title: Hematopoietic ABCA1 deletion promotes monocytosis and worsens diet-induced insulin resistance in mice.
abstract: Low-grade chronic inflammation plays an important role in the pathogenesis of obesity-induced insulin resistance. ABCA1 is essential for reverse cholesterol transport and HDL synthesis, and protects against macrophage inflammation. In the present study, the effects of ABCA1 deficiency in hematopoietic cells on diet-induced inflammation and insulin resistance were tested in vivo using bone marrow transplanted (BMT)-WT and BMT-ABCA1(-/-) mice. When challenged with a high-fat high-carbohydrate diabetogenic diet with added cholesterol (HFHSC), BMT-ABCA1(-/-) mice displayed enhanced insulin resistance and impaired glucose tolerance as compared with BMT-WT mice. The worsened insulin resistance and impaired glucose tolerance in BMT-ABCA1(-/-) mice were accompanied by increased macrophage accumulation and inflammation in adipose tissue and liver. Moreover, BMT-ABCA1(-/-) mice had significantly higher hematopoietic stem cell proliferation, myeloid cell expansion, and monocytosis when challenged with the HFHSC diet. In vitro studies indicated that macrophages from ABCA1(-/-) mice showed significantly increased inflammatory responses induced by saturated fatty acids. Taken together, these studies point to an important role for hematopoietic ABCA1 in modulating a feed-forward mechanism in obesity such that inflamed tissue macrophages stimulate the production of more monocytes, leading to an exacerbation of inflammation and associated disease processes.
authors.affiliation: Diabetes Obesity Center for Excellence, Division of Metabolism, Endocrinology and Nutrition, University of Washington, Seattle, WA 98109 crtang@u.washington.edu.
authors.forename: Chongren
authors.initials: C
authors.lastname: Tang
authors.affiliation: Diabetes Obesity Center for Excellence, Division of Metabolism, Endocrinology and Nutrition, University of Washington, Seattle, WA 98109.
authors.forename: Yuhua
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Diabetes Obesity Center for Excellence, Division of Metabolism, Endocrinology and Nutrition, University of Washington, Seattle, WA 98109.
authors.forename: Wendy
authors.initials: W
authors.lastname: Yang
authors.affiliation: Diabetes Obesity Center for Excellence, Division of Metabolism, Endocrinology and Nutrition, University of Washington, Seattle, WA 98109.
authors.forename: Carl
authors.initials: C
authors.lastname: Storey
authors.affiliation: Diabetes Obesity Center for Excellence, Division of Metabolism, Endocrinology and Nutrition, University of Washington, Seattle, WA 98109.
authors.forename: Tim S
authors.initials: TS
authors.lastname: McMillen
authors.affiliation: Diabetes Obesity Center for Excellence, Division of Metabolism, Endocrinology and Nutrition, University of Washington, Seattle, WA 98109.
authors.forename: Barbara A
authors.initials: BA
authors.lastname: Houston
authors.affiliation: Diabetes Obesity Center for Excellence, Division of Metabolism, Endocrinology and Nutrition, University of Washington, Seattle, WA 98109.
authors.forename: Jay W
authors.initials: JW
authors.lastname: Heinecke
authors.affiliation: Diabetes Obesity Center for Excellence, Division of Metabolism, Endocrinology and Nutrition, University of Washington, Seattle, WA 98109.
authors.forename: Renee C
authors.initials: RC
authors.lastname: LeBoeuf
mesh_terms: D064286:ATP Binding Cassette Transporter 1 / Q000097:blood / Q000172:deficiency* / Q000235:genetics; D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D002784:Cholesterol / Q000378:metabolism / Q000494:pharmacology; D059305:Diet, High-Fat; D018149:Glucose Intolerance / Q000378:metabolism; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D007333:Insulin Resistance / Q000502:physiology*; D008099:Liver / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D009000:Monocytes / Q000378:metabolism / Q000473:pathology; D009196:Myeloproliferative Disorders / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009765:Obesity / Q000473:pathology; D011973:Receptors, LDL / Q000378:metabolism
chemical_list: D064286:ATP Binding Cassette Transporter 1; D002784:Cholesterol; D011973:Receptors, LDL; C577833:Abca1 protein, mouse
keywords: ATP binding cassette transporter A1; adipose tissue; cholesterol; diabetes; high density lipoprotein; macrophages; obesity