Knockout of secretin ameliorates biliary and liver phenotypes during alcohol-induced hepatotoxicity.

Kyritsi, Konstantina; Wu, Nan; Zhou, Tianhao; Carpino, Guido; Baiocchi, Leonardo; Kennedy, Lindsey; Chen, Lixian; Ceci, Ludovica; Meyer, Alison Ann; Barupala, Nipuni; Franchitto, Antonio; Onori, Paolo; Ekser, Burcin; Gaudio, Eugenio; Wu, Chaodong; Marakovits, Corinn; Chakraborty, Sanjukta; Francis, Heather; Glaser, Shannon; Alpini, Gianfranco

Kyritsi, Konstantina; Wu, Nan; Zhou, Tianhao; Carpino, Guido; Baiocchi, Leonardo; Kennedy, Lindsey; Chen, Lixian; Ceci, Ludovica; Meyer, Alison Ann; Barupala, Nipuni; Franchitto, Antonio; Onori, Paolo; Ekser, Burcin; Gaudio, Eugenio; Wu, Chaodong; Marakovits, Corinn; Chakraborty, Sanjukta; Francis, Heather; Glaser, Shannon; Alpini, Gianfranco.

Afiliação

Kyritsi K; Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
Wu N; Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
Zhou T; Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
Carpino G; Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, La Sapienza University of Rome, Rome, Italy.
Baiocchi L; Unit of Hepatology, Tor Vergata University, Rome, Italy.
Kennedy L; Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
Chen L; Division of Research, Indiana Center for Liver Research, Gastroenterology, Medicine, Richard L. Roudebush VA Medical Center and Indiana University, 702 Rotary Circle, Rm. 013C, Indianapolis, IN, 46202-2859, USA.
Ceci L; Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
Meyer AA; Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
Barupala N; Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, La Sapienza University of Rome, Rome, Italy.
Franchitto A; Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
Onori P; Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
Ekser B; Department of Movement, Human and Health Sciences, University of Rome "Foro Italico", Rome, Italy.
Gaudio E; Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, La Sapienza University of Rome, Rome, Italy.
Wu C; Division of Transplant Surgery, Department of Surgery, Indiana University, Indianapolis, IN, USA.
Marakovits C; Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, La Sapienza University of Rome, Rome, Italy.
Chakraborty S; Department of Nutrition, Texas A&M University, College Station, TX, USA.
Francis H; Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
Glaser S; Department of Medical Physiology, Texas A&M University School of Medicine, 8447 Riverside Parkway, MREB II, Room 2342, Bryan, TX, 77807-3260, USA.
Alpini G; Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA. heafranc@iu.edu.

Cell Biosci ; 13(1): 5, 2023 Jan 09.

Article em En | MEDLINE | ID: mdl-36624475

ABSTRACT

ABSTRACT

BACKGROUND:

Alcohol-related liver disease (ALD) is characterized by ductular reaction (DR), liver inflammation, steatosis, fibrosis, and cirrhosis. The secretin (Sct)/secretin receptor (SR) axis (expressed only by cholangiocytes) regulates liver phenotypes in cholestasis. We evaluated the role of Sct signaling on ALD phenotypes.

METHODS:

We used male wild-type and Sct-/- mice fed a control diet (CD) or ethanol (EtOH) for 8 wk. Changes in liver phenotypes were measured in mice, female/male healthy controls, and patients with alcoholic cirrhosis. Since Cyp4a10 and Cyp4a11/22 regulate EtOH liver metabolism, we measured their expression in mouse/human liver. We evaluated (i) the immunoreactivity of the lipogenesis enzyme elongation of very-long-chain fatty acids 1 (Elovl, mainly expressed by hepatocytes) in mouse/human liver sections by immunostaining; (ii) the expression of miR-125b (that is downregulated in cholestasis by Sct) in mouse liver by qPCR; and (iii) total bile acid (BA) levels in mouse liver by enzymatic assay, and the mRNA expression of genes regulating BA synthesis (cholesterol 7a-hydroxylase, Cyp27a1, 12a-hydroxylase, Cyp8b1, and oxysterol 7a-hydroxylase, Cyp7b11) and transport (bile salt export pump, Bsep, Na+-taurocholate cotransporting polypeptide, NTCP, and the organic solute transporter alpha (OSTa) in mouse liver by qPCR.

RESULTS:

In EtOH-fed WT mice there was increased biliary and liver damage compared to control mice, but decreased miR-125b expression, phenotypes that were blunted in EtOH-fed Sct-/- mice. The expression of Cyp4a10 increased in cholangiocytes and hepatocytes from EtOH-fed WT compared to control mice but decreased in EtOH-fed Sct-/- mice. There was increased immunoreactivity of Cyp4a11/22 in patients with alcoholic cirrhosis compared to controls. The expression of miR-125b decreased in EtOH-fed WT mice but returned at normal values in EtOH-fed Sct-/- mice. Elovl1 immunoreactivity increased in patients with alcoholic cirrhosis compared to controls. There was no difference in BA levels between WT mice fed CD or EtOH; BA levels decreased in EtOH-fed Sct-/- compared to EtOH-fed WT mice. There was increased expression of Cyp27a1, Cyp8b1, Cyp7b1, Bsep, NTCP and Osta in total liver from EtOH-fed WT compared to control mice, which decreased in EtOH-fed Sct-/- compared to EtOH-fed WT mice.