title: Dietary macronutrients and the aging liver sinusoidal endothelial cell.
abstract: Fenestrations are pores within the liver sinusoidal endothelial cells (LSECs) that line the sinusoids of the highly vascularized liver. Fenestrations facilitate the transfer of substrates between blood and hepatocytes. With pseudocapillarization of the hepatic sinusoid in old age, there is a loss of fenestrations. LSECs are uniquely exposed to gut-derived dietary and microbial substrates delivered by the portal circulation to the liver. Here we studied the effect of 25 diets varying in content of macronutrients and energy on LSEC fenestrations using the Geometric Framework method in a large cohort of mice aged 15 mo. Macronutrient distribution rather than total food or energy intake was associated with changes in fenestrations. Porosity and frequency were inversely associated with dietary fat intake, while fenestration diameter was inversely associated with protein or carbohydrate intake. Fenestrations were also linked to diet-induced changes in gut microbiome, with increased fenestrations associated with higher abundance of Firmicutes and reduced abundance of Bacteroidetes Diet-induced changes in levels of several fatty acids (C16:0, C19:0, and C20:4) were also significantly inversely associated with fenestrations, suggesting a link between dietary fat and modulation of lipid rafts in the LSECs. Diet influences fenestrations and these data reflect both the key role of the LSECs in clearing gut-derived molecules from the vascular circulation and the impact these molecules have on LSEC morphology.
authors.affiliation: Aging and Alzheimers Institute and ANZAC Research Institute, University of Sydney and Concord Hospital, Sydney, Australia; Charles Perkins Centre, University of Sydney, Sydney, Australia;
authors.forename: Victoria Carroll
authors.identifier: 0000-0002-6346-9928
authors.initials: VC
authors.lastname: Cogger
authors.affiliation: Aging and Alzheimers Institute and ANZAC Research Institute, University of Sydney and Concord Hospital, Sydney, Australia; Faculty of Pharmacy, Universiti Teknologi MARA, Bandar Puncak Alam, Selangor, Malaysia;
authors.forename: Mashani
authors.initials: M
authors.lastname: Mohamad
authors.affiliation: Aging and Alzheimers Institute and ANZAC Research Institute, University of Sydney and Concord Hospital, Sydney, Australia; Charles Perkins Centre, University of Sydney, Sydney, Australia;
authors.forename: Samantha Marie
authors.initials: SM
authors.lastname: Solon-Biet
authors.affiliation: Charles Perkins Centre, University of Sydney, Sydney, Australia; The School of Mathematics and Statistics, University of Sydney, Sydney, Australia;
authors.forename: Alistair M
authors.initials: AM
authors.lastname: Senior
authors.affiliation: Aging and Alzheimers Institute and ANZAC Research Institute, University of Sydney and Concord Hospital, Sydney, Australia;
authors.forename: Alessandra
authors.initials: A
authors.lastname: Warren
authors.affiliation: Aging and Alzheimers Institute and ANZAC Research Institute, University of Sydney and Concord Hospital, Sydney, Australia;
authors.forename: Jennifer Nicole
authors.initials: JN
authors.lastname: O'Reilly
authors.affiliation: Aging and Alzheimers Institute and ANZAC Research Institute, University of Sydney and Concord Hospital, Sydney, Australia; Centro Andaluz de Biología del Desarrollo, Universidad Pablo de Olavide CSIC, CIBERER-Instituto de Salud San Carlos III, Carretera de Utrera Km 1, Sevilla, Spain;
authors.forename: Bui Thanh
authors.initials: BT
authors.lastname: Tung
authors.affiliation: Aging and Alzheimers Institute and ANZAC Research Institute, University of Sydney and Concord Hospital, Sydney, Australia; Centre for Clinical Research and Education, University Hospital of North Norway, Tromsø, Norway;
authors.forename: Dmitri
authors.initials: D
authors.lastname: Svistounov
authors.affiliation: Aging and Alzheimers Institute and ANZAC Research Institute, University of Sydney and Concord Hospital, Sydney, Australia; Department of Cardiovascular Sciences, University of Leicester British Heart Foundation Cardiovascular Research Centre, Leicester, United Kingdom;
authors.forename: Aisling Clare
authors.initials: AC
authors.lastname: McMahon
authors.affiliation: Department of Pathology, University of Otago, and Departments of Surgery, Gastroenterology and Medicine, Canterbury District Health Board, Christchurch, New Zealand; and.
authors.forename: Robin
authors.initials: R
authors.lastname: Fraser
authors.affiliation: Charles Perkins Centre, University of Sydney, Sydney, Australia;
authors.forename: David
authors.initials: D
authors.lastname: Raubenheimer
authors.affiliation: Charles Perkins Centre, University of Sydney, Sydney, Australia; School of Molecular Bioscience, University of Sydney, Sydney, Australia.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Holmes
authors.affiliation: Charles Perkins Centre, University of Sydney, Sydney, Australia;
authors.forename: Stephen James
authors.initials: SJ
authors.lastname: Simpson
authors.affiliation: Aging and Alzheimers Institute and ANZAC Research Institute, University of Sydney and Concord Hospital, Sydney, Australia; Charles Perkins Centre, University of Sydney, Sydney, Australia; david.lecouteur@sydney.edu.au.
authors.forename: David George
authors.initials: DG
authors.lastname: Le Couteur
mesh_terms: D000821:Animal Feed; D000824:Animal Nutritional Physiological Phenomena; D000818:Animals; D015415:Biomarkers / Q000097:blood; D048430:Cell Shape; D016922:Cellular Senescence; D004040:Dietary Carbohydrates / Q000008:administration & dosage / Q000378:metabolism*; D004044:Dietary Proteins / Q000008:administration & dosage / Q000378:metabolism*; D042783:Endothelial Cells / Q000378:metabolism* / Q000648:ultrastructure; D002149:Energy Intake; D005260:Female; D000069196:Gastrointestinal Microbiome; D041981:Gastrointestinal Tract / Q000378:metabolism / Q000382:microbiology; D008099:Liver / Q000098:blood supply*; D008297:Male; D008810:Mice, Inbred C57BL; D009752:Nutritional Status; D009753:Nutritive Value; D016062:Porosity
chemical_list: D015415:Biomarkers; D004040:Dietary Carbohydrates; D004044:Dietary Proteins
keywords: aging; fenestrations; microbiome