Inhibition of TGFβ1 accelerates regeneration of fibrotic rat liver elicited by a novel two-staged hepatectomy.

Abstract

Aims: Emerging evidence is demonstrating that rapid regeneration of remnant liver elicited by associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) may be attenuated in fibrotic livers. However, the molecular mechanisms responsible for this process are largely unknown. It is widely acknowledged that the TGFβ1 signaling axis plays a major role in liver fibrosis. Therefore, the aims of this study were to elucidate the underlying mechanism of liver regeneration during ALPPS with or without fibrosis, specifically focusing on TGFβ1 signaling. Approach: ALPPS was performed in rat models with N-diethylnitrosamine-induced liver fibrosis and no fibrosis. Functional liver remnant regeneration and expression of TGFβ1 were analyzed during the ALPPS procedures. Adeno-associated virus-shTGFβ1 and the small molecule inhibitor LY2157299 (galunisertib) were used separately or in combination to inhibit TGFβ1 signaling in fibrotic rats. Results: Liver regeneration following ALPPS was lower in fibrotic rats than non-fibrotic rats. TGFβ1 was a key mediator of postoperative regeneration in fibrotic liver. Interestingly, AAV-shTGFβ1 accelerated the regeneration of fibrotic functional liver remnant and improved fibrosis, while LY2157299 only enhanced liver regeneration. Moreover, combination treatment elicited a stronger effect. Conclusions: Inhibition of TGFβ1 accelerated regeneration of fibrotic liver, ameliorated liver fibrosis, and improved liver function following ALPPS. Therefore, TGFβ1 is a promising therapeutic target in ALPPS to improve fibrotic liver reserve function and prognosis.

• Authors: Bo Zhang, Fanzheng Meng, Yao Liu, Yubin Yuan, Jizhou Wang, Dehai Wu, Yifeng Cui, Shugeng Zhang, Hongrui Guo, Shuhang Liang, Wei Wang, Matthew Klos, Sherry Morgenstern, Yufeng Liu, Linmao Sun, Kun Ma, Xirui Liu, Yan Wang, Jihua Han, Guangchao Yang, Chenyang Zheng, Xianying Li, Shuo Zhou, Changyong Ji, Qingquan Bai, Jiabei Wang, Lianxin Liu
• Journal: Theranostics (Theranostics) Vol. 11 Issue 10 Pg. 4743-4758 ( 2021) ISSN: 1838-7640 [Electronic] Australia
• PMID: 33754025 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The author(s).

Chemical References

• Pyrazoles
• Quinolines
• Tgfb1 protein, rat
• Transforming Growth Factor beta1
• Diethylnitrosamine
• LY-2157299
• Carbon Tetrachloride

Topics

• Animals
• Carbon Tetrachloride (toxicity)
• Diethylnitrosamine (toxicity)
• Hepatectomy (methods)
• Hepatic Stellate Cells (metabolism)
• Hepatocytes (metabolism)
• Ligation
• Liver (drug effects, physiology)
• Liver Cirrhosis (chemically induced, metabolism, pathology)
• Liver Regeneration (drug effects, physiology)
• Portal Vein (surgery)
• Primary Cell Culture
• Pyrazoles (pharmacology)
• Quinolines (pharmacology)
• Rats
• Signal Transduction
• Transforming Growth Factor beta1 (antagonists & inhibitors, metabolism)