Figure 5.

Circulating systemic sPLA ₂ modulates hepatic transcriptional responses to dietary cholesterol supplementation. A, Plasma sPLA ₂ activity ofMmp9 ^−/− mice administered the pan‐sPLA ₂ inhibitor varespladib (10 mg/kg per day) or vehicle for 5 days (n=4 mice per group). *P<0.05 vs WT, t test. ^† P<0.05 vs untreated, t test. B, Study protocol for varespladib treatment prior to cholesterol supplementation. Mice were fed either regular chow or chow supplemented with 0.15% cholesterol for 2.5 days. Varespladib treatment (10 mg/kg per day for 5 days) started 2.5 days prior to commencement of cholesterol supplementation of the diet. C, Hepatic expression of lipid metabolic genes in WT mice administered varespladib (10 mg/kg per day; n=8 WT without varespladib and n=8 WT with varespladib mice, n=4 per time point). *P≤0.05 vs WT without varespladib at day 2.5. ^† P<0.05 vs day 0. All pairwise multiple comparisons vs control group (Holm–Sidak method), ANOVA. D, Hepatic expression of lipid‐metabolic genes in Mmp9 ^−/− mice administered varespladib (10 mg/kg per day; n=8 Mmp9 ^−/− without varespladib and n=8 Mmp9 ^−/− with varespladib, n=4 per time point). *P<0.05 vs Mmp9 ^−/− without varespladib at day 2.5. ^† P<0.05 vs day 0. All pairwise multiple comparisons vs control group (Holm–Sidak method), ANOVA. Abca1 indicates ATP‐binding cassette sub‐family A member 1; Abcg5/Abcg8, ATP‐binding cassette sub‐family G member 5/8; Cyp27a1, sterol 27 hydroxylase; Cyp7a1, cholesterol 7 alpha hydroxylase; Fasn, fatty acid synthase; Hmgcr, 3‐hydroxy‐3‐methyl‐glutaryl‐coenzyme A reductase; Ldlr, low density lipoprotein receptor; LXR, liver X receptor; Mmp, matrix metalloproteinase gene; MMP, matrix metalloproteinase; Nr1h3/Nr1h2, liver X receptor α/β; Pcsk9, proprotein convertase subtilisin/kexin type 9; sPLA₂, secreted phospholipase A₂; Srebf1, sterol regulatory element binding protein 1; Srebf2, gene for sterol regulatory element binding protein 2; SREBP, sterol regulatory element binding protein; WT, wild type.