Abstract
Treatment of atherosclerotic disease often focuses on reducing plasma LDL-cholesterol or increasing plasma HDL-cholesterol. We examined in vitro the effects on HDL receptor [scavenger receptor class B type I (SR-BI)] activity of three classes of clinical and experimental plasma HDL-cholesterol-elevating compounds: niacin, fibrates, and HDL376. Fenofibrate (FF) and HDL376 were potent (IC50 ∼ 1 μM), direct inhibitors of SR-BI-mediated lipid transport in cells and in liposomes reconstituted with purified SR-BI. FF, a prodrug, was a more potent inhibitor of SR-BI than an activator of peroxisome proliferator-activated receptor a, a target of its active fenofibric acid (FFA) derivative. Nevertheless, FFA, four other fibrates (clofibrate, gemfibrozil, ciprofibrate, and bezafibrate), and niacin had little, if any, effect on SR-BI, suggesting that they do not directly target SR-BI in vivo. However, similarities of HDL376 treatment and SR-BI gene knockout on HDL metabolism in vivo (increased HDL-cholesterol and HDL particle sizes) and structure-activity relationship analysis suggest that SR-BI may be a target of HDL376 in vivo. HDL376 and other inhibitors may help elucidate SR-BI function in diverse mammalian models and determine the therapeutic potential of SR-BI-directed pharmaceuticals.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1832-1845 |
| Number of pages | 14 |
| Journal | Journal of Lipid Research |
| Volume | 48 |
| Issue number | 8 |
| DOIs | |
| State | Published - Aug 2007 |
| Externally published | Yes |
Fingerprint
Keywords
- Fenofibrate
- Fibrates
- HDL376
- High density lipoprotein
- Lipoprotein metabolism
- Niacin
- Scavenger receptor class B type I
- Structure-activity relationship
ASJC Scopus subject areas
- Endocrinology
Cite this
Influence of HDL-cholesterol-elevating drugs on the in vitro activity of the HDL receptor SR-BI. / Nieland, Thomas J F; Shaw, Jared T.; Jaipuri, Firoz A.; Maliga, Zoltan; Duffner, Jay L.; Koehler, Angela N.; Krieger, Monty.
In: Journal of Lipid Research, Vol. 48, No. 8, 08.2007, p. 1832-1845.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Influence of HDL-cholesterol-elevating drugs on the in vitro activity of the HDL receptor SR-BI
AU - Nieland, Thomas J F
AU - Shaw, Jared T.
AU - Jaipuri, Firoz A.
AU - Maliga, Zoltan
AU - Duffner, Jay L.
AU - Koehler, Angela N.
AU - Krieger, Monty
PY - 2007/8
Y1 - 2007/8
N2 - Treatment of atherosclerotic disease often focuses on reducing plasma LDL-cholesterol or increasing plasma HDL-cholesterol. We examined in vitro the effects on HDL receptor [scavenger receptor class B type I (SR-BI)] activity of three classes of clinical and experimental plasma HDL-cholesterol-elevating compounds: niacin, fibrates, and HDL376. Fenofibrate (FF) and HDL376 were potent (IC50 ∼ 1 μM), direct inhibitors of SR-BI-mediated lipid transport in cells and in liposomes reconstituted with purified SR-BI. FF, a prodrug, was a more potent inhibitor of SR-BI than an activator of peroxisome proliferator-activated receptor a, a target of its active fenofibric acid (FFA) derivative. Nevertheless, FFA, four other fibrates (clofibrate, gemfibrozil, ciprofibrate, and bezafibrate), and niacin had little, if any, effect on SR-BI, suggesting that they do not directly target SR-BI in vivo. However, similarities of HDL376 treatment and SR-BI gene knockout on HDL metabolism in vivo (increased HDL-cholesterol and HDL particle sizes) and structure-activity relationship analysis suggest that SR-BI may be a target of HDL376 in vivo. HDL376 and other inhibitors may help elucidate SR-BI function in diverse mammalian models and determine the therapeutic potential of SR-BI-directed pharmaceuticals.
AB - Treatment of atherosclerotic disease often focuses on reducing plasma LDL-cholesterol or increasing plasma HDL-cholesterol. We examined in vitro the effects on HDL receptor [scavenger receptor class B type I (SR-BI)] activity of three classes of clinical and experimental plasma HDL-cholesterol-elevating compounds: niacin, fibrates, and HDL376. Fenofibrate (FF) and HDL376 were potent (IC50 ∼ 1 μM), direct inhibitors of SR-BI-mediated lipid transport in cells and in liposomes reconstituted with purified SR-BI. FF, a prodrug, was a more potent inhibitor of SR-BI than an activator of peroxisome proliferator-activated receptor a, a target of its active fenofibric acid (FFA) derivative. Nevertheless, FFA, four other fibrates (clofibrate, gemfibrozil, ciprofibrate, and bezafibrate), and niacin had little, if any, effect on SR-BI, suggesting that they do not directly target SR-BI in vivo. However, similarities of HDL376 treatment and SR-BI gene knockout on HDL metabolism in vivo (increased HDL-cholesterol and HDL particle sizes) and structure-activity relationship analysis suggest that SR-BI may be a target of HDL376 in vivo. HDL376 and other inhibitors may help elucidate SR-BI function in diverse mammalian models and determine the therapeutic potential of SR-BI-directed pharmaceuticals.
KW - Fenofibrate
KW - Fibrates
KW - HDL376
KW - High density lipoprotein
KW - Lipoprotein metabolism
KW - Niacin
KW - Scavenger receptor class B type I
KW - Structure-activity relationship
UR - http://www.scopus.com/inward/record.url?scp=34548177832&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=34548177832&partnerID=8YFLogxK
U2 - 10.1194/jlr.M700209-JLR200
DO - 10.1194/jlr.M700209-JLR200
M3 - Article
C2 - 17533223
AN - SCOPUS:34548177832
VL - 48
SP - 1832
EP - 1845
JO - Journal of Lipid Research
JF - Journal of Lipid Research
SN - 0022-2275
IS - 8
ER -