Intestinal Sirtuin 1 Controls Liver Regeneration via Regulating the Intestinal Farnesoid X Receptor/Fibroblast Growth Factor 15 Axis in Mice

Background & Aims: The contribution of the gut–liver axis during liver regeneration remains poorly understood. Understanding the mechanisms underlying this process is critical for developing novel therapeutic strategies for liver diseases and transplantation. Here, we aimed at defining the role of intestinal sirtuin-1 during liver regeneration in mice.

Methods: We performed partial hepatectomy to intestinal-specific sirtuin-1 knockout mice (SIRTintKO) and wild-type littermates. Immunostaining and immunoblotting were performed on liver and intestinal tissues to assess proliferation and senescence, as well as farnesoid X receptor and fibroblast growth factor-15 protein expression. Bulk RNA sequencing was performed on liver tissues.

Results: We found that SIRTintKO mice had significantly reduced hepatocyte proliferation and increased hepatocyte senescence, accompanied by accumulation of bile acids in the liver that was associated with profuse parenchymal damage. Still, SIRTintKO restored liver mass at comparable levels to wild-type mice at 10 days after partial hepatectomy, which was accompanied by the activation of liver progenitor cells in the livers of knockout mice. Transcriptomic analysis of bulk RNA sequencing data from liver tissue samples at the priming (6 hours) and proliferative phase (24 hours) after partial hepatectomy highlighted that impaired hepatocyte proliferation in SIRTintKO mice coincided with the downregulation of the signal transducer and activator of transcription pathway and disruption of amino acid and lipid metabolism. Mechanistically, intestinal sirtuin-1 depletion was associated with reduced expression of farnesoid X receptor and fibroblast growth factor-15 in the small intestine. The intestinal-specific activation of farnesoid X receptor with fexaramine treatment successfully re-established hepatocyte proliferation and restored the liver parenchyma integrity in SIRTintKO mice.

Conclusions: Intestinal sirtuin-1 is a key regulator of liver regeneration through upstream control of the farnesoid X receptor/fibroblast growth factor-15 axis following partial hepatectomy.