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 ob/ob 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.), n = 8) and FF (50 mg·kg(1-)·day(-1) p.o., n = 8). Twelve untreated ob/ob 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.
Unitat de Recerca Biomèdica (CRB-URB), Hospital Universitari de Sant Joan, Institut d'Investigació Sanitària Pere Virgili (IISPV), Universitat Rovira i Virgili , Reus, Spain.
Anna
A
Rull
Benjamine
B
Geeraert
Gerard
G
Aragonès
Raúl
R
Beltrán-Debón
Esther
E
Rodríguez-Gallego
Anabel
A
García-Heredia
Juan
J
Pedro-Botet
Jorge
J
Joven
Paul
P
Holvoet
Jordi
J
Camps
D000818:Animals; D004195:Disease Models, Animal; D005234:Fatty Liver / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D011345:Fenofibrate / Q000009:adverse effects*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D006949:Hyperlipidemias / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D007004:Hypoglycemic Agents / Q000009:adverse effects*; D000960:Hypolipidemic Agents / Q000009:adverse effects*; D008099:Liver / Q000737:chemistry / Q000378:metabolism / Q000473:pathology; D008297:Male; D055442:Metabolome; D051379:Mice; D008822:Mice, Transgenic; D009765:Obesity / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D047492:Peroxisome Proliferator-Activated Receptors / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D025941:Protein Interaction Mapping; D000077154:Rosiglitazone; D015398:Signal Transduction; D045162:Thiazolidinediones / Q000009:adverse effects*; D059467:Transcriptome
D007004:Hypoglycemic Agents; D000960:Hypolipidemic Agents; D047492:Peroxisome Proliferator-Activated Receptors; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D011345:Fenofibrate