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

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

Ductular Reactions in Liver Injury, Regeneration, and Disease Progression—An Overview

“…The major transporters and exchangers involved in this process include water channel molecules such as aquaporins, Na+/glucose transporters, and Cl − /HCO 3 − exchangers. Additionally, cholangiocytes express xenobiotic enzymes, such as CYP2E1 and CYP1A2 [23,24]. Cholangiocytes secrete factors such as mucins, defensins, and immunoglobulins, such as IgA, thus protecting the biliary system [25].…”

Enteroendocrine cells and gut hormones as potential targets in the crossroad of the gut-kidney axis communication

“…Research conducted in different contexts can provide valuable insights into the potential mechanisms and pathways through which secretin operates in the kidney. An illustrative example can be found in liver fibrosis, where secretin has been shown to initiate the upregulation of TGF-β1 signaling ( Kyritsi et al, 2023 ). This signaling cascade is well-known for its ability to induce renal fibrosis in murine models of UUO, concurrently triggering anti-inflammatory reactions and pro-fibrotic responses.…”