title: The effect of diet on the response of low-density lipoprotein receptor knockout mice to the liver X receptor agonist T1317.
abstract: It has been previously observed that low-density lipoprotein receptor knockout (LDLR--/--) mice fed a Western-type diet without cholate and given the liver X receptor agonist T1317 develop a persistent and enhanced hypertriglyceridemia. In contrast, LDLR--/-- mice fed a Paigen diet with cholate exhibit only a transient increase in plasma triglycerides when given T1317. Cholate as an activator of farnesoid X receptor may attenuate T1317-induced triglyceridemia. To determine if cholate was responsible for this transient nature of the hypertriglyceridemia, we orally administered T1317 to LDLR--/-- mice fed a modified Paigen diet without cholate. T1317 transiently elevated plasma triglycerides by increasing plasma very-low-density lipoprotein. Cholesterol and triglyceride levels in plasma very-low-density lipoprotein in T1317-treated mice decreased from peak levels to levels found in vehicle-treated mice after 8 weeks of treatment. A gradual decline of hepatic cholesterol and a transient increase in hepatic triglycerides were also observed in T1317-treated mice. T1317 only transiently activated the expression of genes related to liver de novo lipogenesis, whereas genes related to lipid metabolism were induced in T1317-treated mice, including a gradual increase in plasma lipoprotein lipase activity. Atheroprotective effects of T1317 were observed in the innominate artery and aortic arch but not in the aortic sinus. This work indicates that some component(s) in the Paigen diet other than cholate affect the T1317-induced gene expression profile and ameliorate its effects on lipid synthesis, which lead to hypertriglyceridemia and fatty liver. These findings are important for liver X receptor-related pharmaceutical development for the treatment of cardiovascular disease.
authors.affiliation: Section of Cardiology, Department of Internal Medicine, JiShuiTan Hospital, Beijing, PR China. dpeng@uchicago.edu
authors.forename: Lu
authors.initials: L
authors.lastname: Peng
authors.forename: Richard A
authors.initials: RA
authors.lastname: Hiipakka
authors.forename: Jing-Tian
authors.initials: JT
authors.lastname: Xie
authors.forename: John M
authors.initials: JM
authors.lastname: Kokontis
authors.forename: Shutsung
authors.initials: S
authors.lastname: Liao
authors.forename: Dacheng
authors.initials: D
authors.lastname: Peng
mesh_terms: D000818:Animals; D020355:Cholates / Q000008:administration & dosage*; D004041:Dietary Fats / Q000008:administration & dosage*; D020869:Gene Expression Profiling / Q000379:methods; D006845:Hydrocarbons, Fluorinated / Q000008:administration & dosage*; D000071518:Liver X Receptors; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D057093:Orphan Nuclear Receptors / Q000819:agonists* / Q000502:physiology; D011973:Receptors, LDL / Q000172:deficiency* / Q000235:genetics; D013449:Sulfonamides / Q000008:administration & dosage*; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
chemical_list: D020355:Cholates; D004041:Dietary Fats; D006845:Hydrocarbons, Fluorinated; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D011973:Receptors, LDL; D013449:Sulfonamides; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides