Hypertriglyceridemia in lecithin-cholesterol acyltransferase-deficient mice is associated with hepatic overproduction of triglycerides, increased lipogenesis, and improved glucose tolerance.

Abstract

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.

• Authors: Dominic S Ng, Chunhui Xie, Graham F Maguire, Xianghong Zhu, Francisca Ugwu, Eric Lam, Philip W Connelly
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 279 Issue 9 Pg. 7636-42 (Feb 27 2004) ISSN: 0021-9258 [Print] United States
• PMID: 14668345 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Blood Glucose
• CCAAT-Enhancer-Binding Proteins
• DNA-Binding Proteins
• Fatty Acids, Nonesterified
• Insulin
• Lipids
• Lipoproteins, HDL
• Lipoproteins, LDL
• Lipoproteins, VLDL
• Liver X Receptors
• NR1H3 protein, human
• Nr1h3 protein, mouse
• Orphan Nuclear Receptors
• RNA, Messenger
• Receptors, Cytoplasmic and Nuclear
• Receptors, LDL
• Srebf1 protein, mouse
• Sterol Regulatory Element Binding Protein 1
• Transcription Factors
• Triglycerides
• Cholesterol
• Phosphatidylcholine-Sterol O-Acyltransferase
• Fatty Acid Synthases
• Acetyl-CoA Carboxylase

Topics

• Acetyl-CoA Carboxylase (genetics)
• Animals
• Blood Glucose (analysis)
• CCAAT-Enhancer-Binding Proteins (genetics)
• Cholesterol (blood)
• DNA-Binding Proteins (genetics)
• Fasting
• Fatty Acid Synthases (genetics)
• Fatty Acids, Nonesterified (metabolism)
• Hypertriglyceridemia (enzymology)
• Insulin (blood)
• Lecithin Cholesterol Acyltransferase Deficiency (blood)
• Lipids (blood)
• Lipoproteins, HDL (blood)
• Lipoproteins, LDL (blood)
• Lipoproteins, VLDL (blood, metabolism)
• Liver (chemistry, metabolism)
• Liver X Receptors
• Mice
• Mice, Knockout
• Orphan Nuclear Receptors
• Phosphatidylcholine-Sterol O-Acyltransferase (genetics, physiology)
• RNA, Messenger (analysis)
• Receptors, Cytoplasmic and Nuclear (genetics)
• Receptors, LDL (deficiency, genetics)
• Reverse Transcriptase Polymerase Chain Reaction
• Sterol Regulatory Element Binding Protein 1
• Transcription Factors
• Triglycerides (blood)