Adiponectin fine‐tuning of liver regeneration dynamics revealed through cellular network modelling

Abstract

Key pointsr Loss of adiponectin delays the initiation of liver regeneration after partial hepatectomy, but later accelerates regeneration.r Loss of adiponectin modulates these regeneration kinetics through decreased hepatocyte response to inflammation and increased growth factor bioavailability.r Increased adiponectin suppresses liver regeneration through decreased growth factor bioavailability.r Our predictive computational model was able to connect these molecular regulatory events to tissue physiology.Abstract Following partial hepatectomy, the liver initiates a regenerative programme involving hepatocyte priming and replication driven by the coordinated actions of cytokine and growth factors. We investigated the mechanisms underlying adiponectin's (Adn) regulation of liver regeneration through modulation of these mediators. Adn -/-mice showed delayed onset of hepatocyte replication, but accelerated cell cycle progression relative to wild-type mice, suggesting Adn has multiple effects fine-tuning the kinetics of liver regeneration. We developed a computational model describing the molecular and physiological kinetics of liver regeneration in Adn -/-mice. We employed this computational model to evaluate the underlying regulatory mechanisms. Our analysis predicted that Adn is required for an efficient early cytokine response to partial hepatectomy, but is inhibitory to later growth factor actions. Consistent with this prediction, Adn knockout reduced hepatocyte responses to interleukin-6 during the priming phase, but enhanced growth factor levels through peak hepatocyte replication. By contrast, supraphysiological concentrations of Adn resulting from rosiglitazone treatment suppressed regeneration by reducing growth factor levels during S phase, consistent with computational predictions. Together, these results revealed that Adn fine-tunes the progression of liver regeneration through dynamically modulating molecular mediator networks and cellular interactions within the liver. Abbreviations Adn, adiponectin; Adn -/-, adiponectin knockout; Ang-1, angiogenin-1; β, response parameter; CCl 4 , carbon tetrachloride; DLS, dynamic local sensitivity; ECM, extracellular matrix; FGF-2 or bFGF, fibroblast growth factor 2; GF, growth factor; HGF, hepatocyte growth factor; IE, immediate early; IL-6, interleukin 6; JAK, Janus kinase; k i SOCS3 , SOCS3 inhibition parameter of STAT3 production; k M XX , Michaelis-Menten constant; k prol , replication rate; k P , P to R rate parameter; k Q , Q to P rate parameter; k R , R to Q rate parameter; k up , GF uptake rate by ECM; k XX , XX production rate; k 1 -k 7 , steady-state molecular production rates; κ XX , XX degradation rate; M, metabolic demand; M/N, metabolic load; N, number of hepatocytes; P, primed; PBS, phase-based sensitivity; PHx, partial hepatectomy; PS, pulsatile sensitivity; PSA, pulsatile sensitivity analysis; pSTAT3, phosphorylated STAT3; proSTAT3, monomeric STAT3; θ, threshold parameter; Q, quiescent; R, replicating; SHP-1, Src homology region 2 domain-containing...

Systems analysis of non-parenchymal cell modulation of liver repair across multiple regeneration modes

“…We have used this approach in a previous study to investigate the molecular factors governing the altered liver regeneration dynamics caused by ablation of the gene adiponectin (Adn). Our modeling approach suggested that the delay and acceleration of regeneration observed in Adn−/− mice was caused by decreased priming in hepatocytes (seen as decreased STAT3 phosphorylation during the first 6 h post-PHx) and enhanced growth factor signaling (observable by 20–40 h post-PHx) [ 34 ]. We then measured STAT3 phosphorylation and growth factor levels in liver lysates of Adn−/− mice and found reduced STAT3 phosphorylation at 3 and 6 h post-PHx coupled with high levels of ANG-1, FGF-2, and HGF proteins from 6 to 42 h post-PHx.…”

“…Parametric sensitivity analysis of the computational model revealed that regeneration is dynamically controlled and that not all factors respond the same across all times. This result coupled with the pulsatile sensitivity analysis recently performed on the original model proposed by Furchtgott et al [ 29 ] indicates that treatments designed to improve regenerative ability during chronic disease or following liver transplant may need to be dynamic as well [ 34 ]. Extending the results of simulations of chronic disease states in rats to the human model may assist in scheduling treatments for patients suffering from chronic diseases post-transplantation to maximize regeneration.…”

“…Table 1 states that the approximate biological correlate of the [IL-6] variable in the model is the “Cytokine microenvironment of the liver”. As previously described in [ 13 ] and in [ 34 ], the [IL-6] variable should be considered a lumped variable representing the physiological impact of general cytokine signaling rather than an exact analogue to IL-6 protein levels. Therefore, we used the name [IL-6] for this variable with parameters derived from TNF.…”

Adiponectin as an Anti-fibrotic and Anti-inflammatory Adipokine in the Liver

“…Interestingly, adiponectin impacts the development of hepatic fibrosis via multiple mechanisms, with both direct anti-fibrotic effects on HSCs, as well as indirect anti-fibrotic roles via its anti-inflammatory activities [7–9]. Recent evidence also suggests that adiponectin can influence the regulation of hepatocyte proliferation [10], which may also influence the fibrogenic response to liver injury. Herein, we review the recent findings regarding the protective effects of adiponectin in hepatic inflammation and fibrosis, as well as briefly summarizing the contributions of other key adipokines.…”

Modulation of Cell Death and Survival by Adipokines in the Liver

“…For example, adiponectin represses late-stage regeneration of hepatocytes due to unavailability of growth factors in adiponectin knockout mice model. 20) Mechanistically, hepatocyte growth factor (HGF) and fibroblast growth factor-2 (FGF-2) produced from hepatic stellate cells (HSCs) promote cell cycle progression of hepatocytes. 21,22) However, adiponectin induces apoptosis and inhibits activation of HSCs.…”