• Liver injury
• Macrophage inflammation
• Pentabromoethylbenzene
• TWEAK

• Animals
• Male
• Female
• Cytokine TWEAK/metabolism
• Pregnancy
• Diet, Western/adverse effects
• Prenatal Exposure Delayed Effects
• Macrophages/drug effects
• Macrophages/metabolism
• Chemical and Drug Induced Liver Injury/metabolism
• Chemical and Drug Induced Liver Injury/pathology
• Chemical and Drug Induced Liver Injury/etiology
• Liver/drug effects
• Liver/metabolism
• Liver/pathology
• Mice
• Mice, Inbred C57BL
• NF-kappa B/metabolism
• NLR Family, Pyrin Domain-Containing 3 Protein/metabolism
• Inflammasomes/metabolism
• Inflammasomes/drug effects

• primary biliary cirrhosis
• apoptosis

• Chronic Liver Injury
• LPLC
• Liver Regeneration

• Humans
• Liver Regeneration
• Interferon-gamma
• Liver Diseases
• Killer Cells, Natural
• Macrophages

Hepatocyte nuclear factor 4α (HNF4α) and glucocorticoid receptor (GR), master regulators of liver metabolism, are down-regulated in fatty liver diseases. The present study aimed to elucidate the role of down-regulation of HNF4α and GR in fatty liver and hyperlipidemia.

Adult mice with liver-specific heterozygote (HET) and knockout (KO) of HNF4α or GR were fed a high-fat-high-sugar diet (HFHS) for 15 days. Alterations in hepatic and circulating lipids were determined with analytical kits, and changes in hepatic mRNA and protein expression in these mice were quantified by real-time PCR and Western blotting. Serum and hepatic levels of bile acids were quantified by LC-MS/MS. The roles of HNF4α and GR in regulating hepatic gene expression were determined using luciferase reporter assays.

Compared to HFHS-fed wildtype mice, HNF4α HET mice had down-regulation of lipid catabolic genes, induction of lipogenic genes, and increased hepatic and blood levels of lipids, whereas HNF4α KO mice had fatty liver but mild hypolipidemia, down-regulation of lipid-efflux genes, and induction of genes for uptake, synthesis, and storage of lipids. Serum levels of chenodeoxycholic acid and deoxycholic acid tended to be decreased in the HNF4α HET mice but dramatically increased in the HNF4α KO mice, which was associated with marked down-regulation of cytochrome P450 7a1, the rate-limiting enzyme for bile acid synthesis. Hepatic mRNA and protein expression of sterol-regulatory-element-binding protein-1 (SREBP-1), a master lipogenic regulator, was induced in HFHS-fed HNF4α HET mice. In reporter assays, HNF4α cooperated with the corepressor small heterodimer partner to potently inhibit the transactivation of mouse and human SREBP-1C promoter by liver X receptor. Hepatic nuclear GR proteins tended to be decreased in the HNF4α KO mice. HFHS-fed mice with liver-specific KO of GR had increased hepatic lipids and induction of SREBP-1C and PPARγ, which was associated with a marked decrease in hepatic levels of HNF4α proteins in these mice. In reporter assays, GR and HNF4α synergistically/additively induced lipid catabolic genes.

induction of lipid catabolic genes and suppression of lipogenic genes by HNF4α and GR may mediate the early resistance to HFHS-induced fatty liver and hyperlipidemia.

The online version contains supplementary material available at 10.1186/s12944-022-01654-6.

• GR
• HNF4α
• LXR
• PPARα
• SREBP-1C
• fatty liver
• heterozygote
• high-fat diet
• hyperlipidemia
• knockout

Chronic hepatitis C virus (HCV) infection induces profound alterations in the cytokine and chemokine signatures in peripheral blood. Clearance of HCV by antivirals results in host immune modification, which may interfere with immune-mediated cancer surveillance. Identifying HCV patients who remain at risk of hepatocellular carcinoma (HCC) following HCV eradication remains an unmet need. We hypothesized that antiviral therapy-induced immune reconstruction may be relevant to HCC development.

To investigate the impact of differential dynamics of cytokine expression on the development of HCC following successful antiviral therapy.

One hundred treatment-naïve HCV patients with advanced fibrosis (F3/4) treated with direct-acting antivirals (DAAs) or peginterferon/ribavirin who achieved sustained virologic response [SVR, defined as undetectable HCV RNA throughout 12 wk (SVR12) for the DAA group or 24 wk (SVR24) for the interferon group after completion of antiviral therapy] were enrolled since 2003. The primary endpoint was the development of new-onset HCC. Standard HCC surveillance (abdominal ultrasound and α-fetoprotein) was performed every six months during the follow-up. Overall, 64 serum cytokines were detected by the multiplex immunoassay at baseline and 24 wk after end-of-treatment.

HCC developed in 12 of the 97 patients over 459 person-years after HCV eradication. In univariate analysis, the Fibrosis-4 index (FIB-4), hemoglobin A1c (HbA1c), the dynamics of tumor necrosis factor-α (TNF-α), and TNF-like weak inducer of apoptosis (TWEAK) after antiviral therapy were significant HCC predictors. The multivariate Cox regression model showed that ΔTNF-α (≤ -5.7 pg/mL) was the most important risk factor for HCC (HR = 11.54, 95%CI: 2.27-58.72, P = 0.003 in overall cases; HR = 9.98, 95%CI: 1.88-52.87, P = 0.007 in the interferon group). An HCC predictive model comprising FIB-4, HbA1c, ΔTNF-α, and ΔTWEAK had excellent performance, with 3-, 5-, 10-, and 13-year areas under the curve of 0.882, 0.864, 0.903, and 1.000, respectively. The 5-year accumulative risks of HCC were 0%, 16.9%, and 40.0% in the low-, intermediate-, and high-risk groups, respectively.

Downregulation of serum TNF-α significantly increases the risk of HCC after HCV eradication. A predictive model consisting of cytokine kinetics could ameliorate personalized HCC surveillance strategies for post-SVR HCV patients.

• Hepatitis C virus
• Hepatocellular carcinoma
• Sustained virologic response
• Tumor necrosis factor-α
• Tumor necrosis factor-like weak inducer of apoptosis
• Cytokine

• Antiviral Agents/therapeutic use
• Carcinoma, Hepatocellular/drug therapy
• Carcinoma, Hepatocellular/epidemiology
• Cytokines
• Hepacivirus
• Hepatitis C, Chronic/complications
• Hepatitis C, Chronic/diagnosis
• Hepatitis C, Chronic/drug therapy
• Humans
• Liver Neoplasms/drug therapy
• Liver Neoplasms/epidemiology
• Risk Factors
• Sustained Virologic Response
• Tumor Necrosis Factor-alpha

Non-alcoholic fatty liver disease is the most common liver disease globally and in its inflammatory form, non-alcoholic steatohepatitis (NASH), can progress to cirrhosis and hepatocellular carcinoma (HCC). Currently, patient education and lifestyle changes are the major tools to prevent the continued progression of NASH. Emerging therapies in NASH target known pathological processes involved in the progression of the disease including inflammation, fibrosis, oxidative stress and hepatocyte apoptosis. Human amniotic epithelial cells (hAECs) were previously shown to be beneficial in experimental models of chronic liver injury, reducing hepatic inflammation and fibrosis. Previous studies have shown that liver progenitor cells (LPCs) response plays a significant role in the development of fibrosis and HCC in mouse models of fatty liver disease. In this study, we examined the effect hAECs have on the LPC response and hepatic oxidative stress in an experimental model of NASH.

Experimental NASH was induced in C57BL/6 J male mice using a high-fat, high fructose diet for 42 weeks. Mice received either a single intraperitoneal injection of 2 × 10⁶ hAECs at week 34 or an additional hAEC dose at week 38. Changes to the LPC response and oxidative stress regulators were measured.

hAEC administration significantly reduced the expansion of LPCs and their mitogens, IL-6, IFNγ and TWEAK. hAEC administration also reduced neutrophil infiltration and myeloperoxidase production with a concurrent increase in heme oxygenase-1 production. These observations were accompanied by a significant increase in total levels of anti-fibrotic IFNβ in mice treated with a single dose of hAECs, which appeared to be independent of c-GAS-STING activation.

Expansion of liver progenitor cells, hepatic inflammation and oxidative stress associated with experimental NASH were attenuated by hAEC administration. Given that repeated doses did not significantly increase efficacy, future studies assessing the impact of dose escalation and/or timing of dose may provide insights into clinical translation.

The online version contains supplementary material available at 10.1186/s13287-021-02476-6.

• Amnion epithelial cells
• Fatty liver disease
• Hepatic oxidative stress
• Liver progenitor cells
• NASH/NAFLD
• Regenerative medicine

• CD68
• ginger
• immunohistochemistry
• inflammatory cytokines
• monosodium glutamate

• Chronic liver disease
• Fibrosis
• Hepatic stellate cells
• Liver progenitor cells
• Thioacetamide

• Animals
• Cells, Cultured
• Chemical and Drug Induced Liver Injury/etiology
• Chemical and Drug Induced Liver Injury/metabolism
• Chemical and Drug Induced Liver Injury/pathology
• Coculture Techniques
• Disease Models, Animal
• Hepatic Stellate Cells/cytology
• Hepatic Stellate Cells/metabolism
• Liver/cytology
• Liver/metabolism
• Liver Cirrhosis/etiology
• Liver Cirrhosis/metabolism
• Liver Cirrhosis/pathology
• Liver Regeneration/physiology
• Male
• Mice
• Mice, Inbred C57BL
• Stem Cells/cytology
• Stem Cells/metabolism
• Thioacetamide/toxicity

• P30 DK048522 NIDDK NIH HHS
• R01 DK099205 NIDDK NIH HHS
• U01 AA029019 NIAAA NIH HHS

The liver is a unique parenchymal organ with a regenerative capacity allowing it to restore up to 70% of its volume. Although knowledge of this phenomenon dates back to Greek mythology (the story of Prometheus), many aspects of liver regeneration are still not understood. A variety of different factors, including inflammatory cytokines, growth factors, and bile acids, promote liver regeneration and control the final size of the organ during typical regeneration, which is performed by mature hepatocytes, and during alternative regeneration, which is performed by recently identified resident stem cells called “hepatic progenitor cells”. Hepatic progenitor cells drive liver regeneration when hepatocytes are unable to restore the liver mass, such as in cases of chronic injury or excessive acute injury. In liver maintenance, the body mass ratio is essential for homeostasis because the liver has numerous functions; therefore, a greater understanding of this process will lead to better control of liver injuries, improved transplantation of small grafts and the discovery of new methods for the treatment of liver diseases. The current review sheds light on the key molecular pathways and cells involved in typical and progenitor-dependent liver mass regeneration after various acute or chronic injuries. Subsequent studies and a better understanding of liver regeneration will lead to the development of new therapeutic methods for liver diseases.

• Liver regeneration
• Molecular pathways
• Hepatic progenitor cells
• Cytokines
• Micro ribonucleic acid
• Partial hepatectomy

• biomarker
• chronic liver disease
• extracellular vesicles
• hepatic fibrosis
• therapy

• Jagged1
• NOTCH
• hepatic progenitor cell
• hepatic stellate cell

Liver fibrosis is a common consequence of chronic liver disease. Over time, liver fibrosis can develop into liver cirrhosis. Current therapies for liver fibrosis are limited, and liver transplant is the only curative therapy for patients who progress to end-stage disease. A potential approach to treat chronic liver disease with increasing interest is cell-based therapy. Among the multiple cell types which have been proposed for therapeutic uses, human amnion epithelial cells and amniotic fluid-derived mesenchymal cells are promising. These cells are highly abundant, and their use poses no ethical concern. Furthermore, they exert potent anti-inflammatory and antifibrotic effects in animal models of liver injury. This review highlights the therapeutic characteristics and discusses how human amnion epithelial cells can be utilised as a therapeutic tool for chronic liver disease.

• Alcoholic liver disease
• Cirrhosis
• Hepatitis
• Myofibroblast
• Non-alcoholic fatty liver disease
• Non-alcoholic steatohepatitis

• Biliary atresia
• Fn14+ cells
• HPCs
• Liver fibrosis
• α-SMA+ cells

• hepatic progenitor cells
• hepatic stellate cells
• macrophages

• Antiviral immunity
• Lymphoid organs
• Lymphotoxin
• Lymphotoxin beta receptor
• Type I interferon

TNF superfamily members, including TNF-related weak inducer of apoptosis (TWEAK) and Glucocorticoid-Induced TNFR-Related Protein Ligand (GITRL) have been described as serum based biomarkers for inflammatory and immune mediated diseases. However, up to now the role of TWEAK and GITRL has not been analyzed in critical illness and sepsis.

GITRL and TWEAK serum concentrations were measured in 121 critically ill patients (84 fulfilled with septic disease), in comparison to 50 healthy controls. Results were correlated with clinical data.

Serum levels of TWEAK and GITRL were strongly decreased in critically ill patients compared with healthy controls. Concentrations of TWEAK (but not GITRL) were further decreased in patients with sepsis and correlated with routinely used markers of inflammation and bacterial infection such as C-reactive protein, procalcitonin and Interleukin-6. Notably, we failed to detect a correlation to other TNFR ligands such as TNF or APRIL. Finally, TWEAK levels of the upper quartile of the cohort were prognostic for mortality during ICU treatment.

TWEAK and GITRL levels were lower in intensive care unit medical patients. Levels of TWEAK were further decreased in septic patients, and alterations in TWEAK concentrations were linked to an unfavorable outcome. Together with recently published results on other TNFR ligands, these data indicate specific functions of the different TNFR ligands in septic diseases.

• carcinogenesis
• chronic liver disease
• fibrosis
• liver progenitor cells
• liver regeneration

• Cell of origin
• Chemoresistant cancer stem cells
• Hepatic progenitor cell features
• Microenvironment
• Phenotype switching
• Prognosis
• Tumor behavior

• Fn14
• TNF superfamily
• TNFR superfamily
• TWEAK
• non-canonical NFκB signaling

• Liver progenitor cells (LPCs)
• hepatic stellate cells (HSCs)
• liver cirrhosis
• liver failure
• liver regeneration
• mesenchymal stem cells (MSCs)
• stem cells

• HNF4A
• HepaRG progenitor cell
• Hepatogenesis
• LXRα/NR1H3