Rosiglitazone and Fenofibrate Exacerbate Liver Steatosis in a Mouse Model of Obesity and Hyperlipidemia. A Transcriptomic and Metabolomic Study

Peroxisome proliferator-activated receptors (PPAR) play an important role in the regulation of lipid and glucose metabolism, inflammatory, and vascular responses. We show the effect of treatment with two PPAR agonists, fenofibrate (FF) and rosiglitazone (RSG), on <i>ob</i>/<i>ob</i> and LDLR-double deficient mice, by combined gene-expression and metabolomic analyses. Male mice were daily treated for 12 weeks with RSG (10 mg·kg^1–·day^–1 per os (p.o.), <i>n</i> = 8) and FF (50 mg·kg^1–·day^–1 p.o., <i>n</i> = 8). Twelve untreated <i>ob</i>/<i>ob</i> and LDLR-double deficient mice were used as controls. To integrate the transcriptomic and metabolomic results, we designed a hierarchical algorithm, based on the average linkage method in clustering. Data were also interpreted with the Ingenuity Pathway Analysis program. FF and RSG treatments significantly increased the hepatic triglyceride content in the liver when compared with the control group, and the treatments induced an increase in the number and size of hepatic lipid droplets. Both drugs simultaneously activate pro-steatotic and antisteatotic metabolic pathways with a well-ordered result of aggravation of the hepatic lipid accumulation. The present study is a cautionary note not only to researchers on the basic mechanism of the action of PPAR activators but also to the use of these compounds in clinical practice

Paraoxonase‑1 Deficiency Is Associated with Severe Liver Steatosis in Mice Fed a High-fat High-cholesterol Diet: A Metabolomic Approach

Oxidative stress is a determinant of liver steatosis and the progression to more severe forms of disease. The present study investigated the effect of paraoxonase-1 (PON1) deficiency on histological alterations and hepatic metabolism in mice fed a high-fat high-cholesterol diet. We performed nontargeted metabolomics on liver tissues from 8 male PON1-deficient mice and 8 wild-type animals fed a high-fat, high-cholesterol diet for 22 weeks. We also measured 8-oxo-20-deoxyguanosine, reduced and oxidized glutathione, malondialdehyde, 8-isoprostanes and protein carbonyl concentrations. Results indicated lipid droplets in 14.5% of the hepatocytes of wild-type mice and in 83.3% of the PON1-deficient animals (<i>P</i> < 0.001). The metabolomic assay included 322 biochemical compounds, 169 of which were significantly decreased and 16 increased in PON1-deficient mice. There were significant increases in lipid peroxide concentrations and oxidative stress markers. We also found decreased glycolysis and the Krebs cycle. The urea cycle was decreased, and the pyrimidine cycle had a significant increase in orotate. The pathways of triglyceride and phospholipid synthesis were significantly increased. We conclude that PON1 deficiency is associated with oxidative stress and metabolic alterations leading to steatosis in the livers of mice receiving a high-fat high-cholesterol diet