Overexpression of SR-BI by adenoviral vector reverses the fibrateinduced hypercholesterolemia of apolipoprotein E-deficient mice.

Abstract

The hypercholesterolemia characteristic of apolipoprotein (apoE)-deficient mice fed on a regular chow diet is caused by the abnormal accumulation of apoB-48-carrying remnants of chylomicrons and very low density lipoproteins in the plasma. Treatment of apoE-deficient mice with ciprofibrate or other peroxisome proliferator-activated receptor alpha agonists severely aggravates their hypercholesterolemia by interfering with one or more mechanisms of remnant removal from the circulation that do not require mediation by apoE (Fu, T., Kashireddy, P., and Borensztajn, J. (2003) Biochem. J. 373, 941-947). In the present investigation we report that ciprofibrate treatment causes the down-regulation of hepatic scavenger receptor class B, type I (SR-BI) protein expression in the livers of apoE-deficient mice. On cessation of the treatment SR-BI expression returns to its pretreatment levels, coinciding with a reversal of the hypercholesterolemia to base-line concentrations. Restoration of SR-BI expression in ciprofibrate-treated apoE-deficient mice by recombinant adenoviral gene transfer abolishes the ciprofibrate-induced over accumulation of apoB-48-carrying remnants in the plasma. We also report that remnants isolated from the plasma of ciprofibrate-treated apoE-deficient mice bind to murine SR-BI expressed in stably transfected cultured cells. These observations suggest that, in addition to its well established role as high density lipoprotein receptor, SR-BI can also function as a remnant receptor responsible for the clearance of remnants from the circulation of apoE-deficient mice.

• Authors: Tao Fu, Karen F Kozarsky, Jayme Borensztajn
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 278 Issue 52 Pg. 52559-63 (Dec 26 2003) ISSN: 0021-9258 [Print] United States
• PMID: 14570884 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Apolipoproteins E
• CD36 Antigens
• Fibric Acids
• Hypolipidemic Agents
• Membrane Proteins
• Peroxisome Proliferators
• Receptors, Cytoplasmic and Nuclear
• Receptors, Immunologic
• Receptors, Lipoprotein
• Receptors, Scavenger
• Scarb1 protein, mouse
• Scavenger Receptors, Class B
• Succinimides
• Transcription Factors
• cholesteryl 5-carboxypentyl ether N-hydroxysuccinimide ester
• Clofibric Acid
• Cholesterol
• ciprofibrate

Topics

• Adenoviridae (genetics)
• Animals
• Apolipoproteins E (genetics, physiology)
• CD36 Antigens (metabolism)
• CHO Cells
• Cholesterol (analogs & derivatives, metabolism, pharmacology)
• Clofibric Acid (analogs & derivatives, pharmacology)
• Cricetinae
• Down-Regulation
• Female
• Fibric Acids
• Gene Transfer Techniques
• Genetic Vectors
• Hypercholesterolemia (metabolism)
• Hypolipidemic Agents (pharmacology)
• Immunoblotting
• Liver (metabolism)
• Membrane Proteins
• Mice
• Mice, Inbred C57BL
• Peroxisome Proliferators (pharmacology)
• Receptors, Cytoplasmic and Nuclear (antagonists & inhibitors)
• Receptors, Immunologic
• Receptors, Lipoprotein
• Receptors, Scavenger
• Scavenger Receptors, Class B
• Succinimides (pharmacology)
• Time Factors
• Transcription Factors (antagonists & inhibitors)
• Transfection