Hepatic cholesterol metabolism and resistance to dietary cholesterol in LXRbeta-deficient mice.
The nuclear oxysterol-receptor paralogues LXRalpha and LXRbeta share a high degree of amino acid identity and bind endogenous oxysterol ligands with similar affinities. While LXRalpha has been established as an important regulator of cholesterol catabolism in cholesterol-fed mice, little is known about the function of LXRbeta in vivo. We have generated mouse lines with targeted disruptions of each of these LXR receptors and have compared their responses to dietary cholesterol. Serum and hepatic cholesterol levels and lipoprotein profiles of cholesterol-fed animals revealed no significant differences between LXRbeta(-/-) and wild-type mice. Steady-state mRNA levels of 3-hydroxy-3-methylglutaryl coenzyme A reductase, farnesyl diphosphate synthase, and squalene synthase were increased in LXRbeta(-/-) mice compared with LXRbeta(+/+) mice, when fed standard chow. The mRNA levels for cholesterol 7alpha-hydroxylase, oxysterol 7alpha-hydroxylase, sterol 12alpha-hydroxylase, and sterol 27-hydroxylase, respectively, were comparable in these strains, both on standard and 2% cholesterol chow. Our results indicate that LXRbeta(-/-) mice - in contrast to LXRalpha(-/-) mice - maintain their resistance to dietary cholesterol, despite subtle effects on the expression of genes coding for enzymes involved in lipid metabolism. Thus, our data indicate that LXRbeta has no complete overlapping function compared with LXRalpha in the liver.
Department of Biosciences at Novum, Karolinska Institutet, Huddinge, Sweden.
S
S
Alberti
G
G
Schuster
P
P
Parini
D
D
Feltkamp
U
U
Diczfalusy
M
M
Rudling
B
B
Angelin
I
I
Björkhem
S
S
Pettersson
J A
JA
Gustafsson
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism*; D002791:Cholesterol, Dietary / Q000378:metabolism; D004268:DNA-Binding Proteins; D013186:Farnesyl-Diphosphate Farnesyltransferase / Q000037:antagonists & inhibitors; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D006888:Hydroxycholesterols / Q000097:blood; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism; D050356:Lipid Metabolism; D008074:Lipoproteins / Q000097:blood; D008099:Liver / Q000033:anatomy & histology / Q000378:metabolism*; D000071518:Liver X Receptors; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000502:physiology*; D014158:Transcription, Genetic
D001647:Bile Acids and Salts; D002791:Cholesterol, Dietary; D004268:DNA-Binding Proteins; D006888:Hydroxycholesterols; D008074:Lipoproteins; D000071518:Liver X Receptors; C000605214:Nr1h3 protein, mouse; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear; D002784:Cholesterol; D006903:Hydroxymethylglutaryl CoA Reductases; D013186:Farnesyl-Diphosphate Farnesyltransferase; D000410:Alanine Transaminase