Reg3α and Reg3β Expressions Followed by JAK2/STAT3 Activation Play a Pivotal Role in the Acceleration of Liver Hypertrophy in a Rat ALPPS Model

Abstract

To explore the underlying mechanism of rapid liver hypertrophy by liver partition in associating liver partition and portal vein ligation for staged hepatectomy (ALPPS), liver partition at different sites was investigated. Increased inflammatory cytokines owing to the liver partition have been reportedly responsible. If this were true, rapid liver hypertrophy should be achieved regardless of where the liver was split. A male Sprague-Dawley rat model was created, in which a liver split was placed inside the portal vein ligated lobe (PiLL), in addition to the ALPPS and portal vein ligation (PVL) models. Liver regeneration rate, inflammatory cytokine levels, activation status of the Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) pathway and expressions of regenerating islet-derived (Reg)3α and Reg3β were investigated. The liver regeneration rate was significantly higher in the ALPPS group than in the PiLL group, whereas inflammatory cytokine levels were nearly equal. Additional volume increase in ALPPS group over PVL and PiLL groups was JAK2/STAT3-dependent. Reg3α and Reg3β expressions were observed only in the ALPPS group. An increase in inflammatory cytokines was not enough to describe the mechanism of rapid liver hypertrophy in ALPPS. Expressions of Reg3α and Reg3β could play an important role in conjunction with an activation of the JAK2/STAT3 pathway.

The Role of Farnesoid X Receptor in Accelerated Liver Regeneration in Rats Subjected to ALPPS

“…Upon binding, Fgfr4 can signal mitosis independently of Foxm1b via mitogen activated protein kinases (MAPK) and via the nuclear factor kappa-light-chain-enhancer of activated B-cells (NF-κB). Activation of the Stat3 pathway by Fgf15 binding to Fgfr4 [ 42 ] has been observed following ALPPS [ 43 , 44 ], but did not play a role in our model given the downregulation of Foxm1b , a downstream target of Stat3 [ 8 ]. Alternatively, BAs can bind to the nuclear receptor pregnane X receptor (PXR) and trigger mitosis while bypassing Stat3 and Foxm1b.…”

MMP2/9 downregulation is responsible for hepatic function recovery in cirrhotic rats following associating liver partition and portal vein ligation for staged hepatectomy

“…A previous study has demonstrated that the expression of PCNA is about ten-fold higher in rats after ALPPS compared with the transection and left lateral lobe resection groups, and four-fold higher compared with the PVL group (24). Intriguingly, both Borger et al and Otsuka et al proposed that there may be other signaling pathways involved in the accelerated liver regeneration after ALPPS (25,26). Therefore, this current study performed bioinformatics analyses to screen the differentially expressed genes before and after ALPPS and PVL in rats.…”

Upregulation of Reg IV and Hgf mRNAs by Intermittent Hypoxia via Downregulation of microRNA-499 in Cardiomyocytes

“…Type I (and Type II) Reg proteins are expressed in regenerating islets [ 39 , 52 ] and involved in β-cell regeneration [ 3 , 40 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 ]. It has been suggested that Reg family proteins are involved in cellular proliferation in exocrine pancreatic cells [ 62 , 63 ], gastrointestinal cells [ 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 ], hepatic cells [ 76 , 77 , 78 , 79 , 80 ], salivary ductal cells [ 81 , 82 , 83 ], bone and muscle cells [ 84 , 85 ], neuronal cells [ 86 ], and cardiovascular cells [ 30 , 32 , 87 , 88 ].…”