MILD DYSLIPIDEMIA IN MICE FOLLOWING TARGETED INACTIVATION OF THE HEPATIC LIPASE GENE

In order to gain better understanding of the function of hepatic lipas e (HL) in vivo, we have generated mice that lack HL using gene targeti ng in embryonic stem cells. No mRNA for HL was detected in the liver o f homozygous mutants, and no HL activity was detected in their plasma. Total cholesterol levels in plasma of mutant mice were increased by a bout 30% compared with wild type animals. Plasma phospholipids and hig h density lipoprotein (HDL) cholesterol were also increased, but plasm a levels of triglycerides were not altered. Analysis of density fracti ons of plasma lipoproteins revealed that HDL(1) (d = 1.02-1.04) was in creased in homozygous mutants fed regular chow. In response to a diet containing high fat and high cholesterol, HDL cholesterol was doubled in the mutants, but was slightly decreased in the wild type mice. Thes e results clearly demonstrate the importance of HL in HDL remodeling a nd metabolism in vivo. Various earlier studies suggested a role of HL in metabolism of triglyceride-rich particles, but the mutant mice appe ar to have no impairment in clearing them; the mutants clear exogenous ly introduced chylomicrons from plasma at a normal rate, and they tole rate acute fat loading as well as normal animals unless the loading is extreme. These differences may reflect species differences. However, it is also possible that the consequence of absence of HL as in our mu tants is different from the consequence when nonfunctional HL protein is present as in the human HL-deficient patients and in rats treated w ith HL antibodies. We hypothesize that absence of HL in mutant mice al lows other lipases to bind to the sites in the liver normally occupied by HL and facilitate the clearance of triglyceride-rich particles in these mice.