The farnesoid X-receptor is an essential regulator of cholesterol homeostasis.
To address the importance of the farnesoid X-receptor (FXR; NR1H4) for normal cholesterol homeostasis, we evaluated the major pathways of cholesterol metabolism in the FXR-deficient (-/-) mouse model. Compared with wild-type, FXR(-/-) mice have increased plasma high density lipoprotein (HDL) cholesterol and a markedly reduced rate of plasma HDL cholesterol ester clearance. Concomitantly, FXR(-/-) mice exhibit reduced expression of hepatic genes involved in reverse cholesterol transport, most notably, that for scavenger receptor BI. FXR(-/-) mice also have increased: (i) plasma non-HDL cholesterol and triglyceride levels, (ii) apolipoprotein B-containing lipoprotein synthesis, and (iii) intestinal cholesterol absorption. Surprisingly, biliary cholesterol elimination was increased in FXR(-/-) mice, despite decreased expression of hepatic genes thought to be involved in this process. These data demonstrate that FXR is a critical regulator of normal cholesterol metabolism and that genetic changes affecting FXR function have the potential to be pro-atherogenic.
Lambert
Gilles
G
Molecular Disease Branch, NHLBI, National Institutes of Health (NIH), Bethesda, Maryland 20892, USA.
Amar
Marcelo J A
MJ
Guo
Grace
G
Brewer
H Bryan
HB
Gonzalez
Frank J
FJ
Sinal
Christopher J
CJ
D000818:Animals; D001055:Apolipoproteins B / Q000097:blood; D001692:Biological Transport; D015152:Blotting, Northern; D015153:Blotting, Western; D002784:Cholesterol / Q000097:blood / Q000378:metabolism*; D004268:DNA-Binding Proteins; D007082:Ileum / Q000378:metabolism; D007700:Kinetics; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008954:Models, Biological; D012333:RNA, Messenger / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D013997:Time Factors; D014157:Transcription Factors; D014280:Triglycerides / Q000097:blood; D000099150:Receptor, Farnesoid X-Activated
D001055:Apolipoproteins B; D002784:Cholesterol; D004268:DNA-Binding Proteins; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D014280:Triglycerides; D000099150:Receptor, Farnesoid X-Activated