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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 and Hiroyuki Arai^*,1

^* Department of Health Chemistry, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan;

Laboratory of Cellular Biochemistry, Riken, Saitama, Japan;

Pharmacology and Pathology Research Center, Chugai Research Institute For Medical Science, Inc., Shizuoka, Japan;

Department of Clinical Pharmacology, Research Institute, International Medical Center of Japan, Tokyo, Japan;

^|| Department of Food Science and Nutrition, Faculty of Human Life and Environment, Nara Women’s University, Nara, Japan; and

^¶ Department of Internal Medicine, Institute of Clinical Medicine, University of Tsukuba, Ibaraki, Japan

¹Correspondence: Department of Health Chemistry, Graduate School of Pharmaceutical Sciences, University of Tokyo, 7–3-1, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. E-mail: harai{at}mol.f.u-tokyo.ac.jp

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 (PPAR-)-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- 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.—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. Regulation of hepatic cholesterol synthesis by a novel protein (SPF) that accelerates cholesterol biosynthesis