Effects of a thyromimetic on apolipoprotein B-100 in rats.
We have studied the effects of a cardiac sparing thyromimetic, CGS 23425, on postprandial levels of triglycerides, abundance of apolipoprotein B (apo B) protein and hepatic apo B mRNA expression in rats. When compared with control rats, triglyceride clearance was significantly accelerated by treatment with CGS 23425. A full return to baseline values was achieved within 8 h after ingesting a large quantity of fat, as compared to >24 h in control animals. The abundance of apo B-100 protein in CGS 23425-treated hyperlipidemic rats decreased in a dose-dependent manner, but levels of apo B-48 were not significantly affected. Like L-tri-iodothyronine (L-T(3)), treatment with 30 microg/kg CGS 23425 for 6 or 9 days decreased the levels of apo B-100 protein by 80% and 40% respectively. This change was paralleled by a 27% reduction in hepatic apo B-100 mRNA. To investigate a potential mechanism of CGS 23425 action, we measured in vitro apo B mRNA editing activity in hepatocellular extract from control or CGS 23425-treated rats. Treatment with CGS 23425 increased activity of the hepatic apo B-100 editosome, apobec-1. In human hepatoma cells which lack apobec-1 activity, apo B-100 mRNA levels remained the same in cells treated with or without the agent. In summary, these observations show that CGS 23425 decreases the levels of apo B-100 in rats. This action of CGS 23425 involves apo B-100 mRNA editing activity.
Wada
Y
Y
Departments of Medicine and Biochemistry and Molecular Biology, University of Calgary, Calgary, Alberta, Canada.
Matsubara
S
S
Dufresne
J
J
Hargrove
G M
GM
Stephan
Z F
ZF
Steele
R E
RE
Wong
N C
NC
D000071479:APOBEC-1 Deaminase; D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D053299:Apolipoprotein B-100; D001055:Apolipoproteins B / Q000097:blood* / Q000235:genetics; D003564:Cytidine Deaminase / Q000502:physiology; D006038:Glyoxylates / Q000494:pharmacology*; D006801:Humans; D006937:Hypercholesterolemia / Q000097:blood; D008099:Liver / Q000378:metabolism; D008297:Male; D019518:Postprandial Period; D017393:RNA Editing / Q000187:drug effects; D012333:RNA, Messenger / Q000037:antagonists & inhibitors; D051381:Rats; D017207:Rats, Sprague-Dawley; D014280:Triglycerides / Q000097:blood; D014284:Triiodothyronine / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
D000924:Anticholesteremic Agents; D053299:Apolipoprotein B-100; D001055:Apolipoproteins B; C108180:CGS 23425; D006038:Glyoxylates; D012333:RNA, Messenger; D014280:Triglycerides; D014284:Triiodothyronine; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D000071479:APOBEC-1 Deaminase; C000605089:APOBEC1 protein, human; C000605091:Apobec1 protein, rat; D003564:Cytidine Deaminase