Liver Cell Injury Research Articles

Major Histocompatibility Complex Class I-Related Chain A Alleles and Histology of Nonalcoholic Fatty Liver Disease.

Major histocompatibility complex class I‐related chain A (MICA) is a highly polymorphic gene that modulates immune surveillance by binding to its receptor on natural killer cells, and its genetic polymorphisms have been associated with chronic immune‐mediated diseases. The progressive form of nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), is characterized by accumulation of fat and inflammatory cells in the hepatic parenchyma, potentially leading to liver cell injury and fibrosis. To date, there are no data describing the potential role of MICA in the pathogenesis of NAFLD. Therefore, our aim was to assess the association between MICA polymorphism and NASH and its histologic features. A total of 134 subjects were included. DNA from patients with biopsy‐proven NAFLD were genotyped using polymerase chain reaction–sequence‐specific oligonucleotide for MICA alleles. Liver biopsies were assessed for histologic diagnosis of NASH and specific pathologic features, including stage of fibrosis and grade of inflammation. Multivariate analysis was performed to draw associations between MICA alleles and the different variables; P ≤ 0.05 was considered significant. Univariate analysis showed that MICA*011 (odds ratio [OR], 7.14; 95% confidence interval [CI], 1.24‐41.0; P = 0.04) was associated with a higher risk for histologic NASH. Multivariate analysis showed that MICA*002 was independently associated with a lower risk for focal hepatocyte necrosis (OR, 0.24; 95% CI, 0.08‐0.74; P = 0.013) and advanced fibrosis (OR, 0.11; 95% CI, 0.02‐0.70; P = 0.019). MICA*017 was independently associated with a higher risk for lymphocyte‐mediated inflammation (OR, 5.12; 95% CI, 1.12‐23.5; P = 0.035). Conclusion: MICA alleles may be associated with NASH and its histologic features of inflammation and fibrosis. Additional research is required to investigate the potential role of MICA in increased risk or protection against NAFLD.

Protective effect of Lycium barbarum polysaccharide on ethanol-induced injury in human hepatocyte and its mechanism.

The purpose of this research is to study the effect of Lycium barbarum polysaccharide on ethanol-induced liver injury and its mechanism. The cell survival rate, the apoptosis rate, and the intracellular ROS level was detected by MTT assay, flow cytometry, laser confocal microscopy, and fluorescence spectrophotometry, respectively. The antioxidativeindices were determined by ELISA kits and the protein level was detected by western blot. The result showed Lycium barbarum polysaccharide could protect ethanol-induced cell injury by reducing cell apoptosis and regulating the levels of indicators related to oxidative stress, such as ROS, MDA, SOD, etc. In addition, LBP could increase the nuclear expression of Nrf2 protein and significantly up-regulate the expression levels of Nrf2 protein and its downstream proteins, such as HO-1, NQO1, and GCLC in the cell nucleus. Therefore, Lycium barbarum polysaccharide has a protective effect on ethanol-induced liver cell injury and it plays the role in cell apoptosis pathway and oxidative stress pathway. PRACTICAL APPLICATIONS: Lycium barbarum is a kind of food that can be used as food and medicine in China. The result showed that Lycium barbarum polysaccharide could protect ethanol-induced liver cell injury, which is beneficial to the application of LBP in functional food.

From the Editor's Desk…

From the Editor's Desk…

Chlorpyrifos induces the apoptosis and necroptosis of L8824 cells through the ROS/PTEN/PI3K/AKT axis

Excessive chlorpyrifos (CPF) in the environment causes toxicity to nontarget organisms by triggering oxidative stress. Phosphatase and tensin homolog deleted on chromosome ten (PTEN) plays an important role in controlling apoptosis and necrosis by negatively regulating the phosphatidylinositol 3-kinase/threonine kinase (PI3K/AKT) pathway. However, the effects of different concentrations of CPF on grass fish liver cell injury and the role of the ROS/PTEN/PI3K/AKT axis remain poorly understood. In this study, L8824 cells treated with different concentrations of CPF (0, 40, 60, or 80 μM) were used as the research object. The results showed that the median inhibitory concentration (IC50) was 112.226 μM. As the CPF concentrations increased, the ROS and MDA levels increased, and the T-AOC levels and SOD/GPx/GST activities decreased. As PTEN expression increased, PI3K/AKT, BCL-2, and Caspase-8 expression dramatically decreased. Conversely, RIPK1/RIPK3/MLKL and Bax/Cyt-c/Caspase-3 expression increased. Additionally, necroptosis increased in a dose-dependent manner, while apoptosis first increased and then decreased. In conclusion, our study showed that CPF could trigger oxidative stress and induce apoptosis and necroptosis in fish liver cells by regulating the ROS/PTEN/PI3K/AKT axis, and the type of damage induced was dose-dependent. These results are meaningful for toxicological studies of CPF and efforts to protect the ecosystem.

Pyrazinamide enhances lipid peroxidation and antioxidant levels to induce liver injury in rat models through PI3k/Akt inhibition.

Pyrazinamide (PZA) is an anti-tuberculosis drug known to causes liver injury. phosphatidylinositol-3-kinase/protein kinase B (PI3K/Akt) signaling protects against liver injury by promoting cellular antioxidant defenses and reducing intracellular reactive oxygen species (ROS) and lipid peroxidation. The regulatory mechanisms and functions of PI3K/Akt signaling during the hepatotoxicity of PZA are however not fully understood. Rats were administered PZA or/and the PI3K activator (740Y-P) for 7days. The levels of serum parameters were examined via standard enzymatic techniques and the pathological status of the liver was confirmed by H & E staining. The levels of lipid peroxidation and antioxidant production were determined using commercial kits. Liver apoptosis was assessed by TUNEL staining. The expression of apoptosis-related proteins and PI3K/Akt signaling were assessed by western blot analysis. PZA treatment significantly increased serum alanine transaminase, aspartate transaminase, gamma-glutamyl transpeptidase and tall bilirubin leading to liver damage in rats. PZA also facilitated lipid peroxidation and suppressed antioxidant defenses. PZA led to apoptotic induction in rat liver cells through the downregulation of Bcl-2 and the upregulation of Bax and caspase-3. PZA also dramatically inhibited PI3K/Akt signaling in rat liver cells. We further verified that PI3K/Akt signaling in response to 740Y-P could attenuate hepatic injury, lipid peroxidation and apoptosis in rat liver cells in response to PZA. We reveal that PZA-induced liver injury in rats occurs through PI3k/Akt signaling, the recovery of which prevents liver injury in rat models.

Genome-wide and Mendelian randomisation studies of liver MRI yield insights into the pathogenesis of steatohepatitis

Background & AimsMRI-based corrected T1 (cT1) is a non-invasive method to grade the severity of steatohepatitis and liver fibrosis. We aimed to identify genetic variants influencing liver cT1 and use genetics to understand mechanisms underlying liver fibroinflammatory disease and its link with other metabolic traits and diseases.MethodsFirst, we performed a genome-wide association study (GWAS) in 14,440 Europeans, with liver cT1 measures, from the UK Biobank. Second, we explored the effects of the cT1 variants on liver blood tests, and a range of metabolic traits and diseases. Third, we used Mendelian randomisation to test the causal effects of 24 predominantly metabolic traits on liver cT1 measures.ResultsWe identified 6 independent genetic variants associated with liver cT1 that reached the GWAS significance threshold (p <5×10-8). Four of the variants (rs759359281 in SLC30A10, rs13107325 in SLC39A8, rs58542926 in TM6SF2, rs738409 in PNPLA3) were also associated with elevated aminotransferases and had variable effects on liver fat and other metabolic traits. Insulin resistance, type 2 diabetes, non-alcoholic fatty liver and body mass index were causally associated with elevated cT1, whilst favourable adiposity (instrumented by variants associated with higher adiposity but lower risk of cardiometabolic disease and lower liver fat) was found to be protective.ConclusionThe association between 2 metal ion transporters and cT1 indicates an important new mechanism in steatohepatitis. Future studies are needed to determine whether interventions targeting the identified transporters might prevent liver disease in at-risk individuals.Lay summaryWe estimated levels of liver inflammation and scarring based on magnetic resonance imaging of 14,440 UK Biobank participants. We performed a genetic study and identified variations in 6 genes associated with levels of liver inflammation and scarring. Participants with variations in 4 of these genes also had higher levels of markers of liver cell injury in blood samples, further validating their role in liver health. Two identified genes are involved in the transport of metal ions in our body. Further investigation of these variations may lead to better detection, assessment, and/or treatment of liver inflammation and scarring.

Dendrobium officinale polysaccharides protected against ethanol-induced acute liver injury in vivo and in vitro via the TLR4/NF-κB signaling pathway

Alcohol-induced liver injury is characterized by strong inflammation. Polysaccharides separated from herbs can prevent ethanol-induced liver injury. Dendrobium officinale Kimura et Migo leaves (D. officinale) are a new food resource that contains a certain amount of polysaccharide. However, the hepatoprotective effects and the potential mechanisms of D. officinale polysaccharide (DOP) remain unknown. Thus, this study aimed to assess the hepatoprotective effects and potential mechanism in vivo and in vitro of DOP. Male Sprague–Dawley rats were used to establish alcohol-induced liver injury models through the oral gavage of absolute alcohol (5 mL/kg) after the oral administration of DOP (400 and 100 mg/kg) for 30 days. Hematoxylin–eosin staining was used for the histological assessments of hepatocyte degeneration, and the AST and ALT levels in the serum and liver tissue were measured. The inflammatory markers were evaluated using ELISA and immunohistochemistry. The potential mechanism of DOP in alcohol-induced liver cell (LO2) injury in vitro was further identified. Results showed that DOP clearly decreased the AST in the serum and hepatic tissue, obviously reduced the production of inflammatory cytokines (such as IL-1β, IL-6, and TNF-α), and can successfully inhibit NF-κB phosphorylation in vivo. In vitro experiments indicated that DOP increased the LO2 cell viability; prevented LDH release prominently; reduced the secretion of IL-1β, IL-6, and TNF-α; and reversed the expression of IL-1β, IL-6, TNF-α, caspase 1, NLRP3, p-NF-κB, and TLR4. Overall, DOP can alleviate ethanol-induced acute liver injury via the TLR4/NF-κB signaling pathway.

Antioxidant, Hypolipidemic and Hepatic Protective Activities of Polysaccharides from Phascolosoma esculenta.

The aims of this study were to investigate the antioxidant, hypolipidemic and hepatic protective effects of Phascolosoma esculenta polysaccharides (PEP). PEP was prepared from Phascolosoma esculenta by enzyme hydrolysis and its characterization was analyzed. The antioxidant activities of PEP were evaluated by the assays of scavenging 1,1-Diphenyl-2-picrylhydrazyl (DPPH), superoxide anion, hydroxyl radicals and chelating ferrous ion in vitro. It showed that PEP could scavenge radicals effectively and had favorable antioxidant activities. In the meantime, the hypolipidemic effect of PEP was investigated in vivo by using mice model fed with high-fat diet with or without PEP treatment. Compared with the hyperlipidemic mice without treatment, the serum levels of total cholesterol (TC) (30.1–35.7%, p < 0.01), triglyceride (TG) (24.5–50.8%, p < 0.01 or p < 0.05), low-density lipoprotein cholesterol (LDL-C) (49.6–56.8%, p < 0.01) and liver levels of TC (21.0–28.4%, p < 0.01), TG (23.8–37.0%, p < 0.01) decreased significantly, whereas serum high-density lipoprotein cholesterol (HDL-C) (47.7–59.9%, p < 0.01 or p < 0.05) increased significantly after treatment with different dosage of PEP (0.2, 0.4 and 0.8 g per kg body weight, respectively). In addition, superoxide dismutase (SOD) (10.2–22.2% and 18.8–26.9%, p < 0.05), glutathione peroxidase (GSH-Px) (11.9–15.4% and 26.6–30.4%, p < 0.05) activities in serum and liver enhanced markedly while aspartate aminotransferase (AST) (18.7–29.6% and 42.4–58.0%, p < 0.05), alanine transaminase (ALT) (42.7–46.0% and 31.2–42.2%, p < 0.05) activities, as well as the levels of malondialdehyde (MDA) (15.9–24.4% and 15.0–16.8%, p < 0.01 or p < 0.05) in serum and liver reduced markedly. Moreover, the histopathological observation of livers indicated that PEP could attenuate liver cell injury. The animal experimental results demonstrated that PEP exerted hypolipidemic and hepatoprotective roles in hyperlipidemic mice. In summary, our results above suggest that PEP might be a potential natural antioxidant and utilized as a therapeutic candidate for hyperlipidemia.

The implementation of drug reposition for alcoholic hepatitis based on a sub-pathway integration strategy.

BackgroundAlcoholic hepatitis (AH) is one of the most severe forms of liver disease. The therapies which are currently available are not entirely effective, and thus novel therapies are urgently needed. However, the development of these novel therapies is limited due to incomplete information about the molecular mechanisms involved in AH.MethodsThe microarray data (GSE28619) was downloaded from the Gene Expression Omnibus (GEO) database. The differentially expressed genes (DEGs) between the AH and the control samples were identified using the significant analysis of microarrays (SAM) method. Metabolic sub-pathways were identified using the SubpathwayMiner R package. Cell Counting Kit-8 (CCK-8) was used to evaluate the cell viability of AML-12 cells treated with different concentrations of ethanol or riboflavin. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were employed to show the hepatocyte function.ResultsA total of 1,041 genes were determined to be expressed differentially. We then identified 11 metabolic sub-pathways that could be involved in the development of AH. This was followed by a final integrated analysis of the sub-pathways involved in AH as well as the sub-pathways involved in the drug-affected cases. The final integration results led to the identification of 64 small molecular drugs. A potential novel drug (riboflavin) involved in the fatty acid metabolism pathway was identified for further investigation. Riboflavin at the 60 nM for 24 h could reverse ethanol-induced AML-12 cell injury and could markedly decrease ALT and AST activity. The decrease in the activities of these two enzymes was observed in a dose-dependent manner when it was compared to ethanol alone, which suggests that riboflavin has a protective effect against liver cell injury caused by alcoholism.ConclusionsTo summarize, the candidate agents which are identified in the present study might give practitioners insight into the development of novel therapeutic approaches for AH.

Alanine Aminotransferase and 20-Year Risk of Major Chronic Diseases and Death in a Healthy Cohort Aged 30 to 49 Years.

PurposeAlanine aminotransferase is the most frequently used marker of liver cell injury. We examined the association between alanine aminotransferase levels and long-term absolute risks of morbidity and mortality in healthy Danish people aged 30–49 years.Patients and MethodsWe divided 671 healthy participants from the Ebeltoft Health Promotion Project into four categories based on their baseline alanine aminotransferase values: low (≤10U/l), medium-low (men: 11–34U/l, women: 11–22U/l), medium-high (men: 35–69U/l, women: 23–44U/l) and high (men: ≥70U/l, women: ≥45U/l), and followed them through Danish healthcare registries for up to 20 years. We examined mortality and absolute risks of liver disease, overall cancer, ischemic heart disease, and diabetes.ResultsThe risk of any cancer was highest for participants with “low alanine aminotransferase” or “high alanine aminotransferase” (20-year risk: 17.2% [95% confidence interval (CI): 6.3–32.7%] and 18.2% [95% CI: 5.7–36.3%], respectively). The risk of diabetes was highest for participants with “medium-high alanine aminotransferase” or “high alanine aminotransferase” (20-year risk: 12.1% [95% CI: 7.3–18.3%] and 9.1% [95% CI: 1.6–25.1%], respectively). Participants with “high alanine aminotransferase” had the highest 20-year risk of liver disease (20-year risk: 13.6% [95% CI: 3.4–30.9%], while it was 1.0% or less in the other groups). The chance of being alive after 20 years without having been diagnosed with liver disease, cancer, ischemic heart disease, or diabetes was lowest in the “high alanine aminotransferase” group (50% [95% CI: 28–68%]) and 72–79% in the other groups.ConclusionOur findings suggest that persons with high or abnormally low alanine aminotransferase measurements are at increased long-term risk of several chronic diseases.

Effect of HBx on inflammation and mitochondrial oxidative stress in mouse hepatocytes

Hepatitis B virus × protein (HBx) serves an important role in the pathogenesis of the hepatitis B virus infection. Previous studies have reported that the interaction between HBx and hepatocyte mitochondria is an important factor leading to liver cell injury and apoptosis, ultimately inducing the formation of liver cancer. In the present study, a mouse model expressing HBx was constructed using hydrodynamic in vivo transfection based on the interaction between HBx and cytochrome c oxidase (COX) subunit III. The specific mechanism of HBx-induced oxidative stress in mouse hepatocytes and the subsequent effect on mitochondrial function and inflammatory injury was assessed. The results demonstrated that HBx reduced the activity of COX and the expression of superoxide dismutase and upregulated the expression of malondialdehyde, NF-κB and phospho-AKT, thus increasing oxidative stress. In addition, HBx induced an increase in interleukin (IL)-6, IL-1β and IL-18 expression levels, which created an inflammatory microenvironment in the liver, further promoting hepatocyte inflammatory injury. Therefore, it was proposed that HBx may affect hepatocyte mitochondrial respiration by reducing the activity of cytochrome c oxidase, leading to mitochondrial dysfunction and inducing hepatocyte inflammation and injury.

Are Liver Pericytes Just Precursors of Myofibroblasts in Hepatic Diseases? Insights from the Crosstalk between Perivascular and Inflammatory Cells in Liver Injury and Repair.

Cirrhosis, a late form of liver disease, is characterized by extensive scarring due to exacerbated secretion of extracellular matrix proteins by myofibroblasts that develop during this process. These myofibroblasts arise mainly from hepatic stellate cells (HSCs), liver-specific pericytes that become activated at the onset of liver injury. Consequently, HSCs tend to be viewed mainly as myofibroblast precursors in a fibrotic process driven by inflammation. Here, the molecular interactions between liver pericytes and inflammatory cells such as macrophages and neutrophils at the first moments after injury and during the healing process are brought into focus. Data on HSCs and pericytes from other tissues indicate that these cells are able to sense pathogen- and damage-associated molecular patterns and have an important proinflammatory role in the initial stages of liver injury. On the other hand, further data suggest that as the healing process evolves, activated HSCs play a role in skewing the initial proinflammatory (M1) macrophage polarization by contributing to the emergence of alternatively activated, pro-regenerative (M2-like) macrophages. Finally, data suggesting that some HSCs activated during liver injury could behave as hepatic progenitor or stem cells will be discussed.

An HBV-encoded miRNA activates innate immunity to restrict HBV replication.

We previously identified that hepatitis B virus (HBV) encodes a microRNA (HBV-miR-3) that restrains HBV replication by targeting the HBV transcript. However, whether HBV-miR-3 affects host innate immunity to modulate HBV replication remains unclear. Here, we examined the vital functions of HBV-miR-3 in the innate immune response after HBV infection. We found that HBV-miR-3 expression gradually increased in a dose- and time-dependent manner in HBV-infected HepG2-NTCP cells. HBV-miR-3 activated the JAK/STAT signaling pathway by downregulating SOCS5 in hepatocytes, thereby enhancing the IFN-induced anti-HBV effect. In addition, HBV-miR-3 in exosomes facilitated the M1 polarization of macrophages. Furthermore, exosomes containing HBV-miR-3 enhanced the secretion of IL-6 via inhibiting the SOCS5-mediated ubiquitination of EGFR. In short, these results demonstrate that HBV-miR-3 activates the innate immune response to restrain HBV replication by multiple pathways, which may suppress HBV-induced acute liver cell injury and affect the progression of persistent HBV infection.

Cadmium-induced cytotoxicity in mouse liver cells is associated with the disruption of autophagic flux via inhibiting the fusion of autophagosomes and lysosomes

Cadmium (Cd) is an important environmental pollutant. Previous studies have shown that Cd can induce liver cell injury; however, the toxicity mechanisms of Cd have not been fully elucidated. This study aimed to further confirm the hepatotoxic effects of Cd in mouse liver cells by various methods both in vivo and in vitro. In addition, it found that Cd induced autophagy but also caused autophagy blockade, and autophagy blockade intensified Cd-induced injury in liver cells. Subsequently, the study investigated the effects of Cd on lysosomes and found that Cd induced lysosomal acidification, promoted the expression of lysosomal-associated membrane protein 2 and lysosomal hydrolase cathepsin B both in vivo and in vitro, and enhanced the lysosomal degradation capacity. It indicated that Cd triggered lysosomal activation. However, the fusion of autophagosomes with lysosomes was inhibited by Cd both in vivo and in vitro. Next, the expression of Rab7, a key protein that regulates autophagosome–lysosome fusion, was examined. Cd was found to inhibit Rab7 expression both in vivo and in vitro. In conclusion, the results indicated that Cd obstructed the autophagic flux by inhibiting the fusion of autophagosomes with lysosomes, thus exacerbating the Cd-induced hepatotoxicity. Moreover, the molecular mechanism of Cd-induced inhibition of autophagosome–lysosome fusion is probably related to the Cd-induced downregulation of Rab7.

Insulin sensitizer MSDC-0602K in non-alcoholic steatohepatitis: A randomized, double-blind, placebo-controlled phase IIb study

MSDC-0602K is a novel insulin sensitizer designed to preferentially target the mitochondrial pyruvate carrier while minimizing direct binding to the transcriptional factor PPARγ. Herein, we aimed to assess the efficacy and safety of MSDC-0602K in patients with non-alcoholic steatohepatitis. Patients with biopsy-confirmed NASH and fibrosis (F1-F3) were randomized to daily oral placebo, or 1 of 3 MSDC-0602K doses in a 52-week double-blind study. The primary efficacy endpoint was hepatic histological improvement of ≥2 points in non-alcoholic fatty liver disease activity score (NAS) with a ≥1-point reduction in either ballooning or lobular inflammation and no increase in fibrosis stage at 12 months. Secondary endpoints included NAS improvement without worsening fibrosis, NASH resolution, and fibrosis reduction. Exploratory endpoints included changes in insulin sensitivity, liver injury and liver fibrosis markers. Patients were randomly assigned to placebo (n = 94), or 62.5 mg (n = 99), 125 mg (n = 98), or 250 mg (n = 101) of MSDC-0602K. At baseline, glycated hemoglobin was 6.4 ± 1.0%, 61.5% of patients had fibrosis F2/F3 and the average NAS was 5.3. The primary endpoint was reached in 29.7%, 29.8%, 32.9% and 39.5% of patients in the placebo, 62.5 mg, 125 mg and 250 mg dose arms, respectively, with adjusted odds ratios relative to placebo of 0.89 (95% CI 0.44-1.81), 1.22 (95% CI 0.60-2.48), and 1.64 (95% CI 0.83-3.27). The 2 highest doses of MSDC-0602K led to significant reductions in glucose, glycated hemoglobin, insulin, liver enzymes and NAS compared to placebo. The incidence of hypoglycemia and PPARγ-agonist-associated events such as edema and fractures were similar in the placebo and MSDC-0602K groups. MSDC-0602K did not demonstrate statistically significant effects on primary and secondary liver histology endpoints. However, effects on non-invasive measures of liver cell injury and glucose metabolism support further exploration of MSDC-0602K's safety and potential efficacy in patients with type 2 diabetes and liver injury. [ClinicalTrials.gov Identifier: NCT02784444]. First-generation insulin sensitizers are used to treat type 2 diabetes, but are associated with side effects including edema, bone fractures, and hypoglycemia. MSDC-0602K is a second-generation insulin sensitizer designed to reduce these side effects. We hypothesized that insulin sensitization could improve non-alcoholic steatohepatitis. In the current study of patients with non-alcoholic steatohepatitis, MSDC-0602K did not demonstrate significant effects on liver histology with the biopsy techniques used. However, useful information was gained for the design of future studies and MSDC-0602K significantly decreased fasting glucose, insulin, glycated hemoglobin, and markers of liver injury without dose-limiting side effects.

Jak-Stat Signaling Induced by Interleukin-6 Family Cytokines in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide. It can be caused by chronic liver cell injury with resulting sustained inflammation, e.g., triggered by infections with hepatitis viruses B (HBV) and C (HCV). Death of hepatocytes leads to the activation of compensatory mechanisms, which can ultimately result in liver fibrosis and cirrhosis. Another common feature is the infiltration of the liver with inflammatory cells, which secrete cytokines and chemokines that act directly on the hepatocytes. Among several secreted proteins, members of the interleukin-6 (IL-6) family of cytokines have emerged as important regulatory proteins that might constitute an attractive target for therapeutic intervention. The IL-6-type cytokines activate multiple intracellular signaling pathways, and especially the Jak/STAT cascade has been shown to be crucial for HCC development. In this review, we give an overview about HCC pathogenesis with respect to IL-6-type cytokines and the Jak/STAT pathway. We highlight the role of mutations in genes encoding several proteins involved in the cytokine/Jak/STAT axis and summarize current knowledge about IL-6 family cytokines in this context. We further discuss possible anti-cytokine therapies for HCC patients in comparison to already established therapies.

LncRNA H19/microRNA-675/PPARα axis regulates liver cell injury and energy metabolism remodelling induced by hepatitis B X protein via Akt/mTOR signalling

Emerging evidence indicates that the lncRNAs/microRNA/mRNA axis plays important roles in a variety of diseases. This study was aimed to investigate the potential roles and underlying molecular mechanisms of lncRNA H19 and H19-derived miR-675 in regulating hepatitis B virus (HBV)-associated liver injury. mRNA and miR-675 levels were determined by quantitative real-time PCR (qRT-PCR), protein levels were determined by western blot, cell viability was measured by the MTT assay, cell apoptosis was measured by flow cytometry, inflammatory cytokine production was determined by ELISA, oxidative stress and energy metabolism were assessed by commercial kits, and the target relationship between PPARα and miR-675 was confirmed by the dual-luciferase reporter assay. The results showed that the expression of lncRNA H19 and miR-675 was up-regulated in patients with chronic hepatitis B (n = 20). Inhibition of lncRNA H19 or miR-675 in L02 cells increased cell viability, suppressed hepatitis B X protein (HBx)-induced cell apoptosis, inflammatory cytokine production, and oxidative stress, and remodelled energy metabolism. Furthermore, PPARα was found to be a target gene of miR-675. The expression of PPARα was down-regulated in patients with chronic hepatitis B, and there was a negative correlation between the expression of lncRNA H19 and PPARα, or between miR-675 and PPARα. Moreover, by knocking down the expression of PPARα, the actions (apoptosis, inflammatory factors, oxidative stress, and energy metabolism) of lncRNA H19 or miR-675 inhibition in HBx-induced L02 cells were at least partially reversed. In addition, HBx-induced elevated levels of p-AktSer473, p-AktThr308 and p-mTORSer2448 were down-regulated by lncRNA H19 or miR-675 inhibition. Furthermore, PPARα knockdown partly reversed the down-regulated effects of H19 or miR-675 inhibition. Taken together, these data indicate that the lncRNA H19/miR-675/PPARα axis regulates liver cell injury and energy metabolism remodelling induced by HBx, which may be related to the modulation of Akt/mTOR signalling.

The role of stem cells in liver injury and repair

ABSTRACTIntroduction: Liver disease is an increasing cause of worldwide mortality, and currently the only curative treatment for end-stage liver disease is whole organ allograft transplantation. Whilst this is an effective treatment, there is a shortage of suitable grafts and consequently some patients die whilst on the waiting list. Cell therapy provides an alternative treatment to increase liver function and potentially ameliorate fibrosis.Areas covered: In this review, we discuss the different cellular sources for therapy investigated to date in humans including mature hepatocytes, hematopoietic stem cells, mesenchymal stromal cells and hepatic progenitor cells. Cells investigated in animals include embryonic stem cells, induced pluripotent stem cells and directly reprogrammed cells. We then appraise the experience and evidence base underlying each cell type.Expert opinion: We discuss how this field may evolve in the years to come focusing on opportunities to enhance the intrinsic regenerative response with therapeutic targets and cell therapies. Growing expertise in tissue engineering will likely lead to increasingly complex bio-reactors and bio-artificial livers, which open a further avenue to restore liver function and delay or prevent the need for transplantation.

A Structured Literature Review of the Epidemiology and Disease Burden of Non-Alcoholic Steatohepatitis (NASH).

IntroductionNon-Alcoholic Steatohepatitis (NASH) is a chronic, progressive disease characterized by fatty liver and liver cell injury, advancing to fibrosis, cirrhosis and hepatocellular carcinoma (HCC). Diagnosis involves liver biopsy; however, as a result of its high cost and invasiveness, NASH remains underdiagnosed, and accurate burden of disease (BoD) data are lacking. Our aim was to understand the epidemiological and BoD landscape in NASH and identify knowledge gaps.MethodsThe Ovid search engine was used to conduct a structured review, following quality systematic principles. It included publications that reported on epidemiology, quality of life (QoL) and BoD outcomes in NASH adults. Searches were limited to English language studies published between January 2007 and September 2017. Additional grey literature searches were conducted. A total of 53 references were selected; 38 were peer-reviewed and 15 were grey literature sources.ResultsNASH is estimated to affect 3–5% of the global population, most suffering from several comorbidities. Advancing fibrosis drives clinical outcomes, with approximately 20% of patients developing cirrhosis and/or HCC, the latter being a leading cause of death in NASH. A recent model predicted the 15-year survival of advanced fibrosis patients at F3 and F4 as 51.0% and 28.4%, respectively. The limited data consistently show that NASH patients experience significantly poorer QoL and higher costs compared to non-NASH patients.ConclusionThis first broad-ranging examination of NASH literature revealed a paucity of evidence, with poor-quality, small studies found. The overwhelming impact of NASH and its patient and healthcare burden is evident. Further evidence is needed to improve our understanding of NASH, especially as fibrosis stages advance.FundingGilead Science Inc.Electronic supplementary materialThe online version of this article (10.1007/s12325-019-00960-3) contains supplementary material, which is available to authorized users.

Serum Ferritin level, microalbuminuria and non-alcoholic fatty liver disease in type 2 diabetic patients

BackgroundNon-alcoholic fatty liver disease (NAFLD) was considered one of the most common causes of chronic liver disease and is considered the hepatic manifestation of type 2 diabetes mellitus (T2DM). The factors that lead to marked fibrosis and liver cell injury in NAFLD are still remaining undiscovered. Patients and methodsThis study included (40) type 2 diabetic patients with NAFLD and (40) diabetic patients without NAFLD beside 15 healthy persons as a control group. All of them were subjected to full history taking, thorough clinical examination with especial stress on body weight (BW), height, body mass index (BMI), waist-hip ratio, blood pressure. Laboratory tests included serum total cholesterol (TC), triglycerides (TG), low density lipoprotein (LDL) and high-density lipoprotein (HDL), fasting blood glucose (FBG) and 2-h postprandial blood glucose (PBG), serum Ferritin and urine microalbuminuria (MAU). ResultsDuration of diabetes, BW, BMI and blood pressure were significantly higher in NAFLD group (P = 0.001). FBG, PBG, TC, TG, LDL, serum Ferritin and MAU were significantly increased in NAFLD group with significant difference between two studied groups as regard HDL. There was a highly significant correlation between serum Ferritin with BW, BMI, duration of diabetes, TC, TG, LDL and MAU. There was a significant correlation between serum Ferritin with age, waist hip ratio, duration of diabetes, SBP, FBG, PBG and HDL. There was a significant correlation between MAU and age, weight, BMI, waist hip ratio, duration of diabetes, DBP, FBG TC, TG, LDL and HDL. ConclusionNAFLD is a common liver disorder in diabetic patients. NAFLD is significantly associated with microalbuminuria and elevated serum Ferritin.