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A synthetic farnesoid X receptor (FXR) agonist promotes cholesterol lowering in models of dyslipidemia.
- Source :
-
American journal of physiology. Gastrointestinal and liver physiology [Am J Physiol Gastrointest Liver Physiol] 2009 Mar; Vol. 296 (3), pp. G543-52. Date of Electronic Publication: 2009 Jan 08. - Publication Year :
- 2009
-
Abstract
- The nuclear hormone receptor farnesoid X receptor (FXR) plays a critical role in the regulation of bile acid, triglyceride (TG), and cholesterol homeostasis. WAY-362450 (FXR-450/XL335) is a potent synthetic FXR agonist as characterized in luciferase reporter assays and in mediating FXR target gene regulation in primary human and immortalized mouse hepatocytes. In vivo, WAY-362450 dose dependently decreased serum TG levels after 7 days of oral dosing in western diet-fed low-density lipoprotein receptor-/- mice and in the diabetic mouse strains KK-Ay and db/db comparable to that achieved with the peroxisome proliferator activated receptor-alpha agonist, fenofibrate. WAY-362450 treatment also reduced serum cholesterol levels via reductions in LDLc, VLDLc, and HDLc lipoprotein fractions that were not accompanied by hepatic cholesterol accumulation. This cholesterol lowering was dependent on FXR as demonstrated in a hypothyroid-induced hypercholesterolemia setting in FXR-/- mice. In fructose-fed models, WAY-362450 also decreased TG and VLDLc levels in rats and hamsters but significantly increased HDLc levels in rats while reducing HDLc levels in hamsters. The differential effect of WAY-362450 on HDLc is likely due to a murine-specific induction of endothelial lipase and scavenger receptor-BI that does not occur in rats. These studies demonstrate a consistent ability of WAY-362450 to lower both serum TG and cholesterol levels and suggest that synthetic FXR agonists may have clinical utility in the treatment of mixed dyslipidemia.
- Subjects :
- Animals
Apolipoprotein A-I blood
Apolipoprotein A-I genetics
Azepines chemistry
Cells, Cultured
Cholesterol pharmacology
DNA-Binding Proteins metabolism
Disease Models, Animal
Dyslipidemias complications
Female
Fructose pharmacology
Humans
Hyperglycemia complications
Hyperglycemia genetics
Hyperinsulinism complications
Hyperinsulinism genetics
Indoles chemistry
Kidney cytology
Male
Mice
Mice, Inbred C57BL
Mice, Mutant Strains
Mice, Transgenic
Rats
Rats, Sprague-Dawley
Receptors, Cytoplasmic and Nuclear metabolism
Receptors, LDL genetics
Receptors, Leptin genetics
Transcription Factors metabolism
Triglycerides blood
Azepines pharmacology
Cholesterol blood
DNA-Binding Proteins agonists
Dyslipidemias drug therapy
Dyslipidemias metabolism
Indoles pharmacology
Receptors, Cytoplasmic and Nuclear agonists
Transcription Factors agonists
Subjects
Details
- Language :
- English
- ISSN :
- 0193-1857
- Volume :
- 296
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- American journal of physiology. Gastrointestinal and liver physiology
- Publication Type :
- Academic Journal
- Accession number :
- 19136377
- Full Text :
- https://doi.org/10.1152/ajpgi.90585.2008