Relation between hepatic expression of ATP-binding cassette transporters G5 and G8 and biliary cholesterol secretion in mice.
OBJECTIVE
Mutations in genes encoding the ATP-binding cassette (ABC)-transporters ABCG5 and ABCG8 underlie sitosterolemia, which is characterized by elevated plasma levels of phytosterols due to increased intestinal absorption and impaired biliary secretion of sterols. The aim of our study was to correlate the expression levels of Abcg5 and Abcg8 to biliary cholesterol secretion in various (genetically-modified) mouse models.


METHODS
Bile was collected from genetically-modified mice fed a chow diet, or from mice fed either a chow diet, or chow supplemented with either 1% diosgenin, 0.1% simvastatin, or a synthetic liver X receptor agonist, for determination of biliary lipids. Livers and small intestines were harvested and expression levels of Abcg5, Abcg8 and Abcb4 were determined by real-time polymerase chain reaction.


RESULTS
Intestinal expression of Abcg5 and Abcg8 did not show much variation between the various models. In contrast, a linear correlation between hepatic expression levels of Abcg5 and Abcg8 and biliary cholesterol secretion rates was found. This relation was independent of Abcb4-mediated phospholipid secretion. However, in diosgenin-fed mice showing cholesterol hypersecretion, hepatic Abcg5 and Abcg8 expression levels remained unchanged.


CONCLUSIONS
Our results strongly support a role for Abcg5 and Abcg8 in regulation of biliary cholesterol secretion, but also indicate the existence of a largely independent route of cholesterol secretion.
Kosters
Astrid
A
Department of Experimental Hepatology, AMC Liver Center, Academic Medical Center, Meibergdreef 69-71, Amsterdam 1105 BK, The Netherlands. a.kosters@amc.uva.nl
Frijters
Raoul J J M
RJ
Schaap
Frank G
FG
Vink
Edwin
E
Plösch
Torsten
T
Ottenhoff
Roelof
R
Jirsa
Milan
M
De Cuyper
Iris M
IM
Kuipers
Folkert
F
Groen
Albert K
AK
D000071018:ATP Binding Cassette Transporter, Subfamily G, Member 5; D000071019:ATP Binding Cassette Transporter, Subfamily G, Member 8; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology; D001646:Bile / Q000378:metabolism*; D002784:Cholesterol / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics; D004144:Diosgenin / Q000494:pharmacology; D006845:Hydrocarbons, Fluorinated; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D007413:Intestinal Mucosa / Q000378:metabolism; D008074:Lipoproteins / Q000235:genetics / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic / Q000235:genetics; D010743:Phospholipids / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D019821:Simvastatin / Q000494:pharmacology; D051782:Sterol Regulatory Element Binding Protein 2; D013449:Sulfonamides; D014157:Transcription Factors / Q000235:genetics; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
D000071018:ATP Binding Cassette Transporter, Subfamily G, Member 5; D000071019:ATP Binding Cassette Transporter, Subfamily G, Member 8; D018528:ATP-Binding Cassette Transporters; D000924:Anticholesteremic Agents; D002784:Cholesterol; D004268:DNA-Binding Proteins; D004144:Diosgenin; D006845:Hydrocarbons, Fluorinated; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008074:Lipoproteins; D010743:Phospholipids; D012333:RNA, Messenger; D019821:Simvastatin; D051782:Sterol Regulatory Element Binding Protein 2; D013449:Sulfonamides; D014157:Transcription Factors; C462600:ABCG5 protein, mouse; C462601:ABCG8 protein, mouse; C497391:Srebf2 protein, mouse; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides