Hypertriglyceridemia in lecithin-cholesterol acyltransferase-deficient mice is associated with hepatic overproduction of triglycerides, increased lipogenesis, and improved glucose tolerance.
Lecithin-cholesterol acyltransferase deficiency is frequently associated with hypertriglyceridemia (HTG) in animal models and humans. We investigated the mechanism of HTG in the ldlr-/- x lcat-/- (double knockout (dko)) mice using the ldlr-/- x lcat+/+ (knock-out (ko)) littermates as control. Mean fasting triglyceride (TG) levels in the dko mice were elevated 1.75-fold compared with their controls (p < 0.002). Both the very low density lipoprotein and the low density lipoprotein/intermediate density lipoprotein fractions separated by fast protein liquid chromatography were TG-enriched in the dko mice. In vitro lipolysis assay revealed that the dko mouse very low density lipoprotein (d < 1.019 g/ml) fraction separated by ultracentrifugation was a more efficient substrate for lipolysis by exogenous bovine lipoprotein lipase. Post-heparin lipoprotein lipase activity was reduced by 61% in the dko mice. Hepatic TG production rate, determined after intravenous Triton WR1339 injection, was increased 8-fold in the dko mice. Hepatic mRNA levels of sterol regulatory element binding protein-1 (srebp-1) and its target genes acetyl-CoA carboxylase-1 (acc-1), fatty acid synthase (fas), and stearoyl-CoA desaturase-1 (scd-1) were significantly elevated in the dko mice compared with the ko control. The hepatic mRNA levels of LXRalpha (lxralpha) and its target genes including angiopoietin-like protein 3 (angptl-3) in the dko mice were unchanged. Fasting glucose and insulin levels were reduced by 31 and 42%, respectively in the dko mice, in conjunction with a 49% reduction in hepatic pepck-1 mRNA (p = 0.014). Both the HTG and the improved fasting glucose phenotype seen in the dko mice are at least in part attributable to an up-regulation of the hepatic srebp-1c gene.
Ng
Dominic S
DS
Department of Medicine, St. Michael's Hospital, Toronto, Ontario M5B 1A6, Canada. ngd@smh.toronto.on.ca
Xie
Chunhui
C
Maguire
Graham F
GF
Zhu
Xianghong
X
Ugwu
Francisca
F
Lam
Eric
E
Connelly
Philip W
PW
D000103:Acetyl-CoA Carboxylase / Q000235:genetics; D000818:Animals; D001786:Blood Glucose / Q000032:analysis*; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics; D002784:Cholesterol / Q000097:blood; D004268:DNA-Binding Proteins / Q000235:genetics; D005215:Fasting; D064429:Fatty Acid Synthases / Q000235:genetics; D005230:Fatty Acids, Nonesterified / Q000378:metabolism; D015228:Hypertriglyceridemia / Q000201:enzymology*; D007328:Insulin / Q000097:blood; D007863:Lecithin Cholesterol Acyltransferase Deficiency / Q000097:blood*; D008055:Lipids / Q000097:blood*; D008075:Lipoproteins, HDL / Q000097:blood; D008077:Lipoproteins, LDL / Q000097:blood; D008079:Lipoproteins, VLDL / Q000097:blood / Q000378:metabolism; D008099:Liver / Q000737:chemistry / Q000378:metabolism*; D000071518:Liver X Receptors; D051379:Mice; D018345:Mice, Knockout; D057093:Orphan Nuclear Receptors; D007862:Phosphatidylcholine-Sterol O-Acyltransferase / Q000235:genetics / Q000502:physiology; D012333:RNA, Messenger / Q000032:analysis; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors; D014280:Triglycerides / Q000097:blood*
D001786:Blood Glucose; D022762:CCAAT-Enhancer-Binding Proteins; D004268:DNA-Binding Proteins; D005230:Fatty Acids, Nonesterified; D007328:Insulin; D008055:Lipids; D008075:Lipoproteins, HDL; D008077:Lipoproteins, LDL; D008079:Lipoproteins, VLDL; D000071518:Liver X Receptors; C000605213:NR1H3 protein, human; C000605214:Nr1h3 protein, mouse; D057093:Orphan Nuclear Receptors; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D011973:Receptors, LDL; C497388:Srebf1 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors; D014280:Triglycerides; D002784:Cholesterol; D007862:Phosphatidylcholine-Sterol O-Acyltransferase; D064429:Fatty Acid Synthases; D000103:Acetyl-CoA Carboxylase