Post-transcriptional stimulation of the assembly and secretion of triglyceride-rich apolipoprotein B lipoproteins in a mouse with selective deficiency of brown adipose tissue, obesity, and insulin resistance.
A mouse model of insulin resistance and its associated dyslipidemia was generated by crossing mice expressing human apolipoprotein B (apoB) with mice lacking only brown adipose tissue (BATless). On a high fat diet, male apoB/BATless mice became obese, hypercholesterolemic, hypertriglyceridemic, and hyperinsulinemic compared with control apoB mice. Fast performance liquid chromatography revealed increased triglyceride concentrations in intermediate density lipoprotein/low density lipoprotein (LDL) and reduced high density lipoprotein cholesterol concentrations. Inhibition of lipolysis by the drug, tetrahydrolipostatin, demonstrated that very low density lipoprotein-sized particles were initially secreted. Metabolic studies employing Triton WR-1339 and either [(3)H]glycerol or [(3)H]palmitate showed that the hypertriglyceridemia in apoB/BATless mice was due to the increased synthesis and secretion of triglyceride. Furthermore, lipoprotein lipase and hepatic lipase activities were not defective. ApoB was also secreted at increased rates in the apoB/BATless mice. Similar levels of apoB mRNA in apoB and apoB/BATless mice indicated that apoB secretion was regulated post-transcriptionally. LDL receptor mRNA was increased in the apoB/BATless mice, indicating that the observed increase in apoB-lipoprotein secretion was not due to their decreased reuptake. Finally, mRNA levels of the large subunit of microsomal triglyceride transfer protein, a required component for very low density protein assembly, were not different between apoB and apoB/BATless mice. This rodent model should prove useful in exploring mechanisms underlying the regulation of apoB secretion in the context of insulin resistance.
Siri
P
P
Division of Preventive Medicine & Nutrition, Department of Medicine, College of Physicians & Surgeons, Columbia University, New York, New York 10032, USA.
Candela
N
N
Zhang
Y L
YL
Ko
C
C
Eusufzai
S
S
Ginsberg
H N
HN
Huang
L S
LS
D002001:Adipose Tissue, Brown / Q000378:metabolism*; D000818:Animals; D001055:Apolipoproteins B / Q000378:metabolism*; D001483:Base Sequence; D017931:DNA Primers; D006949:Hyperlipidemias / Q000235:genetics / Q000378:metabolism; D007333:Insulin Resistance; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009765:Obesity / Q000235:genetics / Q000378:metabolism*; D012323:RNA Processing, Post-Transcriptional; D012333:RNA, Messenger / Q000235:genetics; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism; D014280:Triglycerides / Q000378:metabolism*
D001055:Apolipoproteins B; D017931:DNA Primers; D012333:RNA, Messenger; D011973:Receptors, LDL; D014280:Triglycerides