Regulation of hepatic cholesterol synthesis by a novel protein (SPF) that accelerates cholesterol biosynthesis

Norihito Shibata, Kou Ichi Jishage, Makoto Arita, Miho Watanabe, Yosuke Kawase, Kiyotaka Nishikawa, Yasuhiro Natori, Hiroyasu Inoue, Hitoshi Shimano, Nobuhiro Yamada, Masafumi Tsujimoto, Hiroyuki Arai

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

Supernatant protein factor (SPF) is a novel cholesterol biosynthesis-accelerating protein expressed in liver and small intestine. Here, we report on the physiological role of SPF by using Spf-deficient mice. Although plasma cholesterol levels were similar in chow-fed Spf-/- and wild-type (WT) mice, fasting significantly decreased plasma cholesterol levels in Spf-/- mice but not in WT mice. While fasting reduced hepatic cholesterol synthesis rate in WT mice, a more pronounced reduction was observed in Spf-/- mice. The expression of cholesterogenic enzymes was dramatically suppressed by fasting both in WT and Spf-/- mice. In contrast, hepatic SPF expression of WT mice was up-regulated by fasting in peroxisome proliferator-activated receptor α (PPAR-α)-dependent manner. These results indicate that in WT mice, the decrease of hepatic cholesterol synthesis under fasting conditions is at least in part compensated by SPF up-regulation. Fibrates, which function as a PPAR-α agonist and are widely used as hypotriglycemic drugs, reduced hepatic cholesterol synthesis and plasma cholesterol levels by approximately one-half in Spf-/- mice but not in WT mice. These findings suggest that co-administration of fibrates and an SPF inhibitor may reduce not only plasma triglyceride but also cholesterol levels, indicating that SPF is a promising hypocholesterolemic drug target.

Original languageEnglish
Pages (from-to)E2231-E2239
JournalFASEB Journal
Volume20
Issue number14
DOIs
Publication statusPublished - 2006 Dec 1
Externally publishedYes

Keywords

  • Fasting
  • Fibrate
  • Peroxisome proliferator-activated receptor α
  • Squalene monooxygenase

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

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  • Cite this

    Shibata, N., Jishage, K. I., Arita, M., Watanabe, M., Kawase, Y., Nishikawa, K., Natori, Y., Inoue, H., Shimano, H., Yamada, N., Tsujimoto, M., & Arai, H. (2006). Regulation of hepatic cholesterol synthesis by a novel protein (SPF) that accelerates cholesterol biosynthesis. FASEB Journal, 20(14), E2231-E2239. https://doi.org/10.1096/fj.06-6368fje