The peroxisome proliferator-activated receptor alpha (PPARalpha) agonist ciprofibrate inhibits apolipoprotein B mRNA editing in low density lipoprotein receptor-deficient mice: effects on plasma lipoproteins and the development of atherosclerotic lesions.
Low density lipoprotein receptor (LDLR)-deficient mice fed a chow diet have a mild hypercholesterolemia caused by the abnormal accumulation in the plasma of apolipoprotein B (apoB)-100- and apoB-48-carrying intermediate density lipoproteins (IDL) and low density lipoproteins (LDL). Treatment of LDLR-deficient mice with ciprofibrate caused a marked decrease in plasma apoB-48-carrying IDL and LDL but at the same time caused a large accumulation of triglyceride-depleted apoB-100-carrying IDL and LDL, resulting in a significant increase in plasma cholesterol levels. These plasma lipoprotein changes were associated with an increase in the hepatic secretion of apoB-100-carrying very low density lipoproteins (VLDL) and a decrease in the secretion of apoB-48-carrying VLDL, accompanied by a significant decrease in hepatic apoB mRNA editing. Hepatic apobec-1 complementation factor mRNA and protein abundance were significantly decreased, whereas apobec-1 mRNA and protein abundance remained unchanged. No changes in apoB mRNA editing occurred in the intestine of the treated animals. After 150 days of treatment with ciprofibrate, consistent with the increased plasma accumulation of apoB-100-carrying IDL and LDL, the LDLR-deficient mice displayed severe atherosclerotic lesions in the aorta. These findings demonstrate that ciprofibrate treatment decreases hepatic apoB mRNA editing and alters the pattern of hepatic lipoprotein secretion toward apoB-100-associated VLDL, changes that in turn lead to increased atherosclerosis.
Fu
Tao
T
Department of Pathology, Northwestern University Feinberg School of Medicine, 303 E Chicago Avenue, Chicago, IL 60611, USA.
Mukhopadhyay
Debnath
D
Davidson
Nicholas O
NO
Borensztajn
Jayme
J
D000818:Animals; D001011:Aorta / Q000378:metabolism; D001055:Apolipoproteins B / Q000378:metabolism*; D001161:Arteriosclerosis / Q000378:metabolism; D015153:Blotting, Western; D002784:Cholesterol / Q000378:metabolism; D002995:Clofibric Acid / Q000031:analogs & derivatives* / Q000494:pharmacology*; D003593:Cytoplasm / Q000378:metabolism; D005260:Female; D058607:Fibric Acids; D007413:Intestinal Mucosa / Q000378:metabolism; D050356:Lipid Metabolism; D008074:Lipoproteins / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D020025:Peroxisome Proliferators / Q000494:pharmacology*; D011092:Polyethylene Glycols / Q000494:pharmacology; D012313:RNA / Q000378:metabolism; D017393:RNA Editing; D012333:RNA, Messenger / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists*; D011973:Receptors, LDL / Q000235:genetics*; D013997:Time Factors; D014157:Transcription Factors / Q000819:agonists*; D014280:Triglycerides / Q000378:metabolism
D001055:Apolipoproteins B; D058607:Fibric Acids; D008074:Lipoproteins; D008077:Lipoproteins, LDL; D020025:Peroxisome Proliferators; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D011973:Receptors, LDL; D014157:Transcription Factors; D014280:Triglycerides; D011092:Polyethylene Glycols; D002995:Clofibric Acid; D012313:RNA; D002784:Cholesterol; C019304:ciprofibrate; C016811:tyloxapol