Triglyceridemia and peroxisome proliferator-activated receptor-alpha expression are not connected in fenofibrate-treated pregnant rats.
To investigate the response to fenofibrate in pregnant rats, 0 mg, 100 mg or 200 mg of fenofibrate per kilogram body weight oral doses were given twice a day from day 16 of gestation and studied at day 20. Virgin rats were studied in parallel. Whereas in pregnant rats plasma triglycerides significantly increased, in virgin rats, fenofibrate decreased plasma triglycerides which accumulated in liver. Fenofibrate faithfully modulated the hepatic expression of PPARalpha responsive genes. Fenofibrate increased mRNA contents corresponding to both acyl-CoA oxidase, carnitine palmitoyltransferase (CPT), and peroxisome proliferator-activated receptor alpha (PPAR), and lowered mRNA amounts of apolipoproteins B and C-III, both in virgin and pregnant rats. However, genes related to hepatic lipogenesis, such as PPARy and stearoyl-CoA desaturase (SCD), showed an augmented expression by fenofibrate in virgin rats, but not in pregnant animals. We propose that the opposite effects of fenofibrate treatment in virgin and pregnant rats are a consequence of the enhanced capability for VLDL-triglyceride production in the latter, further promoted by the elevated amount of free fatty acids (FFA), which reach the liver in treated pregnant rats and were not sufficiently oxidized and/or stored, and therefore would have to be canalized as triglycerides to the plasma. Thus, the present study shows how fenofibrate, in spite of efficiently exerting its expected molecular effects in the liver (i.e., to induce fatty acid and lipoprotein catabolism, and to reduce TG-rich lipoprotein secretion), was unable to reverse the typical hypertriglyceridaemia of gestation.
Soria
Ana
A
Facultad de Farmacia, Universidad San Pablo-CEU, Montepríncipe, Boadilla del Monte, Madrid, Spain.
González
Maria del Carmen
Mdel C
Vidal
Hubert
H
Herrera
Emilio
E
Bocos
Carlos
C
D042962:Acyl-CoA Oxidase / Q000378:metabolism; D000818:Animals; D002334:Carnitine O-Palmitoyltransferase / Q000235:genetics / Q000378:metabolism; D005260:Female; D011345:Fenofibrate / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects; D000960:Hypolipidemic Agents / Q000494:pharmacology*; D008079:Lipoproteins, VLDL / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D047493:PPAR alpha / Q000378:metabolism*; D047495:PPAR gamma / Q000378:metabolism; D011247:Pregnancy; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013230:Stearoyl-CoA Desaturase / Q000235:genetics / Q000378:metabolism; D014280:Triglycerides / Q000097:blood* / Q000378:metabolism
D000960:Hypolipidemic Agents; D008079:Lipoproteins, VLDL; D047493:PPAR alpha; D047495:PPAR gamma; D012333:RNA, Messenger; D014280:Triglycerides; C030106:very low density lipoprotein triglyceride; D013230:Stearoyl-CoA Desaturase; D042962:Acyl-CoA Oxidase; D002334:Carnitine O-Palmitoyltransferase; D011345:Fenofibrate