Opposing roles of peroxisome proliferator-activated receptor alpha and growth hormone in the regulation of CYP4A11 expression in a transgenic mouse model.
CYP4A11 transgenic mice (CYP4A11 Tg) were generated to examine in vivo regulation of the human CYP4A11 gene. Expression of CYP4A11 in mice yields liver and kidney P450 4A11 levels similar to those found in the corresponding human tissues and leads to an increased microsomal capacity for omega-hydroxylation of lauric acid. Fasted CYP4A11 Tg mice exhibit 2-3-fold increases in hepatic CYP4A11 mRNA and protein, and this response is absent in peroxisome proliferator-activated receptor alpha (PPARalpha) null mice. Dietary administration of either of the PPARalpha agonists, fenofibrate or clofibric acid, increases hepatic and renal CYP4A11 levels by 2-3-fold, and these responses were also abrogated in PPARalpha null mice. Basal liver CYP4A11 levels are reduced differentially in PPARalpha-/- females (>95%) and males (<50%) compared with PPARalpha-/+ mice. Quantitative and temporal differences in growth hormone secretion are known to alter hepatic lipid metabolism and to underlie sexually dimorphic gene expression, respectively. Continuous infusion of low levels of growth hormone reduced CYP4A11 expression by 50% in PPARalpha-proficient male and female transgenic mice. A larger decrease was observed for the expression of CYP4A11 in PPARalpha-/- CYP4A11 Tg male mice to levels similar to that of female PPARalpha-deficient mice. These results suggest that PPARalpha contributes to the maintenance of basal CYP4A11 expression and mediates CYP4A11 induction in response to fibrates or fasting. In contrast, increased exposure to growth hormone down-regulates CYP4A11 expression in liver.
Savas
Üzen
Ü
From the Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California 92037.
Machemer
Daniel E W
DEW
Department of Pharmacology, University of California, San Diego, La Jolla, California 92093.
Hsu
Mei-Hui
MH
From the Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California 92037.
Gaynor
Pryce
P
Institute for Biomedical Research, Hackensack University Medical Center, Hackensack, New Jersey 07601.
Lasker
Jerome M
JM
Institute for Biomedical Research, Hackensack University Medical Center, Hackensack, New Jersey 07601.
Tukey
Robert H
RH
Department of Pharmacology, University of California, San Diego, La Jolla, California 92093.
Johnson
Eric F
EF
From the Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California 92037. Electronic address: johnson@scripps.edu.
D000818:Animals; D002995:Clofibric Acid / Q000494:pharmacology; D042926:Cytochrome P-450 CYP4A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics* / Q000378:metabolism*; D005215:Fasting / Q000502:physiology; D005260:Female; D011345:Fenofibrate / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000502:physiology; D013006:Growth Hormone / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D000960:Hypolipidemic Agents / Q000494:pharmacology; D007668:Kidney / Q000201:enzymology; D008099:Liver / Q000201:enzymology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008862:Microsomes, Liver / Q000201:enzymology; D047493:PPAR alpha / Q000819:agonists / Q000378:metabolism*; D011247:Pregnancy; D012333:RNA, Messenger / Q000378:metabolism; D012727:Sex Characteristics
D000960:Hypolipidemic Agents; D047493:PPAR alpha; D012333:RNA, Messenger; D002995:Clofibric Acid; D013006:Growth Hormone; D003577:Cytochrome P-450 Enzyme System; C465478:CYP4A11 protein, human; D042926:Cytochrome P-450 CYP4A; D011345:Fenofibrate