title: Macrophage-specific apoE gene repair reduces diet-induced hyperlipidemia and atherosclerosis in hypomorphic Apoe mice.
abstract: BACKGROUND
  Apolipoprotein (apo) E is best known for its ability to lower plasma cholesterol and protect against atherosclerosis. Although the liver is the major source of plasma apoE, extra-hepatic sources of apoE, including from macrophages, account for up to 10% of plasma apoE levels. This study examined the contribution of macrophage-derived apoE expression levels in diet-induced hyperlipidemia and atherosclerosis.
  
  
  RESULTS
  Hypomorphic apoE (Apoe(h/h)) mice expressing wildtype mouse apoE at ∼2-5% of physiological levels in all tissues were derived by gene targeting in embryonic stem cells. Cre-mediated gene repair of the Apoe(h/h) allele in Apoe(h/h)LysM-Cre mice raised apoE expression levels by 26 fold in freshly isolated peritoneal macrophages, restoring it to 37% of levels seen in wildtype mice. Chow-fed Apoe(h/h)LysM-Cre and Apoe(h/h) mice displayed similar plasma apoE and cholesterol levels (55.53±2.90 mg/dl versus 62.70±2.77 mg/dl, n = 12). When fed a high-cholesterol diet (HCD) for 16 weeks, Apoe(h/h)LysM-Cre mice displayed a 3-fold increase in plasma apoE and a concomitant 32% decrease in plasma cholesterol when compared to Apoe(h/h) mice (602.20±22.30 mg/dl versus 888.80±24.99 mg/dl, n = 7). On HCD, Apoe(h/h)LysM-Cre mice showed increased apoE immunoreactivity in lesional macrophages and liver-associated Kupffer cells but not hepatocytes. In addition, Apoe(h/h)LysM-Cre mice developed 35% less atherosclerotic lesions in the aortic root than Apoe(h/h) mice (167×10(3)±16×10(3) µm(2) versus 259×10(3)±56×10(3) µm(2), n = 7). This difference in atherosclerosis lesions size was proportional to the observed reduction in plasma cholesterol.
  
  
  CONCLUSIONS
  Macrophage-derived apoE raises plasma apoE levels in response to diet-induced hyperlipidemia and by such reduces atherosclerosis proportionally to the extent to which it lowers plasma cholesterol levels.
authors.affiliation: Department of Surgery, University of California San Francisco, VA Medical Center, San Francisco, California, United States of America.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Gaudreault
authors.forename: Nikit
authors.initials: N
authors.lastname: Kumar
authors.forename: Victor R
authors.initials: VR
authors.lastname: Olivas
authors.forename: Delphine
authors.initials: D
authors.lastname: Eberlé
authors.forename: Joseph H
authors.initials: JH
authors.lastname: Rapp
authors.forename: Robert L
authors.initials: RL
authors.lastname: Raffai
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000097:blood / Q000172:deficiency* / Q000235:genetics*; D050197:Atherosclerosis / Q000097:blood / Q000209:etiology / Q000517:prevention & control* / Q000628:therapy; D002784:Cholesterol / Q000097:blood; D004036:Diet, Atherogenic; D015870:Gene Expression; D015316:Genetic Therapy; D006949:Hyperlipidemias / Q000097:blood / Q000209:etiology / Q000517:prevention & control* / Q000628:therapy; D007728:Kupffer Cells / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
chemical_list: D001057:Apolipoproteins E; D012333:RNA, Messenger; D002784:Cholesterol