Impact of cholesterol metabolism and the LXRα-SREBP-1c pathway on nonalcoholic fatty liver disease

  • Authors:
    • Makoto Nakamuta
    • Tatsuya Fujino
    • Ryoko Yada
    • Masayoshi Yada
    • Kenichiro Yasutake
    • Tsuyoshi Yoshimoto
    • Naohiko Harada
    • Nobito Higuchi
    • Masaki Kato
    • Motoyuki Kohjima
    • Akinobu Taketomi
    • Yoshihiko Maehara
    • Manabu Nakashima
    • Kazuhiro Kotoh
    • Munechika Enjoji
  • View Affiliations

  • Published online on: May 1, 2009     https://doi.org/10.3892/ijmm_00000170
  • Pages: 603-608
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Abstract

We previously studied fatty acid metabolism in the liver of nonalcoholic fatty liver disease (NAFLD) and reported the activation of the LXRα-SREBP-1c pathway in hepatocytes. LXRα regulates cholesterol metabolism as well as fatty acid metabolism, and its agonistic ligands are oxysterols. Moreover, there is some evidence that excess cholesterol intake is involved in the onset of NAFLD. Therefore, in this study, we examined the expression of cholesterol metabolism-associated genes in the NAFLD liver by real-time PCR. Expression of LXRα and ACAT1 was up-regulated in NAFLD and this was more noticeable in non-obese rather than in obese patients. Although the expression of the LDL receptor, which acts on cholesterol uptake, and of SREBP-2, a positive key regulator of cholesterol, was suppressed, the expression of enzymes that promote cholesterol synthesis was uniformly increased in NAFLD. Gene expression of apoB100 and microsomal triglyceride transfer protein, which are associated with VLDL secretion, and ABCG5, which is involved in cholesterol excretion, was significantly elevated in NAFLD. Because cholesterol accumulates in hepatocytes in NAFLD liver, cholesterol uptake and synthesis should be physiologically down-regulated. However, cholesterol synthesis was activated in NAFLD liver, meaning that cholesterol metabolism is dysregulated in NAFLD. Overproduction of cholesterol may lead to an increased level of oxysterols, activation of LXRα and SREBP-1c, and enhanced fatty acid synthesis.

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May 2009
Volume 23 Issue 5

Print ISSN: 1107-3756
Online ISSN:1791-244X

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APA
Nakamuta, M., Fujino, T., Yada, R., Yada, M., Yasutake, K., Yoshimoto, T. ... Enjoji, M. (2009). Impact of cholesterol metabolism and the LXRα-SREBP-1c pathway on nonalcoholic fatty liver disease. International Journal of Molecular Medicine, 23, 603-608. https://doi.org/10.3892/ijmm_00000170
MLA
Nakamuta, M., Fujino, T., Yada, R., Yada, M., Yasutake, K., Yoshimoto, T., Harada, N., Higuchi, N., Kato, M., Kohjima, M., Taketomi, A., Maehara, Y., Nakashima, M., Kotoh, K., Enjoji, M."Impact of cholesterol metabolism and the LXRα-SREBP-1c pathway on nonalcoholic fatty liver disease". International Journal of Molecular Medicine 23.5 (2009): 603-608.
Chicago
Nakamuta, M., Fujino, T., Yada, R., Yada, M., Yasutake, K., Yoshimoto, T., Harada, N., Higuchi, N., Kato, M., Kohjima, M., Taketomi, A., Maehara, Y., Nakashima, M., Kotoh, K., Enjoji, M."Impact of cholesterol metabolism and the LXRα-SREBP-1c pathway on nonalcoholic fatty liver disease". International Journal of Molecular Medicine 23, no. 5 (2009): 603-608. https://doi.org/10.3892/ijmm_00000170