Molecular pathways of liver regeneration: A comprehensive review

Table 1 The main factors driving liver regeneration

Factor of regeneration	Influence on LR
TNF-α	Induction of CDK-1
IL-6	Activation of the JAK/STAT, MAPK, and PI3K/AKT signaling pathways
Hh signaling pathway	ECM remodulation; induction of progenitor cell and liver epithelial cell expansion; induction of glutaminolysis; inhibition of hepatocyte, BEC, Ito cell and progenitor cell apoptosis
ALR	lfALR: Enhancement of the hepatocyte response to IL-6 and STAT3 phosphorylation induction. MAPK signaling pathway activation; NK cells inhibition; increase in IL-6, TNFα and iNOS production by Kupffer cells, sfALR: Inhibition of proapoptotic stimuli
NRF2	Regulation of M phase entry, hepatocyte proliferation, maintenance of newly formed hepatocytes in a differentiated state
Growth factors (HGF, TGF-α, EGF, HB-EGF)	Stimulation of DNA synthesis and cell proliferation via Ras-MAPK and PI3K/AKT signaling pathway activation
BAs	Activation of CDK2, cell cycle, regulation of termination phase and terminate liver size, decrease in the inflammatory cytokine production, enhancement of BA excretion and HCO3ˉ, Clˉ secretion, control of BA polarity
Wnt-β-catenin	Hepatocyte proliferation induction
Notch signaling pathway	Modulation of HPC differentiation toward BECs, regulation of hepatocyte proliferation, mitotic rhythms, cyclin E1, A2 and B1
IL-1	DNA synthesis inhibitor
SOCSs	c-MET and JAK-STAT signaling pathway inhibition
TGF-β1, activin A, BMPs	Induction of apoptosis to correct excessive liver mass
HNF4	Regulation of hepatocyte differentiation, initiation of the termination phase, antagonism YAP and TGF-β/SMAD3, prevention of excessive connective tissue synthesis, inhibition of HPC proliferation and migration
Hippo/YAP signaling pathway	Terminal liver size control

LR: Liver regeneration; TNF-α: Tumor necrosis factor-α; IL-6: Interleukin-6; CDK-1: Cyclin-dependent kinase 1; JAK/STAT: Janus kinase/signal transducer and activator of transcription; Hh: Hedgehog; ECM: Extracellular matrix; MAPK: Mitogen-activated protein kinase; ALR: Augmenter of liver regeneration; lfALR: Long-form ALR; sfALR: Short-form ALR; iNOS: Inducible nitric oxide synthase; NRF2: Nuclear factor erythroid 2-related factor 2; BA: Bile acids; EGF: Epidermal growth factor; HGF: Hepatocyte growth factor; HPC: Hepatic progenitor cells; BEC: Biliary epithelial cells; MET: Methionine; BMP: Bone morphogenetic proteins; HNF4 : Hepatocyte nuclear factor 4 alpha; YAP: Yes-associated protein.

Table 2 Main micro ribonucleic acids influencing liver regeneration

miRNA	Expression change	Target genes	Influence on LR
miR-21	Increased	Rhob, Sox7, Crebl2, Bcl-2, Btg2, Timp3, Reck, Pdcd4, Tgfbi, Smad7, PTEN	Induction
miR -19a	Increased	PTEN	Induction
miR-214	Increased	PTEN	Induction
miR-203	Increased	SOCS3	Induction
miR-27a/b	Increased	Tmub1	Induction
miR-503	Decreased	Cyclin D1, Cyclin E2, CDC25A, CDKN1B, CHK1	Suppression
miR-23a	Decreased	TNF-α, c-Myc CCNL2, HNF4G MET	Suppression
miR-150	Decreased	TNF-α, survivin, FoxP1, c-Myb	Suppression
miR-663	Decreased	TGF-β1, AP-1, Jun-B, Jun-D	Suppression
miR-378	Decreased	Odc1	Suppression
miR-34a	Decreased	INHBB	Suppression
miR-33	Decreased	CDK6, EEF1A1, RAP2A	Suppression
miR-26a	Decreased	MAP3K2, MXI1, SENP5, CCND2, CCNE2	Suppression

miRNA: Micro ribonucleic acids; PTEN: Phosphatase and tensin homolog; LR: Liver regeneration; TNF-α: Tumor necrosis factor-α; CDK-6: Cyclin-dependent kinase 6.