LXR alpha is the dominant regulator of CYP7A1 transcription.
Cholesterol 7 alpha-hydroxylase (CYP7A1) catalyzes the rate-limiting step in the classic pathway of bile acid biosynthesis. Dietary cholesterol stimulates CYP7A1 transcription via activation of oxysterol receptor, LXR alpha, whereas bile acids repress transcription through FXR-mediated induction of SHP protein. The aim of this study was to determine the quantitative role that LXR- and FXR-regulated pathways play in regulating CYP7A1 and SHP in both rat and hamster models. In rats fed a 2% cholesterol diet, both SHP and CYP7A1 mRNA levels were elevated. The inability to induce CYP7A1 mRNA levels by cholesterol feeding in hamsters led to a decline in SHP mRNA levels. Elimination of hepatic bile acid flux by cholestyramine or bile fistula resulted in a marked repression of rat SHP mRNA levels. These results suggest that under conditions of both SHP and LXR alpha activation, stimulatory effect of LXR alpha overrides the inhibitory effect of FXR and results in an induction of rat CYP7A1 mRNA levels.
Gupta
Seema
S
Department of Microbiology and Immunology, Virginia Commonwealth University, MCV Campus, Richmond, VA 23298, USA.
Pandak
William M
WM
Hylemon
Phillip B
PB
D000818:Animals; D002790:Cholesterol 7-alpha-Hydroxylase / Q000235:genetics*; D004268:DNA-Binding Proteins; D015971:Gene Expression Regulation, Enzymologic; D000071518:Liver X Receptors; D008297:Male; D057093:Orphan Nuclear Receptors; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D014158:Transcription, Genetic
D004268:DNA-Binding Proteins; D000071518:Liver X Receptors; C000605215:Nr1h3 protein, rat; D057093:Orphan Nuclear Receptors; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D002790:Cholesterol 7-alpha-Hydroxylase