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

FASEB J. 2006 Dec;20(14):2642-4. doi: 10.1096/fj.06-6368fje. Epub 2006 Oct 31.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carrier Proteins / genetics*
  • Carrier Proteins / metabolism*
  • Cholesterol / biosynthesis*
  • Clofibric Acid / pharmacology
  • Food Deprivation
  • Gene Expression Regulation
  • Hypolipidemic Agents / pharmacology
  • Lipoproteins / genetics*
  • Lipoproteins / metabolism*
  • Liver / drug effects
  • Liver / metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • PPAR alpha / genetics
  • PPAR alpha / metabolism
  • Trans-Activators / genetics*
  • Trans-Activators / metabolism*


  • Carrier Proteins
  • Hypolipidemic Agents
  • Lipoproteins
  • PPAR alpha
  • Trans-Activators
  • tocopherol-associated protein, mouse
  • Clofibric Acid
  • Cholesterol