Alternations in hepatic expression of fatty-acid metabolizing enzymes in ArKO mice and their reversal by the treatment with 17beta-estradiol or a peroxisome proliferator.
We generated aromatase gene knockout mice (ArKO mice) by targeting disruption of Cyp19, which encodes an enzyme responsible for conversion of androgens to estrogens. We found that ArKO males developed hepatic steatosis spontaneously with aging, indicating that the function of Cyp19 is required to maintain constitutive lipid metabolism in male mice. Plasma lipoprotein analysis using a gel permeation chromatography revealed that high density lipoprotein (HDL)-cholesterol levels were slightly higher in ArKO males than in wild-type males, whereas no other obvious alternations in the profiles were detected. Nevertheless, analysis of lipoprotein compositions by SDS-polyacrylamide gel electrophoresis demonstrated apparent reduction in the amounts of apolipoprotein E, functioning in receptor-mediated clearance of lipoproteins in the liver, in the IDL/LDL fraction of ArKO males as compared with that of wild-type males. Biochemical analysis on the ArKO livers revealed suppression of mRNA expression and activity of enzymes involved in fatty acid beta-oxidation. The impairment was reversed to the wild-type levels by treatment with 17beta-estradiol or bezafibrate, the latter is a synthetic peroxisome proliferator. These findings indicated a pivotal role of estrogen in supporting constitutive hepatic expression of genes involved in fatty acid beta-oxidation and in maintaining lipid homeostasis.
Toda
K
K
Department of Medical Chemistry, Kochi Medical School, Nankoku, 783-8505, Kochi, Japan. todak@kochi-ms.ac.jp
Takeda
K
K
Akira
S
S
Saibara
T
T
Okada
T
T
Onishi
S
S
Shizuta
Y
Y
D042964:Acyl-CoA Dehydrogenase; D042962:Acyl-CoA Oxidase; D000818:Animals; D001141:Aromatase / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D001629:Bezafibrate / Q000494:pharmacology*; D002374:Catalase / Q000235:genetics; D003066:Coenzyme A Ligases / Q000235:genetics; D042926:Cytochrome P-450 CYP4A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D004958:Estradiol / Q000494:pharmacology*; D044943:Fatty Acid Desaturases / Q000235:genetics; D005227:Fatty Acids / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects; D050356:Lipid Metabolism; D008074:Lipoproteins / Q000097:blood; D008099:Liver / Q000187:drug effects* / Q000201:enzymology* / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008854:Microscopy, Electron; D006899:Mixed Function Oxygenases / Q000235:genetics; D010084:Oxidation-Reduction; D010088:Oxidoreductases / Q000235:genetics; D020025:Peroxisome Proliferators / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins; D029701:Saccharomyces cerevisiae Proteins; D000098859:Long-Chain-Fatty-Acid-CoA Ligase
D005227:Fatty Acids; D008074:Lipoproteins; D020025:Peroxisome Proliferators; D012333:RNA, Messenger; D012097:Repressor Proteins; D029701:Saccharomyces cerevisiae Proteins; D004958:Estradiol; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D010088:Oxidoreductases; D002374:Catalase; D001141:Aromatase; D042926:Cytochrome P-450 CYP4A; D044943:Fatty Acid Desaturases; D042962:Acyl-CoA Oxidase; D042964:Acyl-CoA Dehydrogenase; D003066:Coenzyme A Ligases; C090799:FAA2 protein, S cerevisiae; D000098859:Long-Chain-Fatty-Acid-CoA Ligase; D001629:Bezafibrate