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

• Published in: Cell & bioscience Vol. 13; no. 1; pp. 5 - 22
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 09.01.2023; BioMed Central; BMC
• Subjects: Bile acids; Biliary senescence; Cytochrome P-450; Ductular reaction; Fatty acids; Fatty liver diseases; Genetic aspects; Hepatic steatosis; Lipogenesis; Liver; Liver cirrhosis; Phenotype; Physiological aspects; RNA; Hepatic steatosis; Biliary senescence; Ductular reaction; Lipogenesis; Fatty liver diseases
• ISSN: 2045-3701; 2045-3701
• DOI: 10.1186/s13578-022-00945-w

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. 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. 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. Targeting Sct/SR signaling may be important for modulating ALD phenotypes.