Paradoxical exacerbation of combined hyperlipidemia in human apolipoprotein A-II transgenic mice treated with fenofibrate.
Apolipoprotein (apo) A-II has been biochemically and genetically linked to familial combined hyperlipidemia. Human ApoA-II transgenic mice and peroxisome proliferator-activated receptor alpha (PPARalpha)-deficient mice share some similar phenotypic characteristics. The aim of this study was to determine whether a fibrate-induced PPARalpha activation corrects the combined hyperlipidemia present in human apoA-II transgenic mice. ApoA-II transgenic mice were treated with fenofibrate (250 mg/kg) for 13 days. After this period, they presented a remarkable 8-fold increase in plasma triglycerides. This was concomitant with a 4-fold increase in non-high-density lipoprotein (non-HDL) cholesterol, a quantitatively similar decrease in HDL cholesterol and a severe reduction in mouse plasma apoA-I and apoA-II. Fenofibrate stimulated liver fatty acid beta-oxidation, increased the transcriptional expression of carnitine palmitoyltransferase 1 and phospholipid transfer protein, and decreased expression of apoA-I and apoC-III. However, very-low-density lipoprotein (VLDL)-triglyceride production and lipoprotein lipase (LPL) activities and the expression of other PPARalpha target genes were similar in mice treated with vehicle and fenofibrate. Further, fenofibrate-treated mice presented decreased in vivo [3H]VLDL catabolism and decreased VLDL-triglyceride hydrolysis by exogenous LPL. Therefore, the paradoxical enhancement of hyperlipidemia in fenofibrate-treated apoA-II transgenic mice is mainly due to decreased VLDL catabolism and, also, to a partial impairment in PPARalpha-signaling.
Ribas
Vicent
V
Servei de Bioquímica i Institut de Recerca, Hospital de la Santa Creu i Sant Pau, 08025 Barcelona, Spain.
Palomer
Xavier
X
Roglans
Núria
N
Rotllan
Noemi
N
Fievet
Catherine
C
Tailleux
Anne
A
Julve
Josep
J
Laguna
Joan Carles
JC
Blanco-Vaca
Francisco
F
Escolà-Gil
Joan Carles
JC
D000818:Animals; D016633:Apolipoprotein A-II / Q000235:genetics*; D001483:Base Sequence; D008076:Cholesterol, HDL / Q000097:blood; D004195:Disease Models, Animal; D011345:Fenofibrate / Q000009:adverse effects*; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D006950:Hyperlipidemia, Familial Combined / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D000960:Hypolipidemic Agents / Q000009:adverse effects*; D008055:Lipids / Q000097:blood; D008071:Lipoprotein Lipase / Q000378:metabolism; D008079:Lipoproteins, VLDL / Q000097:blood; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D047493:PPAR alpha / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014280:Triglycerides / Q000097:blood
D016633:Apolipoprotein A-II; D008076:Cholesterol, HDL; D000960:Hypolipidemic Agents; D008055:Lipids; D008079:Lipoproteins, VLDL; D047493:PPAR alpha; D012333:RNA, Messenger; D014280:Triglycerides; C030106:very low density lipoprotein triglyceride; D008071:Lipoprotein Lipase; D011345:Fenofibrate