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Regulation of hepatic cholesterol synthesis by a novel protein (SPF) that accelerates cholesterol biosynthesis
Author(s) -
Shibata Norihito,
Jishage Kouichi,
Arita Makoto,
Watanabe Miho,
Kawase Yosuke,
Nishikawa Kiyotaka,
Natori Yasuhiro,
Inoue Hiroyasu,
Shimano Hitoshi,
Yamada Nobuhiro,
Tsujimoto Masafumi,
Arai Hiroyuki
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.06-6368fje
Subject(s) - medicine , endocrinology , cholesterol , triglyceride , chemistry , biosynthesis , peroxisome , liver x receptor , receptor , agonist , alpha (finance) , peroxisome proliferator activated receptor , nuclear receptor , enzyme , biology , biochemistry , transcription factor , construct validity , nursing , gene , patient satisfaction
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 dra‐matically 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 a (PPAR‐a)‐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‐a 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 FASEB J. 20, E2231–E2239 (2006)