title: Prolonged exposure of cholestatic rats to complete dark inhibits biliary hyperplasia and liver fibrosis.
abstract: Biliary hyperplasia and liver fibrosis are common features in cholestatic liver disease. Melatonin is synthesized by the pineal gland as well as the liver. Melatonin inhibits biliary hyperplasia of bile duct-ligated (BDL) rats. Since melatonin synthesis (by the enzyme serotonin N-acetyltransferase, AANAT) from the pineal gland increases after dark exposure, we hypothesized that biliary hyperplasia and liver fibrosis are diminished by continuous darkness via increased melatonin synthesis from the pineal gland. Normal or BDL rats (immediately after surgery) were housed with light-dark cycles or complete dark for 1 wk before evaluation of 1) the expression of AANAT in the pineal gland and melatonin levels in pineal gland tissue supernatants and serum; 2) biliary proliferation and intrahepatic bile duct mass, liver histology, and serum chemistry; 3) secretin-stimulated ductal secretion (functional index of biliary growth); 4) collagen deposition, liver fibrosis markers in liver sections, total liver, and cholangiocytes; and 5) expression of clock genes in cholangiocytes. In BDL rats exposed to dark there was 1) enhanced AANAT expression/melatonin secretion in pineal gland and melatonin serum levels; 2) improved liver morphology, serum chemistry and decreased biliary proliferation and secretin-stimulated choleresis; and 4) decreased fibrosis and expression of fibrosis markers in liver sections, total liver and cholangiocytes and reduced biliary expression of the clock genes PER1, BMAL1, CLOCK, and Cry1. Thus prolonged dark exposure may be a beneficial noninvasive therapeutic approach for the management of biliary disorders.
authors.affiliation: Department of Medicine, Division Gastroenterology, Texas A&M University Health Science Center, Temple, Texas;
authors.forename: Yuyan
authors.initials: Y
authors.lastname: Han
authors.affiliation: Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, La Sapienza, Rome, Italy.
authors.forename: Paolo
authors.identifier: http://orcid.org/0000-0002-7195-3760
authors.initials: P
authors.lastname: Onori
authors.affiliation: Research, Central Texas Veterans Health Care System, Temple, Texas; Baylor Scott & White Digestive Disease Research Center, Scott & White, Temple, Texas; Operational Funds, Baylor Scott & White, Temple, Texas; Department of Medicine, Division Gastroenterology, Texas A&M University Health Science Center, Temple, Texas;
authors.forename: Fanyin
authors.initials: F
authors.lastname: Meng
authors.affiliation: Baylor Scott & White Digestive Disease Research Center, Scott & White, Temple, Texas; Department of Medicine, Division Gastroenterology, Texas A&M University Health Science Center, Temple, Texas;
authors.forename: Sharon
authors.initials: S
authors.lastname: DeMorrow
authors.affiliation: Department of Medicine, Division Gastroenterology, Texas A&M University Health Science Center, Temple, Texas;
authors.forename: Julie
authors.initials: J
authors.lastname: Venter
authors.affiliation: Research, Central Texas Veterans Health Care System, Temple, Texas; Baylor Scott & White Digestive Disease Research Center, Scott & White, Temple, Texas; Operational Funds, Baylor Scott & White, Temple, Texas; Department of Medicine, Division Gastroenterology, Texas A&M University Health Science Center, Temple, Texas;
authors.forename: Heather
authors.initials: H
authors.lastname: Francis
authors.affiliation: Eleonora Lorillard Spencer Cenci Foundation, Rome, Italy; Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, La Sapienza, Rome, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Franchitto
authors.affiliation: Department of Medicine, Division Gastroenterology, Texas A&M University Health Science Center, Temple, Texas;
authors.forename: Debolina
authors.initials: D
authors.lastname: Ray
authors.affiliation: Research, Central Texas Veterans Health Care System, Temple, Texas;
authors.forename: Lindsey
authors.initials: L
authors.lastname: Kennedy
authors.affiliation: Pathology, Baylor Scott & White, Temple, Texas; and.
authors.forename: John
authors.initials: J
authors.lastname: Greene
authors.affiliation: Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, La Sapienza, Rome, Italy.
authors.forename: Anastasia
authors.initials: A
authors.lastname: Renzi
authors.affiliation: Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, La Sapienza, Rome, Italy.
authors.forename: Romina
authors.initials: R
authors.lastname: Mancinelli
authors.affiliation: Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, La Sapienza, Rome, Italy.
authors.forename: Eugenio
authors.initials: E
authors.lastname: Gaudio
authors.affiliation: Research, Central Texas Veterans Health Care System, Temple, Texas; Baylor Scott & White Digestive Disease Research Center, Scott & White, Temple, Texas; Department of Medicine, Division Gastroenterology, Texas A&M University Health Science Center, Temple, Texas;
authors.forename: Shannon
authors.initials: S
authors.lastname: Glaser
authors.affiliation: Research, Central Texas Veterans Health Care System, Temple, Texas; Baylor Scott & White Digestive Disease Research Center, Scott & White, Temple, Texas; Department of Medicine, Division Gastroenterology, Texas A&M University Health Science Center, Temple, Texas; galpini@tamu.edu.
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Alpini
mesh_terms: D056930:ARNTL Transcription Factors / Q000235:genetics / Q000378:metabolism; D000818:Animals; D047068:Arylalkylamine N-Acetyltransferase / Q000235:genetics / Q000378:metabolism; D001647:Bile Acids and Salts / Q000378:metabolism; D001652:Bile Ducts / Q000378:metabolism* / Q000473:pathology; D056926:CLOCK Proteins / Q000235:genetics / Q000378:metabolism; D002779:Cholestasis / Q000378:metabolism* / Q000628:therapy; D003094:Collagen / Q000235:genetics / Q000378:metabolism; D056931:Cryptochromes / Q000235:genetics / Q000378:metabolism; D003624:Darkness; D005355:Fibrosis / Q000378:metabolism / Q000628:therapy; D006965:Hyperplasia / Q000378:metabolism / Q000628:therapy; D008099:Liver / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008550:Melatonin / Q000096:biosynthesis* / Q000097:blood; D056950:Period Circadian Proteins / Q000235:genetics / Q000378:metabolism; D010870:Pineal Gland / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344
chemical_list: D056930:ARNTL Transcription Factors; D001647:Bile Acids and Salts; C538965:Cry1 protein, rat; D056931:Cryptochromes; C539024:Per1 protein, rat; D056950:Period Circadian Proteins; D003094:Collagen; D056926:CLOCK Proteins; C520223:Aanat protein, rat; D047068:Arylalkylamine N-Acetyltransferase; D008550:Melatonin
keywords: biliary epithelium; cholestasis; clock genes; melatonin; secretin