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Coordinated alteration of hepatic gene expression in fatty acid and triglyceride synthesis in LCAT-null mice is associated with altered PUFA metabolism

¹Department of Medicine, St. Michael's Hospital; and ²Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada

Submitted 20 December 2004 ; accepted in final form 10 August 2005

Complete lecithin:cholesterol acyltransferase (LCAT) deficiency is associated with fasting hypertriglyceridemia (HTG). We recently reported that, in ldlr^–/–xlcat^–/– mice, fasting HTG is associated with hepatic triglyceride overproduction in association with an upregulation of the hepatic srebp1 gene and altered expression of its target genes in lipogenesis and gluconeogenesis. We further investigated the role of hepatic polyunsaturated fatty acid (PUFA) metabolism in the modulation of the lipid phenotypes. In the ldlr^–/–xlcat^–/– mice, using the ldlr^–/–xlcat^+/+ littermate as controls, the hepatic level of cholesterol esters (CE) were reduced by 61.0% whereas the 20:4-CE and 22:6-CE contents were each reduced by >80%. In contrast, the hepatic levels of 20:4- and 22:6-containing phospholipid (PL) species were either unchanged or mildly elevated. Similar alterations of the hepatic PUFA in CE and in PL were also observed in the lcat^–/– mice compared with their wild-type controls. In ldlr^–/–xlcat^–/– mice, hepatic mRNA level was markedly reduced for -6 desaturase (fads2) (70.2%) and acyl-CoA:cholesterol acyltransferase-2 (soat2) (57.0%). A similar pattern of gene expression change was also observed in the lcat^–/– single-knockout mice. In contrast, the acyl-CoA:diacylglycerol acyltransferase-2 (dgat2) mRNA level was 1.7-fold upregulated in the double-knockout mice. In summary, we observed coordinated alterations in hepatic expression of the gene for fads2, soat2, and dgat2, resulting in a reduction in total hepatic PUFA pool and differentially in the PUFA-CE pool, in association with an increase in dgat2 gene expression for promoting triglyceride synthesis and secretion. Some of the phenotypes are not readily explained by known mechanisms and may represent novel regulatory pathways.

lecithin:cholesterol acyltransferase; hypertriglyceridemia; polyunsaturated fatty acids; phospholipids; diacylglycerol acyltransferase; acyl-coenzyme A:cholesterol acyltransferase; desaturases

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