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We sought to determine whether a combination of purified n-3 fatty acids (n-3) and SC-560 (SC), a cyclooxygenase-1-specific inhibitor, is effective in ameliorating nonalcoholic fatty liver disease in obesity. Female wild-type mice were fed a high-fat and high-cholesterol diet (HF) supplemented with n-3 in the presence or absence of SC. Mice treated with SC alone exhibited no change in liver lipids, whereas n-3-fed mice tended to have lower hepatic lipids. Mice given n-3+SC had significantly lower liver lipids compared with HF controls indicating enhanced lipid clearance. Total and sulfated bile acids were significantly higher only in n-3+SC-treated mice compared with chow diet (CD) controls. Regarding mechanisms, the level of pregnane X receptor (PXR), a nuclear receptor regulating drug/bile detoxification, was significantly higher in mice given n-3 or n-3+SC. Studies in precision-cut liver slices and in cultured hepatoma cells showed that n-3+SC enhanced not only the expression/activation of PXR and its target genes but also the expression of farnesoid X receptor (FXR), another regulator of bile synthesis/clearance, indicating that n-3+SC can induce both PXR and FXR. The mRNA level of FGFR4 which inhibits bile formation showed a significant reduction in Huh 7 cells upon n-3 and n-3+SC treatment. PXR overexpression in hepatoma cells confirmed that n-3 or SC each induced the expression of PXR target genes and in combination had an enhanced effect. Our findings suggest that combining SC with n-3 potentiates its lipid-lowering effect, in part, by enhanced PXR and/or altered FXR/FGFR4 signaling., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objective: PPAR-gamma agonists such as thiazolidinediones, used in patients with insulin resistance have been shown to reduce neointimal hyperplasia in the short term. However recent studies suggest increased cardiovascular risk for some thiazolidinediones. Longer-term animal studies show inhibition of endothelial regrowth post endothelial injury which may account for some of the increased risk. We studied the effect of pioglitazone on VEGF, FGF and insulin stimulated endothelial cells to determine if this was a mechanism of inhibition of endothelial regrowth., Methods and Results: FGF/VEGF stimulated human umbilical vein endothelial cell (HUVEC) proliferation and apoptosis was measured, in vitro, in the presence and absence of hyperinsulinemia, with and without treatment with the PPAR-gamma agonist pioglitazone. Activation of ERK 1/2 and p38MAPK was measured under the same conditions. There was 40% decrease in proliferation with pioglitazone in VEGF stimulated cells, which was reversed by insulin. ERK 1/2 activation was decreased by pioglitazone in VEGF stimulated cells and was partially reversed by insulin. p38MAPK activation was increased by pioglitazone and was unaffected by insulin or VEGF. Pioglitazone also increased endothelial cell apoptosis., Conclusion: PPAR-gamma agonists may have detrimental cardiovascular effects post angioplasty especially in patients with insulin resistance. We have shown that one of the mechanisms may be inhibition of endothelial regrowth and re-endothelialization by inhibition of VEGF/FGF stimulation of the ERK 1/2 pathways in endothelial cells.

Objective: Insulin resistance is an independent risk factor for cardiovascular disease. PPAR-gamma agonists like pioglitazone decrease insulin resistance and have been shown to reduce neointimal hyperplasia in the short-term. However long-term studies on endothelial regrowth and neointimal hyperplasia have not been done., Methods and Results: We used hyperinsulinemic, normoglycemic Zucker fatty rats. Rats were treated with either 10 mg/kg body wt. pioglitazone or placebo till the end of the experiment. Rats underwent carotid angioplasty at age 12-14 weeks, 1 week after treatment was begun. In one set of experiments rats were sacrificed at 6 months and neointimal hyperplasia and VEGF expression was assessed. In another set of experiments rats were sacrificed at 3 and 6 months. Endothelial regrowth was determined. The rats were all normoglycemic and hyperinsulinemic. Pioglitazone treated rats had a significantly lesser degree of neointimal hyperplasia than control rats. Treated rats also had decreased VEGF expression. Endothelial regrowth was decreased in the treated rats at 6 months., Conclusion: We conclude that although pioglitazone decreases neointimal hyperplasia even at 6 months, it retards endothelial regrowth, which could predispose the denuded vessel to thrombotic events. This may be modulated by a suppression of VEGF expression.