title: The apolipoprotein-AI mimetic peptide L4F at a modest dose does not attenuate weight gain, inflammation, or atherosclerosis in LDLR-null mice.
abstract: OBJECTIVE
  High density lipoprotein (HDL) cholesterol levels are inversely related to cardiovascular disease risk and associated with a reduced risk of type 2 diabetes. Apolipoprotein A-I (apoA-I; major HDL protein) mimetics have been reported to reduce atherosclerosis and decrease adiposity. This study investigated the effect of L4F mimetic peptide and apoA-I overexpression on weight gain, insulin resistance, and atherosclerosis in an LDL receptor deficient (Ldlr-/-) model fed a high fat high sucrose with cholesterol (HFHSC) diet.
  
  
  METHODS
  Studies in differentiated 3T3-L1 adipocytes tested whether L4F could inhibit palmitate-induced adipocyte inflammation. In vivo studies used male Ldlr-/- mice fed a HFHSC diet for 12 weeks and were injected daily with L4F (100 µg/mouse) subcutaneously during the last 8 weeks. Wild-type and apoA-I overexpressing Ldlr-/- mice were fed HFHSC diet for 16 weeks.
  
  
  RESULTS
  Neither L4F administration nor apoA-I overexpression affected weight gain, total plasma cholesterol or triglycerides in our studies. While pre-treatment of 3T3-L1 adipocytes with either L4F or HDL abolished palmitate-induced cytokine expression in vitro, L4F treatment did not affect circulating or adipose tissue inflammatory markers in vivo. Neither L4F administration nor apoA-I overexpression affected glucose tolerance. ApoA-I overexpression significantly reduced atherosclerotic lesion size, yet L4F treatment did not affect atherosclerosis.
  
  
  CONCLUSIONS
  Our results suggest that neither L4F (100 µg/day/mouse) nor apoA-I overexpression affects adiposity or insulin resistance in this model. We also were unable to confirm a reduction in atherosclerosis with L4F in our particular model. Further studies on the effect of apoA-I mimetics on atherosclerosis and insulin resistance in a variety of dietary contexts are warranted.
authors.affiliation: Department of Environmental and Occupational Health, University of Washington, Seattle, Washington, United States of America.
authors.forename: Michelle M
authors.initials: MM
authors.lastname: Averill
authors.affiliation: Department of Medicine, University of Washington, Seattle, Washington, United States of America.
authors.forename: Eung Ju
authors.initials: EJ
authors.lastname: Kim
authors.affiliation: Department of Medicine, University of Washington, Seattle, Washington, United States of America.
authors.forename: Leela
authors.initials: L
authors.lastname: Goodspeed
authors.affiliation: Department of Medicine, University of Washington, Seattle, Washington, United States of America.
authors.forename: Shari
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Medicine, University of Washington, Seattle, Washington, United States of America.
authors.forename: Savitha
authors.initials: S
authors.lastname: Subramanian
authors.affiliation: Department of Medicine, University of Washington, Seattle, Washington, United States of America.
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Den Hartigh
authors.affiliation: Department of Medicine, University of Washington, Seattle, Washington, United States of America.
authors.forename: Chongren
authors.initials: C
authors.lastname: Tang
authors.affiliation: Department of Medicine, University of Washington, Seattle, Washington, United States of America.
authors.forename: Yilei
authors.initials: Y
authors.lastname: Ding
authors.affiliation: Department of Pathology, University of Chicago, Chicago, Illinois, United States of America.
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Reardon
authors.affiliation: Department of Pathology, University of Chicago, Chicago, Illinois, United States of America.
authors.forename: Godfrey S
authors.initials: GS
authors.lastname: Getz
authors.affiliation: Department of Medicine, University of Washington, Seattle, Washington, United States of America.
authors.forename: Alan
authors.initials: A
authors.lastname: Chait
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D016632:Apolipoprotein A-I / Q000737:chemistry*; D050197:Atherosclerosis / Q000188:drug therapy*; D018925:Chemokines / Q000235:genetics; D059305:Diet, High-Fat / Q000009:adverse effects; D004040:Dietary Carbohydrates / Q000009:adverse effects; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects; D007249:Inflammation / Q000188:drug therapy; D007333:Insulin Resistance; D008297:Male; D051379:Mice; D057786:Peptidomimetics / Q000494:pharmacology* / Q000627:therapeutic use; D011973:Receptors, LDL / Q000172:deficiency*; D013395:Sucrose / Q000009:adverse effects; D015430:Weight Gain / Q000187:drug effects*
chemical_list: D016632:Apolipoprotein A-I; D018925:Chemokines; D004040:Dietary Carbohydrates; D057786:Peptidomimetics; D011973:Receptors, LDL; D013395:Sucrose