H, Ehrenborg E, Gafvels M (2006). "Promoter analysis of the murine squalene epoxidase gene. Identification of a 205 bp homing region regulated by both SREBPS and NF-Y." Biochim Biophys Acta 1761(10): 1213-27. Epub 2006 Sep 1
Pubmed
IV. Murphy C, Murray AM, Meaney S, Gafvels M (2007). "Regulation by SREBP-2 defines a potential link between isoprenoid and adenosylcobalamin metabolism." Biochem Biophys Res Commun 355(2): 359-64. Epub 2007 Feb 6
Pubmed
I. Murphy C, Parini P, Wang J, Bjorkhem I, Eggertsen G, Gafvels M (2005). "Cholic acid as key regulator of cholesterol synthesis, intestinal absorption and hepatic storage in mice." Biochim Biophys Acta 1735(3): 167-75
Pubmed
II. Wang J, Einarsson C, Murphy C, Parini P, Bjorkhem I, Gafvels M, Eggertsen G (2006). "Studies on LXR- and FXR-mediated effects on cholesterol homeostasis in normal and cholic acid-depleted mice." J Lipid Res 47(2): 421-30. Epub 2005 Nov 1
Pubmed
III. Murphy C, Ledmyr H, Ehrenborg E, Gafvels M (2006). "Promoter analysis of the murine squalene epoxidase gene. Identification of a 205 bp homing region regulated by both SREBPS and NF-Y." Biochim Biophys Acta 1761(10): 1213-27. Epub 2006 Sep 1
Pubmed
IV. Murphy C, Murray AM, Meaney S, Gafvels M (2007). "Regulation by SREBP-2 defines a potential link between isoprenoid and adenosylcobalamin metabolism." Biochem Biophys Res Commun 355(2): 359-64. Epub 2007 Feb 6
Pubmed
Issue date: 2007-05-04
Rights:
Publication year: 2007
ISBN: 978-91-7357-173-9
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