title: The differential effects of low birth weight and Western diet consumption upon early life hepatic fibrosis development in guinea pig.
abstract: Postnatal intake of an energy dense diet, the Western diet (WD), is a strong risk factor for liver fibrosis. Recently, adverse in utero conditions resulting in low birth weight (LBW) have also been associated with postnatal fibrosis development. We assessed the independent and possible synergistic effects of placental insufficiency-induced LBW and postnatal WD consumption on liver fibrosis in early adulthood, with a specific focus on changes in inflammation and apoptosis pathways in association with fibrogenesis. Male LBW (uterine artery ablation) and normal birth weight (NBW) guinea pig pups were fed either a control diet (CD) or WD from weaning to 150 days. Significant steatosis, mild lobular inflammation, apoptosis and mild stage 1 fibrosis (perisinusoidal or portal) were evident in WD-fed offspring (NBW/WD and LBW/WD). In LBW/CD versus NBW/CD offspring, increased transforming growth factor-beta 1 and matrix metallopeptidase mRNA and sma- and Mad-related protein 4 (SMAD4) were present in conjunction with minimal stage 1 portal fibrosis. Further, connective tissue growth factor mRNA was increased and miR-146a expression decreased in LBW offspring, irrespective of diet. Independent of birth weight, WD-fed offspring exhibited increased expression of fibrotic genes as well as elevated inflammatory and apoptotic markers. Moreover, the augmented expression of collagen, type III, alpha 1 and tumor necrosis factor-alpha was associated with increased recruitment of RNA polymerase II and enhanced histone acetylation (K9) to their respective promoters. These data support a role for both LBW and postnatal WD as factors contributing to hepatic fibrosis development in offspring through distinct pathways.
authors.affiliation: Department of Obstetrics and Gynecology, Western University, 1151 Richmond Street, London, ON, Canada, N6A 5C1.|Lawson Research Institute, 268 Grosvenor St, London, ON, Canada, N6A 4V2.|Children's Health Research Institute, 800 Commissioners Road East, London, ON, Canada, N6C 2V5.
authors.forename: Ousseynou
authors.initials: O
authors.lastname: Sarr
authors.affiliation: Department of Physiology and Pharmacology, Western University, 1151 Richmond Street, London, ON, Canada, N6A 5C1.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Blake
authors.affiliation: Department of Physiology and Pharmacology, Western University, 1151 Richmond Street, London, ON, Canada, N6A 5C1.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Thompson
authors.affiliation: Department of Obstetrics and Gynecology, Western University, 1151 Richmond Street, London, ON, Canada, N6A 5C1.
authors.forename: Lin
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Department of Physiology and Pharmacology, Western University, 1151 Richmond Street, London, ON, Canada, N6A 5C1.
authors.forename: Katherine
authors.initials: K
authors.lastname: Rabicki
authors.affiliation: Pathology and Laboratory Medicine, Western University, 1151 Richmond Street, London, ON, Canada, N6A 5C1.
authors.forename: Joanna C
authors.initials: JC
authors.lastname: Walsh
authors.affiliation: Animal Care and Veterinary Services, Western University, 1151 Richmond Street, London, ON, Canada, N6A 5C1.
authors.forename: Ian
authors.initials: I
authors.lastname: Welch
authors.affiliation: Department of Obstetrics and Gynecology, Western University, 1151 Richmond Street, London, ON, Canada, N6A 5C1.|Department of Physiology and Pharmacology, Western University, 1151 Richmond Street, London, ON, Canada, N6A 5C1.|Lawson Research Institute, 268 Grosvenor St, London, ON, Canada, N6A 4V2.|Children's Health Research Institute, 800 Commissioners Road East, London, ON, Canada, N6C 2V5.
authors.forename: Timothy R H
authors.initials: TR
authors.lastname: Regnault
mesh_terms: D000818:Animals; D017209:Apoptosis; D001724:Birth Weight; D003094:Collagen / Q000235:genetics / Q000378:metabolism; D059305:Diet, High-Fat / Q000009:adverse effects*; D005260:Female; D005355:Fibrosis; D006168:Guinea Pigs; D006657:Histones / Q000378:metabolism; D008099:Liver / Q000378:metabolism / Q000473:pathology*; D008107:Liver Diseases / Q000209:etiology*; D008297:Male; D020782:Matrix Metalloproteinases / Q000235:genetics / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics; D012319:RNA Polymerase II / Q000378:metabolism; D051785:Smad Proteins / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: D006657:Histones; C554180:MIRN146 microRNA, rat; D035683:MicroRNAs; D051785:Smad Proteins; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D003094:Collagen; D012319:RNA Polymerase II; D020782:Matrix Metalloproteinases