Pitavastatin ameliorates severe hepatic steatosis in aromatase-deficient (Ar-/-) mice.
Tamoxifen is a potent antagonist of estrogen, and hepatic steatosis is a frequent complication in adjuvant tamoxifen for breast cancer. Impaired hepatic FA beta-oxidation in peroxisomes, microsomes, and mitochondria results in progression of massive hepatic steatosis in estrogen deficiency. This impairment, although latent, is potentially serious: About 3% of the general population in the United States is now suffering from nonalcoholic steatohepatitis associated with obesity and hyperlipidemia. Therefore, in the present study we tried to restore impaired hepatic FA beta-oxidation by administering a novel statin, pitavastatin, to aromatase-deficient (Ar-/-) mice defective in intrinsic estrogen synthesis. Northern blot analysis of Ar-/- mice liver revealed a significant restoration of mRNA expression of essential enzymes involved in FA beta-oxidation such as very long fatty acyl-CoA synthetase in peroxisome, peroxisomal fatty acyl-CoA oxidase, and medium-chain acyl-CoA dehydrogenase. Severe hepatic steatosis observed in Ar-/- mice substantially regressed. Consistent findings were obtained in the in vitro assays of FA beta-oxidation activity. These findings demonstrate that pitavastatin is capable of restoring impaired FA beta-oxidation in vivo via the peroxisome proliferator-activated receptor-alpha-mediated signaling pathway and is potent enough to ameliorate severe hepatic steatosis in mice deficient in intrinsic estrogen.
Egawa
Tetsu
T
Department of Medicine, Kochi Medical School, Nankoku, 783-8505 Japan.
Toda
Katsumi
K
Nemoto
Yoshihisa
Y
Ono
Masafumi
M
Akisaw
Naoaki
N
Saibara
Toshiji
T
Hayashi
Yoshihiro
Y
Hiroi
Makoto
M
Enzan
Hideaki
H
Onishi
Saburo
S
D042964:Acyl-CoA Dehydrogenase / Q000235:genetics; D044942:Acyl-CoA Dehydrogenase, Long-Chain / Q000235:genetics; D042962:Acyl-CoA Oxidase / Q000235:genetics; D000818:Animals; D001054:Apolipoproteins A / Q000235:genetics; D001141:Aromatase / Q000172:deficiency / Q000235:genetics*; D015152:Blotting, Northern; D002374:Catalase / Q000235:genetics; D019392:Cytochrome P-450 CYP2E1 / Q000235:genetics; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D000072470:Cytochrome P450 Family 4; D005227:Fatty Acids / Q000378:metabolism; D005234:Fatty Liver / Q000188:drug therapy* / Q000473:pathology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D005838:Genotype; D024581:Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating) / Q000235:genetics; D008099:Liver / Q000737:chemistry / Q000201:enzymology / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010084:Oxidation-Reduction / Q000187:drug effects; D011804:Quinolines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D014280:Triglycerides / Q000097:blood / Q000378:metabolism
D001054:Apolipoproteins A; C465387:Cyp4a1protein, rat; D005227:Fatty Acids; D011804:Quinolines; D012333:RNA, Messenger; D014280:Triglycerides; C022205:apolipoprotein A-IV; D003577:Cytochrome P-450 Enzyme System; D002374:Catalase; D019392:Cytochrome P-450 CYP2E1; D001141:Aromatase; D000072470:Cytochrome P450 Family 4; D024581:Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating); D042962:Acyl-CoA Oxidase; D042964:Acyl-CoA Dehydrogenase; D044942:Acyl-CoA Dehydrogenase, Long-Chain; C108475:pitavastatin