title: Type I diabetes mellitus decreases in vivo macrophage-to-feces reverse cholesterol transport despite increased biliary sterol secretion in mice.
abstract: Type I diabetes mellitus (T1DM) increases atherosclerotic cardiovascular disease; however, the underlying pathophysiology is still incompletely understood. We investigated whether experimental T1DM impacts HDL-mediated reverse cholesterol transport (RCT). C57BL/6J mice with alloxan-induced T1DM had higher plasma cholesterol levels (P < 0.05), particularly within HDL, and increased hepatic cholesterol content (P < 0.001). T1DM resulted in increased bile flow (2.1-fold; P < 0.05) and biliary secretion of bile acids (BA, 10.5-fold; P < 0.001), phospholipids (4.5-fold; P < 0.001), and cholesterol (5.5-fold; P < 0.05). Hepatic cholesterol synthesis was unaltered, whereas BA synthesis was increased in T1DM (P < 0.001). Mass fecal BA output was significantly higher in T1DM mice (1.5-fold; P < 0.05), fecal neutral sterol excretion did not change due to increased intestinal cholesterol absorption (2.1-fold; P < 0.05). Overall in vivo macrophage-to-feces RCT, using [(3)H]cholesterol-loaded primary mouse macrophage foam cells, was 20% lower in T1DM (P < 0.05), mainly due to reduced tracer excretion within BA (P < 0.05). In vitro experiments revealed unchanged cholesterol efflux toward T1DM HDL, whereas scavenger receptor class BI-mediated selective uptake from T1DM HDL was lower in vitro and in vivo (HDL kinetic experiments) (P < 0.05), conceivably due to increased glycation of HDL-associated proteins (+65%, P < 0.01). In summary, despite higher mass biliary sterol secretion T1DM impairs macrophage-to-feces RCT, mainly by decreasing hepatic selective uptake, a mechanism conceivably contributing to increased cardiovascular disease in T1DM.
authors.affiliation: Department of Pediatrics, Center for Liver, Digestive, and Metabolic Diseases, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Jan
authors.initials: J
authors.lastname: Freark de Boer
authors.affiliation: Department of Pediatrics, Center for Liver, Digestive, and Metabolic Diseases, University Medical Center Groningen, Groningen, The Netherlands; Top Institute Food and Nutrition, Wageningen, The Netherlands.
authors.forename: Wijtske
authors.initials: W
authors.lastname: Annema
authors.affiliation: Department of Pediatrics, Center for Liver, Digestive, and Metabolic Diseases, University Medical Center Groningen, Groningen, The Netherlands; Department of Pathology and Medical Biology, Medical Biology Section, Molecular Genetics, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Marijke
authors.initials: M
authors.lastname: Schreurs
authors.affiliation: Department of Pediatrics, Center for Liver, Digestive, and Metabolic Diseases, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Jelske N
authors.initials: JN
authors.lastname: van der Veen
authors.affiliation: Medizinische Klinik IV-Nephrology, Charite-Campus Benjamin Franklin, Berlin, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: van der Giet
authors.affiliation: Department of Pediatrics, Center for Liver, Digestive, and Metabolic Diseases, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Niels
authors.initials: N
authors.lastname: Nijstad
authors.affiliation: Department of Pediatrics, Center for Liver, Digestive, and Metabolic Diseases, University Medical Center Groningen, Groningen, The Netherlands; Department of Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands;, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Folkert
authors.initials: F
authors.lastname: Kuipers
authors.affiliation: Department of Pediatrics, Center for Liver, Digestive, and Metabolic Diseases, University Medical Center Groningen, Groningen, The Netherlands; Top Institute Food and Nutrition, Wageningen, The Netherlands. Electronic address: u_tietge@yahoo.com.
authors.forename: Uwe J F
authors.initials: UJF
authors.lastname: Tietge
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism*; D001692:Biological Transport / Q000502:physiology*; D002318:Cardiovascular Diseases; D002784:Cholesterol / Q000097:blood / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000097:blood* / Q000378:metabolism; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005243:Feces / Q000737:chemistry*; D008074:Lipoproteins / Q000097:blood; D008099:Liver / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D010743:Phospholipids / Q000097:blood / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D001647:Bile Acids and Salts; D005230:Fatty Acids, Nonesterified; D008074:Lipoproteins; D010743:Phospholipids; D002784:Cholesterol