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J. Biol. Chem., Vol. 279, Issue 9, 7636-7642, February 27, 2004

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Hypertriglyceridemia in Lecithin-cholesterol Acyltransferase-deficient Mice Is Associated with Hepatic Overproduction of Triglycerides, Increased Lipogenesis, and Improved Glucose Tolerance^*

Dominic S. Ng, Chunhui Xie, Graham F. Maguire, Xianghong Zhu, Francisca Ugwu, Eric Lam, and Philip W. Connelly

From the Department of Medicine, St. Michael's Hospital, Toronto, Ontario M5B 1A6, Canada

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 LXR (lxr) 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.

Received for publication, August 26, 2003 , and in revised form, December 9, 2003.

^* This work was supported in part by Heart and Stroke Foundation of Ontario Grants-in-aid N4124 (to D. S. N.) and T4027 (to P. W. C.) and by the Canada Foundation for Innovation New Opportunities (to D. S. N.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Canadian Institute for Health Research New Investigator awardee. To whom correspondence should be addressed: St. Michael's Hospital West Annex 2-015, 38 Shuter St., Toronto, Ontario M5B-1A6, Canada. Tel.: 416-864-5197; Fax: 416-864-5584; E-mail: ngd{at}smh.toronto.on.ca.

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