Regulation of hepatic cholesterol synthesis by a novel protein (SPF) that accelerates cholesterol biosynthesis.
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 alpha (PPAR-alpha)-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-alpha 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
Norihito
N
Department of Health Chemistry, Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
Jishage
Kou-ichi
K
Arita
Makoto
M
Watanabe
Miho
M
Kawase
Yosuke
Y
Nishikawa
Kiyotaka
K
Natori
Yasuhiro
Y
Inoue
Hiroyasu
H
Shimano
Hitoshi
H
Yamada
Nobuhiro
N
Tsujimoto
Masafumi
M
Arai
Hiroyuki
H
D000818:Animals; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism*; D002784:Cholesterol / Q000096:biosynthesis*; D002995:Clofibric Acid / Q000494:pharmacology; D005508:Food Deprivation; D005786:Gene Expression Regulation; D000960:Hypolipidemic Agents / Q000494:pharmacology; D008074:Lipoproteins / Q000235:genetics* / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D047493:PPAR alpha / Q000235:genetics / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism*
D002352:Carrier Proteins; D000960:Hypolipidemic Agents; D008074:Lipoproteins; D047493:PPAR alpha; D015534:Trans-Activators; C500212:tocopherol-associated protein, mouse; D002995:Clofibric Acid; D002784:Cholesterol