Table 4 Effects baricitinib-ly3009104 of AZ876 and GW3965 on plasma cytokines Figure 6 To investigate the effect of 5 or 20 ��mol?kg?1?day?1 AZ876 or GW3965 (17 ��mol?kg?1?day?1) on vessel wall inflammation, monocytes were stained in the aortic root (A). The number … Discussion In this study, we evaluated the effect of the novel LXR agonist AZ876 on plasma lipid levels and atherosclerosis in hyperlipidaemic APOE*3Leiden transgenic mice. AZ876 and GW3965 both markedly inhibited atherosclerosis development, whereas AZ876 induced a more stable lesion phenotype. Additionally, AZ876 showed no adverse effects when given in low dose, pointing to dose-dependency of the effects induced by AZ876. The results of the present study confirm the findings of previous studies in APOE*3Leiden (Grefhorst et al., 2002;Verschuren et al.

, 2009), LDLr�C/�C (Terasaka et al., 2003) and apoE�C/�C (Dai et al., 2007) mice with another LXR agonist, T0901317, with regard to elevation of plasma triglyceride and HDL levels and reduction of atherosclerosis. In wild-type mice, GW3965 (20�C100 mg?kg?1?day?1) has been reported to be a tissue- and gene-selective modulator of LXR activity with less lipogenic effects than T0901317 after a 3 day treatment (Miao et al., 2004). Also in LDLr�C/�C mice, GW3965 (10 mg?kg?1?day?1) did not affect plasma or liver lipid levels when administered for 8 weeks (Quinet et al., 2009). In contrast to these latter reports, we showed that in a more sensitive model of hyperlipidaemia, the APOE*3Leiden mouse, even a relatively low dose of GW3965 given for 20 weeks (17 ��mol?kg?1?day?1, ~10 mg?kg?1?day?1) increased plasma triglyceride levels.

The low dose of 5 ��mol?kg?1?day?1 AZ876 did not affect plasma triglycerides; however, Entinostat the high dose of 20 ��mol?kg?1?day?1 AZ876 did induce hypertriglyceridaemia indicative of a dose-dependent effect. Next to the undesired induction of hypertriglyceridaemia, GW3965 and 20 ��mol?kg?1?day?1 AZ876 increased HDL levels, thereby resembling findings described for T0901317 and fenofibrate-treated APOE*3Leiden mice (Kooistra et al., 2006;Verschuren et al., 2009), as reflected by the appearance of a large cholesteryl ester-rich HDL-1 particle in the lipoprotein profile, containing mainly the apoE, and to a minor extent apoB and no apoAI (Gruen et al., 2005). The appearance of this large HDL-1 particle upon LXR agonist treatment is specific for species without CETP and may have atheroprotective effects by supporting apoAI-independent cholesterol efflux (Jiang et al., 1992). In species containing CETP, like hamsters and cynomolgus monkeys (Groot et al., 2005; Quinet et al., 2009) and APOE*3Leiden.CETP transgenic mice (PCN Rensen and HMG Princen, unpubl. data), this HDL is absent via the action of CETP.