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Pitavastatin ameliorates severe hepatic steatosis in aromatase-deficient (Ar−/−) mice

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Lipids

Abstract

Tamoxifen is a potent antagonist of estrogen, and hepatic steatosis is a frequent complication in adjuvant tamoxifen for breast cancer. Impaired hepatic FA β-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 β-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 β-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 β-oxidation activity. These findings demonstrate that pitavastatin is capable of restoring impaired FA β-oxidation in vivo via the peroxisome proliferator-activated receptor-α-mediated signaling pathway and is potent enough to ameliorate severe hepatic steatosis in mice deficient in intrinsic estrogen.

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Abbreviations

AOX:

peroxisomal acyl-CoA oxidase

Ar+/+ mouse:

wildtype mouse

apo:

apolipoprotein

Ar−/− mouse:

aromatase-deficient mouse

BMI:

body mass index

CYP2EI:

microsomal cytochrome P450 2E1

CYP4A1:

microsomal cytochrome P450 4A1

GAPDH:

glyceraldehyde-3-phosphate dehydrogenase

MCAD:

medium-chain acyl-CoA dehydrogenase

NASH:

nonalcoholic steatohepatitis

PPAR-α:

peroxisome proliferator-activated receptor-α

VLACS:

very long fatty acyl-CoA synthetase

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Authors and Affiliations

  1. Department of Medicine, Kochi Medical School, 783-8505, Nankoku, Japan

    Tetsu Egawa, Yoshihisa Nemoto, Masafumi Ono, Naoaki Akisawa, Toshiji Saibara & Saburo Onishi

  2. Department of Medical Chemistry, Kochi Medical School, 783-8505, Nankoku, Japan

    Katsumi Toda

  3. Department of Pathology, Kochi Medical School, 783-8505, Nankoku, Japan

    Yoshihiro Hayashi, Makoto Hiroi & Hideaki Enzan

Authors
  1. Tetsu Egawa
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  2. Katsumi Toda
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  3. Yoshihisa Nemoto
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  4. Masafumi Ono
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  5. Naoaki Akisawa
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  6. Toshiji Saibara
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  7. Yoshihiro Hayashi
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  8. Makoto Hiroi
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  9. Hideaki Enzan
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  10. Saburo Onishi
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Corresponding author

Correspondence to Toshiji Saibara.

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Egawa, T., Toda, K., Nemoto, Y. et al. Pitavastatin ameliorates severe hepatic steatosis in aromatase-deficient (Ar−/−) mice. Lipids 38, 519–523 (2003). https://doi.org/10.1007/s11745-003-1093-x

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  • DOI: https://doi.org/10.1007/s11745-003-1093-x

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