Hironari Kawai1,2, Yosuke Osawa1,3, Michitaka Matsuda1, Tomoyuki Tsunoda4, Keisuke Yanagida5, Daisuke Hishikawa5, Miku Okawara1, Yuzuru Sakamoto1, Tomonari Shimagaki1, Yuriko Tsutsui1, Yuichi Yoshida1, Shiori Yoshikawa1, Kana Hashi1, Hiroyoshi Doi1, Taizo Mori1, Taiji Yamazoe1, Sachiyo Yoshio1, Masaya Sugiyama6, Daisuke Okuzaki7, Haruki Komatsu8, Ayano Inui4, Miwa Tamura-Nakano9, Chinatsu Oyama9, Hideo Shindou5,10, Hironori Kusano11, Masayoshi Kage12, Toru Ikegami2, Katsuhiko Yanaga2, Tatsuya Kanto1. 1. The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Chiba, Japan. 2. Department of Surgery, The Jikei University School of Medicine, Tokyo, Japan. 3. Department of Gastroenterology, International University of Health and Welfare Hospital, Nasushiobara, Tochigi, Japan. 4. Department of Pediatric Hepatology and Gastroenterology, Saiseikai Yokohama-shi Tobu Hospital, Kanagawa, Japan. 5. Department of Lipid Signaling, National Center for Global Health and Medicine, Tokyo, Japan. 6. Genome Medical Sciences Project, National Center for Global Health and Medicine, Chiba, Japan. 7. Genome information Research Center, Research Institute for Microbial Disease, Osaka University, Suita, Osaka, Japan. 8. Department of Pediatrics, Toho University Medical Center, Sakura hospital, Chiba, Japan. 9. Communal Laboratory, National Center for Global Health and Medicine, Tokyo, Japan. 10. Department of Lipid Science, The University of Tokyo, Tokyo, Japan. 11. Department of Pathology, Kurume University School of Medicine, Fukuoka, Japan. 12. Kurume University Research Center for Innovative Cancer Therapy, Fukuoka, Japan.
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.
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.