Peroxisome proliferator-activated receptor alpha controls the hepatic CYP4A induction adaptive response to starvation and diabetes.
The hepatic CYP4A enzymes are important fatty acid and prostaglandin omega-hydroxylases that are highly inducible by fibric acid hypolipidemic agents and other peroxisome proliferators. Induction of the CYP4A enzymes by peroxisome proliferators is mediated through the nuclear peroxisome proliferator-activated receptor alpha (PPARalpha). Fatty acids have recently been identified as endogenous ligands of PPARalpha, and this receptor has been implicated in the regulation of lipid homeostasis. In the present report we characterized the induction of the hepatic CYP4A genes in rats during the altered lipid metabolism associated with starvation and diabetes. The mRNA levels of CYP4A1, CYP4A2, and CYP4A3 were induced 7-17-fold in the livers of fasted animals and 3-8-fold in the livers of diabetic animals. This was accompanied by corresponding changes in CYP4A protein levels and arachidonic and lauric acid omega-hydroxylase activity. Interestingly, feeding animals after the fasting period caused as much as an 80% suppression of CYP4A mRNA levels, whereas CYP4A protein levels and functional activity returned to control values. A second PPARalpha-responsive gene, acyl-CoA oxidase, was also induced in rat liver by diabetes and fasting. By using PPARalpha-deficient mice, we unambiguously demonstrated that PPARalpha is strictly required for hepatic CYP4A induction by starvation and diabetes. Similarly, induction of hepatic thiolase and bifunctional enzyme also required expression of PPARalpha. This represents the first evidence for the pathophysiologically induced activation of a nuclear receptor.
Kroetz
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DL
Department of Biopharmaceutical Sciences, School of Pharmacy, University of California, San Francisco, California 94143, USA. deanna@itsa.ucsf.edu
Yook
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P
Costet
P
P
Bianchi
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P
Pineau
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T
D015094:3-Hydroxyacyl CoA Dehydrogenases / Q000096:biosynthesis; D000101:Acetyl-CoA C-Acetyltransferase / Q000096:biosynthesis; D000222:Adaptation, Physiological; D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D042926:Cytochrome P-450 CYP4A; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis* / Q000235:genetics; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000378:metabolism*; D004746:Enoyl-CoA Hydratase / Q000096:biosynthesis; D004790:Enzyme Induction; D005502:Food; D007535:Isomerases; D007850:Lauric Acids / Q000378:metabolism; D008099:Liver / Q000201:enzymology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008862:Microsomes, Liver / Q000201:enzymology; D006899:Mixed Function Oxygenases / Q000096:biosynthesis* / Q000235:genetics; D009097:Multienzyme Complexes / Q000096:biosynthesis; D063994:Peroxisomal Bifunctional Enzyme; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D013217:Starvation / Q000150:complications / Q000378:metabolism*; D013311:Streptozocin; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
D007850:Lauric Acids; D009097:Multienzyme Complexes; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; C030358:lauric acid; D016718:Arachidonic Acid; D013311:Streptozocin; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D015094:3-Hydroxyacyl CoA Dehydrogenases; D042926:Cytochrome P-450 CYP4A; D000101:Acetyl-CoA C-Acetyltransferase; C576254:Ehhadh protein, mouse; D004746:Enoyl-CoA Hydratase; D063994:Peroxisomal Bifunctional Enzyme; D007535:Isomerases