Sphingosine‐1‐phosphate promotes tumor development and liver fibrosis in mouse model of congestive hepatopathy

Abstract

Background and Aims Chronic liver congestion reflecting right‐sided heart failure (RHF), Budd‐Chiari syndrome, or Fontan‐associated liver disease (FALD) is involved in liver fibrosis and HCC. However, molecular mechanisms of fibrosis and HCC in chronic liver congestion remain poorly understood. Approach and Results Here, we first demonstrated that chronic liver congestion promoted HCC and metastatic liver tumor growth using murine model of chronic liver congestion by partial inferior vena cava ligation (pIVCL). As the initial step triggering HCC promotion and fibrosis, gut‐derived lipopolysaccharide (LPS) appeared to induce LSECs capillarization in mice and in vitro. LSEC capillarization was also confirmed in patients with FALD. Mitogenic factor, sphingosine‐1‐phosphate (S1P), was increased in congestive liver and expression of sphingosine kinase 1, a major synthetase of S1P, was increased in capillarized LSECs after pIVCL. Inhibition of S1P receptor (S1PR) 1 (Ex26) and S1PR2 (JTE013) mitigated HCC development and liver fibrosis, respectively. Antimicrobial treatment lowered portal blood LPS concentration, LSEC capillarization, and liver S1P concentration accompanied by reduction of HCC development and fibrosis in the congestive liver. Conclusions In conclusion, chronic liver congestion promotes HCC development and liver fibrosis by S1P production from LPS‐induced capillarized LSECs. Careful treatment of both RHF and liver cancer might be necessary for patients with RHF with primary or metastatic liver cancer.

Mulberrin confers protection against hepatic fibrosis by Trim31/Nrf2 signaling

“…Hepatic inflammatory response and oxidative stress contribute to fibrosis progression [ 2 , 4 , 7 , 8 , 18 ]. Active TGF-β promotes hepatocyte injury and the activation of HSCs and fibroblast, leading to collagen formation [ 41 ].…”

“…Active TGF-β promotes hepatocyte injury and the activation of HSCs and fibroblast, leading to collagen formation [ 41 ]. TGF-β1 binds to its receptor and contributes to the phosphorylation of mothers against decapentaplegic homolog SMAD2/3, which is required for their nuclear translocation and transcriptional modulation of their fibrotic target genes including α-SMA, Col1a1, Col3a1 and Fibronectin, ultimately resulting in collagen deposition and fibrosis [ 2 , 4 , 7 , 42 ]. Unfortunately, liver fibrosis is still an intractable disease without effective therapeutic options due to its intricate pathogenesis [ 3 , 5 ].…”

“…Liver fibrosis occurs in many types of liver disease, such as hepatitis and chronic alcoholism, and leads to scarring and injury to the liver [ 1 ]. Liver fibrosis is characterized by excessive accumulation of extracellular matrix (ECM) proteins, hepatocyte damage, distortion of the hepatic lobules, and changes in the vascular architecture [ 2 , 3 ]. HSCs activation plays an essential role in the pathogenesis of liver fibrosis.…”

Establishment of a Rat Model of Liver Venous Deprivation: Simultaneous Portal and Hepatic Vein Ligation

“…Moreover, the size of the FLE lobe (LML) was decreased (growth ratio: −0.28±0. 19) in the e-ALPPS group but was slightly increased in the e-LVD group (growth ratio: 0.47±0.67), which may have resulted from hepatic venous congestion (Fig. 1A, E).…”

“…17,18 Extracellular collagen fibers were stained with picric acid-sirius red. 19 All sections were digitally imaged using a slide scanner (Hamamatsu Electronic, Shizuoka-ken, Japan). Quantitative evaluation of Ki-67 staining was performed.…”