Hepatic overexpression of microsomal triglyceride transfer protein (MTP) results in increased in vivo secretion of VLDL triglycerides and apolipoprotein B.
The microsomal triglyceride transfer protein (MTP) is essential for the hepatic secretion of apolipoprotein (apo) B-containing lipoproteins. Previous studies have indicated that inhibition of MTP results in decreased apoB plasma levels and decreased hepatic triglyceride secretion. However, the metabolic effects of overexpression of MTP have not been investigated. We constructed a recombinant adenovirus expressing MTP (AdhMTP) and used it to assess the effects of hepatic overexpression of MTP in mice. Injection of AdhMTP into C57BL/6 mice resulted in a 3-fold increase in hepatic microsomal triglyceride transfer activity compared to mice injected with Adnull. On day 4 after virus injection, AdhMTP-injected mice had significantly elevated plasma TG levels as compared to control virus (Adnull)-injected mice. Hepatic TG secretion rates were significantly greater in AdhMTP-injected mice (184 +/- 12 mg/kg/h) compared with Adnull-injected mice (65 +/- 9 mg/kg/h, P < 0.001). In addition, hepatic very low density lipoprotein (VLDL) apoB secretion in the AdhMTP-injected group was 74% higher than in the control virus group. Hepatic secretion of apoB-48 and apoB-100 contributed equally to this increase. These results provide the first data that hepatic overexpression of MTP results in increased secretion of VLDL-triglycerides as well as VLDL-apoB in vivo. These results suggest that MTP is rate-limiting for VLDL apoB secretion in wild-type mice under basal chow-fed conditions.
Tietge
U J
UJ
Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Bakillah
A
A
Maugeais
C
C
Tsukamoto
K
K
Hussain
M
M
Rader
D J
DJ
D000818:Animals; D001055:Apolipoproteins B / Q000187:drug effects / Q000378:metabolism; D019556:COS Cells; D002352:Carrier Proteins / Q000494:pharmacology*; D005260:Female; D015870:Gene Expression; D006801:Humans; D007553:Isotope Labeling; D007700:Kinetics; D008079:Lipoproteins, VLDL / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000737:chemistry* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008862:Microsomes, Liver / Q000737:chemistry; D013462:Sulfur Radioisotopes / Q000493:pharmacokinetics; D014162:Transfection; D014280:Triglycerides / Q000378:metabolism
D001055:Apolipoproteins B; D002352:Carrier Proteins; D008079:Lipoproteins, VLDL; D013462:Sulfur Radioisotopes; D014280:Triglycerides; C106092:microsomal triglyceride transfer protein