The latest medical research on Transplant Hepatology

The research magnet gathers the latest research from around the web, based on your specialty area. Below you will find a sample of some of the most recent articles from reputable medical journals about transplant hepatology gathered by our medical AI research bot.

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Non-Invasive Biomarkers for the Diagnosis and Management of Autoimmune Hepatitis.

Hepatology

Autoimmune hepatitis (AIH) is a rare disease of unclear etiology characterized by loss of self-tolerance that can lead to liver injury, cirrhosis, ...

Characterization and role of collagen gene expressing hepatic cells following partial hepatectomy in mice.

Hepatology

The mechanism underlying liver regeneration following partial hepatectomy (PH) is not fully elucidated. We aimed to characterize collagen gene expressing hepatic cells following PH and examine their contribution to liver regeneration.

Col-GFP mice, which express GFP under the control of the collagen gene promoter, were used to detect collagen gene expressing cells following PH. The GFP-expressing cells were analyzed via single-cell RNA sequencing (scRNA-seq). Additionally, Col-ER Cre/RFP and Col-ER Cre/DTA mice were utilized to examine the cell fates and functional roles of collagen gene expressing cells in liver regeneration, respectively. The number of collagen gene expressing cells was found to be increased on day 3 and subsequently decreased on day 7 following PH. ScRNA-seq analysis of sorted collagen gene expressing cells showed that the regenerating liver was characterized by three distinct hepatic stellate cell (HSC) clusters, including one representing classic myofibroblasts. The other HSC clusters included an intermediately activated HSC cluster and a proliferating HSC cluster. Of these, the latter cluster was absent in the carbon tetrachloride (CCl4 )-induced liver fibrosis model. Cell fate tracing analysis using Col-ER-Cre/RFP mice demonstrated that the collagen gene expressing cells escaped death during regeneration and remained in an inactivated state in the liver. Further, depletion of these cells using Col-ER-Cre/DTA mice resulted in impaired liver regeneration.

Heterogeneous HSC clusters, one of which was a unique proliferating cluster, were found to appear in the liver following PH. Collagen gene expressing cells, including HSCs, were found to promote liver regeneration.

PAR2 promotes impaired glucose uptake and insulin resistance in NAFLD through GLUT2 and Akt interference.

Hepatology

Insulin resistance and poor glycemic control are key drivers of the development of non-alcoholic fatty liver disease (NAFLD) and have recently been shown to be associated with fibrosis progression in nonalcoholic steatohepatitis (NASH). However, the underlying mechanisms involving dysfunctional glucose metabolism and relationship with NAFLD/NASH progression remain poorly understood. We set out to determine whether Protease-activated receptor 2 (PAR2), a sensor of extracellular inflammatory and coagulation proteases, links NAFLD and NASH with liver glucose metabolism.

Here, we demonstrate that hepatic expression of PAR2 increases in diabetic NAFLD/NASH patients and mice. Mechanistic studies using whole body and liver-specific PAR2-knock out mice reveal that hepatic PAR2 plays an unexpected role in suppressing glucose internalization, glycogen storage, and insulin signaling through a bifurcating Gq -dependent mechanism. PAR2 activation down-regulates the major glucose transporter of liver, GLUT2, through Gq -MAPK-FoxA3, and inhibits insulin-Akt signaling through Gq -calcium-CaMKK2 pathways. Therapeutic dosing with a liver-homing pepducin, PZ-235, blocked PAR2-Gq signaling and afforded significant improvements in glycemic indices and HbA1c levels in severely diabetic mice.

This work provides evidence that PAR2 is a major regulator of liver glucose homeostasis and a potential new target for the treatment of diabetes and NASH.

Eliminating METTL1-mediated accumulation of PMN-MDSCs prevents HCC recurrence after radiofrequency ablation.

Hepatology

Radiofrequency ablation (RFA) is an important curative therapy in hepatocellular carcinoma (HCC), but recurrence rate remains high as all the other HCC therapeutic modalities. Methyltransferase 1 (METTL1), an enzyme for m7 G tRNA modification, was reported to promote HCC development. Here, we assessed the role of METTL1 in shaping the immunosuppressive tumor microenvironment after insufficient RFA (iRFA).

By IHC and multiplex immunofluorescence (mIF) staining, we showed that METTL1 expression was enhanced in post-RFA recurrent HCC, accompanied by increased CD11b+ CD15+ PMN-MDSCs and decreased CD8+ T cells. Mechanistically, heat-mediated METTL1 upregulation enhanced TGF-β2 translation to form the immunosuppressive environment by induction of MDSC. Liver specific overexpression or knockout of Mettl1 significantly affected the accumulation of PMN-MDSCs and subsequently affected CD8+ T cell infiltration. Complete RFA (cRFA) successfully eliminated the tumor, while iRFA-treated mice exhibited enhanced tumor growth and metastasis with increased PMN-MDSC accumulation and decreased CD8+ T cells compared to sham surgery. Interrupting METTL1-TGF-β2-PMN-MDSC axis by anti-Ly6G antibody, or knockdown of hepatoma-intrinsic Mettl1 or Tgfb2, or TGF-β signaling blockade significantly mitigated tumor progression induced by iRFA and restored CD8+ T cell population.

Our study sheds light on a previsouly unrevealed role of METTL1 in modulating an immunosuppressive microenvironment, and demonstrated that interrupting METTL1- TGF-β2-PMN-MDSC axis could be a novel therapeutic strategy to restore anti-tumor immunity and prevent HCC recurrence after RFA treatment, meriting further clinical studies.

Quaternary Nanoparticles Enable Sustained Release of Bortezomib for Hepatocellular Carcinoma.

Hepatology

Hepatocellular carcinoma (HCC) represents the 3rd leading cause of cancer-related mortality in the world. Over the past 2 decades, there has been minimal improvement in therapies as well as clinical outcomes for Barcelona Clinic Liver Cancer (BCLC)-B patients. These patients are treated with local interventions, including trans-arterial chemoembolization (TACE). Current methodologies only allow sustained intratumoral release measured in hours. Methodologies to allow sustained local release of the drug cargo over days to weeks are acutely needed. We hypothesize that tumor response as well as outcomes of BCLC-B patients can be improved through utilization of a highly cytotoxic agent delivered with a sustained release platform.

High throughput drug screening across 40 HCC patient derived organoids (PDOs) identified bortezomib (BTZ) as a highly cytotoxic small molecule for HCC. We designed and manufactured sustained release BTZ nanoparticles (BTZ-NP), using a novel flash nanocomplexation/nanoprecipitation (FNC/FNP) process. We quantified the release profile and tested the anti-tumoral effects in vivo. The BTZ-NP formulation demonstrated a sustained release of BTZ of 30 days. This BTZ-NP formulation was highly effective in controlling tumor size and improved survival in vivo in 3 animal models of HCC, including when delivered via the hepatic artery, as we envision its delivery in patients. In addition, the BTZ-NP formulation was superior to treatment with doxorubicin-DEB.

The novel BTZ-NP formulation provides a potent and safe treatment of HCC via a localized delivery approach. These results warrant additional pre-clinical studies to advance this technology to human clinical trials.

Progressive cholestasis and associated sclerosing cholangitis are frequent complications of COVID-19 in chronic liver disease patients.

Hepatology

Cholestasis is associated with disease severity and worse outcome in coronavirus disease of 2019 (COVID-19). Cases of secondary sclerosing cholangitis (SSC) after severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection have been described.

Hospitalized patients with COVID-19 between 03/2020 and 07/2021 were included. Patients were stratified as having (i) no chronic liver disease (CLD), (ii) non-advanced (non-ACLD), or (iii) advanced chronic liver disease (ACLD). CLD patients with non-COVID-19 pneumonia were matched to CLD patients with COVID-19 as a control cohort. Liver chemistries before (Pre), at first, second and third blood withdrawal after SARS-CoV-2 infection (T1-T3) and at last available time point (last) were recorded.

496 patients were included. 13.1% (n=65) had CLD (non-ACLD: 70.8%; ACLD: 29.2%); the predominant etiology was non-alcoholic fatty liver disease/non-alcoholic steatohepatitis (NAFLD/NASH; 60.0%). COVID-19-related liver injury was more common among CLD patients (24.6% vs. 10.6%; p=0.001). After SARS-CoV-2 infection, CLD patients exhibited progressive cholestasis with persistently increasing levels of alkaline phosphatase (ALP; Pre: 91.0 vs. T1: 121.0 vs. last: 175.0U/L; p<0.001) and gamma-glutamyl transferase (GGT; Pre: 95.0 vs. T1: 135.0 vs. last: 202.0U/L; p=0.001). 23.1% of CLD patients (n=15/65) developed cholestatic liver failure (cholestasis plus bilirubin ≥6mg/dL) during COVID-19 and 15.4% of patients (n=10/65) developed SSC. SSC was significantly more frequent among CLD patients with COVID-19 than in CLD patients with non-COVID-19 pneumonia (p=0.040). COVID-19-associated SSC occurred predominantly in NAFLD/NASH patients with metabolic risk factors. 26.3% (n=5/19) of ACLD patients experienced hepatic decompensation after SARS-CoV-2 infection.

About 20% of CLD patients develop progressive cholestasis after SARS-CoV-2 infection. NAFLD/NASH patients with metabolic risk factors are at particular risk for developing cholestatic liver failure and/or SSC after COVID-19.

Organoids and Regenerative Hepatology.

Hepatology

The burden of liver diseases is increasing worldwide, with liver transplantation remaining the only treatment option for end-stage liver disease. R...

Beyond circadian rhythms: Emerging roles of ultradian rhythms in control of liver functions.

Hepatology

The mammalian liver must cope with various metabolic and physiological changes that normally recur every day and primarily stem from daily cycles o...

Myeloid p38 activation maintains macrophage-liver crosstalk and BAT thermogenesis through IL-12-FGF21 axis.

Hepatology

Obesity features excessive fat accumulation in several body tissues and induces a state of chronic low-grade inflammation that contributes to the d...

PP2 protects from keratin mutation-associated liver injury and filament disruption via SRC kinase inhibition in male but not female mice.

Hepatology

Hepatocyte keratin polypeptides 8/18 (K8/K18) are unique among intermediate filaments proteins (IFs) in that their mutation predisposes to, rather than causes, human disease. Mice that overexpress human K18 R90C manifest disrupted hepatocyte keratin filaments with hyperphosphorylated keratins and predisposition to Fas-induced liver injury. We hypothesized that high-throughput screening will identify compounds that protect the liver from mutation-triggered predisposition to injury.

Using A549 cells transduced with a lentivirus K18 construct and high-throughput screening, we identified the SRC-family tyrosine kinases inhibitor, PP2, as a compound that reverses keratin filament disruption and protects from apoptotic cell death caused by K18 R90C mutation at this highly conserved arginine. PP2 ameliorated Fas-induced apoptosis and liver injury in male but not female K18 R90C mice. The PP2 male selectivity is due to its lower turnover in male versus female livers. Knockdown of SRC but not another kinase target of PP2, protein tyrosine kinase-6, in A549 cells abrogated the hepatoprotective effect of PP2. Phosphoproteomic analysis and validation showed that the protective effect of PP2 associates with Ser/Thr but not Tyr keratin hypophosphorylation, and differs from the sex-independent effect of the Ser/Thr kinase inhibitor PKC412. Inhibition of RAF kinase, a downstream target of SRC, by vemurafenib had a similar protective effect to PP2 in A549 cells and male K18 R90C mice.

PP2 protects, in a male-selective manner, keratin mutation-induced mouse liver injury by inhibiting SRC-triggered downstream Ser/Thr phosphorylation of K8/K18, which is phenocopied by RAF kinase inhibitor vemurafenib. The PP2/vemurafenib-associated findings, and their unique mechanisms of action, further support the potential role of select kinase inhibition as therapeutic opportunities for keratin and other IF-associated human diseases.

Hepatocellular Cystathionine γ lyase/Hydrogen sulfide Attenuates Non-Alcoholic Fatty Liver Disease by Activating Farnesoid X Receptor.

Hepatology

Hydrogen sulfide (H2 S) plays a protective role in non-alcoholic fatty liver disease (NAFLD). However, whether cystathionine gamma lyase (CSE), a dominant H2 S generating enzyme in hepatocytes, has a role in the pathogenesis of NAFLD is currently unclear.

We showed that CSE protein expression is dramatically down-regulated, especially in fibrotic areas, in livers from NAFLD patients. In high fat diet (HFD)-induced NAFLD mice, or an oleic acid-induced hepatocyte model, the CSE/H2 S pathway is also down-regulated. To illustrate a regulatory role for CSE in NAFLD, we generated a hepatocyte-specific CSE knockout mouse (CSELKO ). Feeding a HFD to CSELKO mice, they showed more hepatic lipid deposition with increased activity of the fatty acid de-novo synthesis pathway, increased hepatic insulin resistance and higher hepatic gluconeogenic ability, compared to CSELoxp control mice. By contrast, H2 S donor treatment attenuated these phenotypes. Furthermore, the protection conferred by H2 S was blocked by Farnesoid X receptor (FXR) knockdown. Consistently, serum deoxycholic acid and lithocholic acid (FXR antagonists) were increased, and tauro-β-muricholic acid (FXR activation elevated) was reduced in CSELKO . CSE/H2 S promoted a novel post-translation modification (sulfhydration) of FXR at Cys138/141 sites, thereby enhancing its activity to modulate expression of target genes related to lipid and glucose metabolism, inflammation, and fibrosis. Sulfhydration proteomics in patient's liver supported the CSE/H2 S modulation noted in the CSELKO mice.

FXR-sulfhydration is a novel post-translational modification affected by hepatic endogenous CSE/H2 S that may promote FXR activity and attenuate NAFLD. Hepatic CSE deficiency promotes development of non-alcoholic steatohepatitis. The interaction between H2 S and FXR may be amenable to therapeutic drug treatment in NAFLD.

Nonalcoholic Fatty Liver Disease and Accelerated Loss of Skeletal Muscle Mass: A Longitudinal Cohort Study.

Hepatology

Whether subjects with non-alcoholic fatty liver disease (NAFLD) are at increased risk of sarcopenia is not well established.

This is a cohort study of 52,815 men and women of 20 years of age or older who underwent at least 2 health check-up exams with bioelectrical impedance analysis and abdominal ultrasound imaging. Bioelectrical impedance analysis was used to calculate appendicular skeletal muscle mass (ASM). NAFLD was assessed by ultrasonography, and its severity was assessed by the NAFLD fibrosis score (NFS). We estimated the 5-year change in ASM comparing participants with and without NAFLD at baseline using mixed linear models. The 5-year change in ASM in participants without and with NAFLD was -225.2 g (95% CI -232.3, -218.0) and -281.3 g (95% CI -292.0, -270.6), respectively (P < 0.001). In multivariable adjusted analysis, the difference in 5-year change in ASM comparing participants with and without NAFLD was -39.9g (95% CI -53.1, -26.8). When participants with NAFLD were further divided by NAFLD severity, ASM loss was much faster in participants with NAFLD with intermediate to high NFS than in those with low NFS.

Participants with NAFLD were at increased risk of sarcopenia, indicated by faster loss of skeletal muscle mass. Patients with NAFLD may need screening and early intervention to mitigate skeletal muscle mass loss.