Hormonal Contribution to Liver Regeneration

Abstract

An understanding of the molecular basis of liver regeneration will open new horizons for the development of novel therapies for chronic liver failure. Such therapies would solve the drawbacks associated with liver transplant, including the shortage of donor organs, long waitlist time, high medical costs, and lifelong use of immunosuppressive agents. Regeneration after partial hepatectomy has been studied in animal models, particularly fumarylacetoacetate hydrolase-deficient (FAH ^-/-) mice and pigs. The process of regeneration is distinctive, complex, and well coordinated, and it depends on the interplay among several signaling pathways (eg, nuclear factor κβ, Notch, Hippo), cytokines (eg, tumor necrosis factor α, interleukin 6), and growth factors (eg, hepatocyte growth factor, epidermal growth factor, vascular endothelial growth factor), and other components. Furthermore, endocrinal hormones (eg, norepinephrine, growth hormone, insulin, thyroid hormones) also can influence the aforementioned pathways and factors. We believe that these endocrinal hormones are important hepatic mitogens that strongly induce and accelerate hepatocyte proliferation (regeneration) by directly and indirectly triggering the activity of the involved signaling pathways, cytokines, growth factors, and transcription factors. The subsequent induction of cyclins and associated cyclin-dependent kinase complexes allow hepatocytes to enter the cell cycle. In this review article, we comprehensively summarize the current knowledge regarding the roles and mechanisms of these hormones in liver regeneration. Articles used for this review were identified by searching MEDLINE and EMBASE databases from inception through June 1, 2019.

Keywords: CDK, cyclin-dependent kinase; EGF, epidermal growth factor; EGFR, EGF receptor; ERK, extracellular signal-regulated kinase; FAH, fumarylacetoacetate hydrolase; GH, growth hormone; Ghr-/-, growth hormone receptor gene knockout; HGF, hepatocyte growth factor; HNF, hepatocyte nuclear factor; HPC, hepatic progenitor cell; IGF, insulinlike growth factor; IL, interleukin; IR, insulin receptor; InsP3, inositol 1,4,5-trisphosphate; JNK, JUN N-terminal kinase; LDLT, living donor liver transplant; LRP, low-density lipoprotein-related protein; MAPK, mitogen-activated protein kinase; NF-κβ, nuclear factor κβ; NOS, nitric oxide synthase; NTBC, 2-nitro-4-trifluoro-methyl-benzoyl-1,3-cyclohexanedione; PCNA, proliferating cell nuclear antigen; PCR, polymerase chain reaction; PH, partial hepatectomy; PI3K, phosphatidylinositol-4,5-bisphosphate 3-kinase; PKB, protein kinase B; PTU, 6-n-propyl-2-thiouracil; ROS, reactive oxygen species; STAT, signal transducer and activator of transcription; T3, triiodothyronine; TGF, transforming growth factor; TNF, tumor necrosis factor; TR, thyroid receptor; hESC, human embryonic stem cell; hiPSC, human induced pluripotent stem cells; mRNA, messenger RNA; mTOR, mammalian target of rapamycin.