Calreticulin regulates hepatic stellate cell activation through modulating TGF-beta-induced Smad signaling.

Liver fibrosis is characterized by excessive deposition of extracellular matrix (ECM) as a wound healing process. Activated hepatic stellate cells (HpSCs) are the major producer of the ECM and play a central role in liver fibrogenesis. It has been widely accepted that elimination of activated HpSCs or reversion to a quiescent state can be a feasible strategy for resolving the disease, further highlighting the urgent need for novel therapeutic targets. Calreticulin (CRT) is a molecular chaperone that normally resides in the endoplasmic reticulum (ER), important in protein folding and trafficking through the secretory pathway. CRT also plays a critical role in calcium (Ca2+) homeostasis, with its Ca2+ storage capacity. In the current study, we aimed to demonstrate its function in directing HpSC activation. In a mouse liver injury model, CRT was up-regulated in HpSCs. In cellular experiments, we further showed that this activation was through modulating the canonical TGF-ß signaling. As down-regulation of CRT in HpSCs elevated intracellular Ca2+ levels through a form of Ca2+ influx, named store-operated Ca2+ entry (SOCE), we examined whether moderating SOCE affected TGF-ß signaling. Interestingly, blocking SOCE had little effect on TGF-ß-induced gene expression. In contrast, inhibition of ER Ca2+ release using the inositol trisphosphate receptor inhibitor 2-APB increased TGF-ß signaling. Treatment with 2-APB did not alter SOCE but decreased intracellular Ca2+ at the basal level. Indeed, adjusting Ca2+ concentrations by EGTA or BAPTA-AM chelation further enhanced TGF-ß-induced signaling. Our results suggest a crucial role of CRT in the liver fibrogenic process through modulating Ca2+ concentrations and TGF-ß signaling in HpSCs, which may provide new information and help advance the current discoveries for liver fibrosis.

Immune Responses to Anti-Hepatitis C Virus Antibodies during Pre-Liver Transplantation Direct-Acting Antiviral Therapy in Hepatitis C Virus-Infected Recipients Associated with Post-Liver Transplantation Allograft Injury.

BACKGROUND AND AIMS: The impact of antibody responses following direct-acting antiviral (DAA) therapy in hepatitis C virus (HCV)-infected recipients before and after liver transplantation (LT) is still undetermined. METHODS: In this observational cohort study, we aimed to explore the association between changes in anti-HCV antibody titers following pre-LT DAA therapy and allograft injury, including biliary complications (BCs) and acute cellular rejection (ACR). RESULTS: A total of 153 cases were enrolled from January 2015 to February 2021. Serum anti-HCV antibody titers were assessed before and after (day 30) LT. Among all recipients, 31/153 (20.3%) had pre-LT DAA therapy (the DAA group) and 122/153 (79.7%) did not undergo pre-LT DAA therapy (the DAA-naïve group). A higher incidence of post-LT BCs was observed in the DAA group (p = 0.028). Compared with the DAA-naïve group, the DAA group had a significantly higher mean level of anti-HCV titer upregulation (p = 0.0024); furthermore, among the recipients with BCs (n = 28) and ACR (n = 41), those in the DAA group exhibited significantly higher mean levels of anti-HCV antibody titer upregulation (p < 0.005). CONCLUSIONS: In conclusion, we speculate that the upregulation of anti-HCV antibody titers, which might have been induced via the restoration of HCV-specific immune responses through pre-LT DAA therapy, was associated with post-LT allograft injury.

Telbivudine-Induced Myopathy: Clinical Features, Histopathological Characteristics, and Risk Factors.

BACKGROUND AND PURPOSE: Oral nucleos(t)ide analogs (NAs) are the mainstay treatment for chronic hepatitis B (CHB). Myotoxicity is an important extrahepatic effect related to NA treatment. Telbivudine is the NA for CHB that is frequently associated with muscle-related side effects. The risk factors for telbivudine-induced myopathy (TIM) are not yet clear. METHODS: This study characterized the clinical, magnetic resonance images (MRI), and pathological features of 12 TIM cases. A group of telbivudine-tolerant (TT) patients with CHB who received regular telbivudine treatment during the same period without the occurrence of myopathy was collected. Demographic and clinical factors were compared between the patients with TIM and the TT controls. Factors independently associated with TIM were identified using logistic regression analysis. RESULTS: The patients with TIM (males/females: 7/5, mean age: 57 years) developed myopathy after using telbivudine for a median period of 19.5 months. Muscle histopathology revealed abnormal proliferation, subsarcolemmal or sarcoplasmic accumulations, and ultrastructural defects of mitochondria. When compared with TT cases, patients with TIM had a lower estimated glomerular filtration rate and were more frequently positive for hepatitis B e antigen (HBeAg). CONCLUSIONS: Mitochondrial abnormalities are characteristic histopathological features, and impaired renal function and HBeAg positivity are risk factors for TIM. Telbivudine-induced mitochondrial dysfunction and immune activation related to mitochondrial damage and HBeAg serostatus changes may underlie TIM. Constant clinical surveillance of myopathy during telbivudine treatment is needed due to the significant latency of its development. Dose adjustment for impaired renal function does not eliminate the risk of TIM occurrence.

Liver Graft MicroRNAs Expression in Different Etiology of Acute Jaundice after Living Donor Liver Transplantation.

Background: Acute jaundice remains a critical problem following liver transplantation. MicroRNAs (miRNAs) are involved in regulating gene expression related to various disease phenotypes and statuses. Aims: To differentiate acute jaundice etiology after living donor liver transplantation (LDLT), we examined the hepatic miRNA expression patterns in several liver graft pathologies. Methods: Eighty liver transplant recipients undergoing post-LDLT graft biopsy for the evaluation of acute jaundice were enrolled in this 1-year prospective study. Using a real-time quantitative reverse transcription-polymerase chain reaction profiling assay, we identified hepatic miRNA (miRNA-122, miRNA-301, miRNA-133a, and miRNA-21) signatures in various allografts pathologies. Results: Pathologic findings of the 80 recipients were as follows: acute cholangitis (AC), 37 (46%); acute rejection (AR), 20 (25%); recurrent hepatitis (RH), 12 (15%); non-specific pathological change, 6 (8%); and fatty change (FC), 5 (6%). None of these identified hepatic miRNAs expression pattern was significantly correlated with serum parameters, including neutrophil-lymphocyte ratio. In AC, hepatic miRNA-122, miRNA-301, miRNA-133a, and miRNA-21 expression was significantly downregulated (p < 0.05). MicroRNA-122 expression was elevated in cases of AR and RH (p < 0.05); miRNA-301 and miRNA-21 expression was higher in RH than in AC (p < 0.05); and miRNA-133a expression was higher in FC than in AR (p < 0.05). Conclusions: Our study suggests that specific hepatic miRNA expression patterns as a checklist may be useful for differential diagnosis of acute jaundice following liver transplantation.

Risk factors for gallbladder polyps observed through second-look abdominal sonography in patients with fatty liver disease.

CONCLUSION: FLD, older age group, and alcohol consumption are major risk factors of GBP formation in Taiwanese population. The presence of GBPs might be revealed in second-look examinations of abdominal sonographies.

Liver Graft Pathology and Low Serum 25-Hydroxyvitamin D after Living Donor Liver Transplantation.

BACKGROUND: Most cases of advanced liver diseases are associated with low serum 25-hydroxyvitamin D and vitamin D deficiency. This phenomenon may occur in living donor liver transplantation (LDLT). AIMS: We conducted this study to explore the interplay between VDR and CYP2R1 in liver graft and compared our findings with the pathological interpretation of serum 25(OH)D concentration. METHODS: In total, 60 patients received liver graft biopsy after LDLT and were separated (1:1) into two groups: graft rejection group and graft non-rejection group. We extracted both of the recipients' and donors' serum DNA to investigate the vitamin D receptor (VDR) rs2228530 and CYP2R1 rs10741657 single nucleotide polymorphisms (SNPs) using real-time polymerase chain reaction. We also extracted DNA from liver graft tissues to explore the genetic alleles of VDR rs2228530 and CYP2R1 rs10741657 after LDLT. Serum biochemistry profile and 25(OH)D concentrations were measured before and after LDLT. RESULTS: There were no significant differences in serum VDR rs2228530 and CYP2R1 rs10741657 genetic alleles between recipients and donors. The percentage of genetic modification was 33.4% (10/30) for the rejection and non-rejection groups in VDR rs2228530, and 66.7% (20/30) for both groups in CYP2R1 rs10741657. Serum 25(OH)D concentrations were significantly lower after LDLT D30 than that before LDLT in the rejection (p = 0.0001) and non-rejection graft pathology (p = 0.0017) groups. CONCLUSIONS: The presence of low serum 25(OH)D concentrations after LDLT suggested that post-transplant low serum 25(OH)D concentrations may develop with the homogenous phenomenon of VDR rs2228530 and CYP2R1 rs10741657 genetic modifications in recipients regardless of graft pathology.

Extremity risk factors of sepsis for gastrointestinal endoscopy in patients with liver cirrhosis.

BACKGROUND: Liver cirrhosis is a well-known risk factor of sepsis after emergent gastrointestinal (GI) endoscopy. Elective GI endoscopy before living donor liver transplantation (LDLT), however, may also carry the septic risk among these patients. METHODS: This retrospective study reviewed the medical records of 642 cirrhotic recipients who underwent GI endoscopy from 2008 to 2016. We analyzed the incidence and risk factors of post-endoscopy sepsis during 2008-2012 (experience cohort). Our protocol changed after 2013 (validation cohort) to include antibiotic prophylaxis. RESULTS: In experience cohort, 36 cases (10.5%) of the 342 LDLT candidates experienced sepsis within 48 h after endoscopy. The sepsis rate was significantly higher in patients with hepatic decompensation than patients without (22.2% vs. 9.6% vs. 2.6% in Child C/B/A groups respectively; ×2 = 20.97, P < 0.001). Using multivariate logistic regression analysis, the factors related to post-endoscopy sepsis were the Child score (OR 1.46; 95% CI 1.24-1.71), Child classes B and C (OR 3.80 and 14.13; 95% CI 1.04-13.95 and 3.97-50.23, respectively), hepatic hydrothorax (OR 4.85; 95% CI 1.37-17.20), and use of antibiotic prophylaxis (OR 0.08; 95% CI 0.01-0.64). In validation cohort, antibiotics were given routinely, and all cases of hepatic hydrothorax (n = 10) were drained. Consequently, 4 (1.3%) episodes of sepsis occurred among 300 LDLT candidates, and the incidence was significantly lower than before (1.3% vs. 10.5%, P < 0.001). CONCLUSIONS: Patients with decompensated cirrhosis and hepatic hydrothorax have higher risk of sepsis following endoscopy. In advanced cirrhotic patients, antibiotic prophylaxis and drainage of hydrothorax may be required to prevent sepsis before elective GI endoscopy.

Immunohistochemistry Staining-Proven Cytomegalovirus Colitis in Living Donor Liver Transplantation.

Background and Aims: Cytomegalovirus (CMV) infection is a common occurrence in liver transplantation (LT) even in an era of preventive strategies. However, the diagnosis of CMV colitis remains challenging. This study aimed to focus on the clinical significance of endoscopic biopsy-proven CMV colitis in patients following living donor liver transplantation (LDLT). Methods: From January 2007 to December 2021, a total of 55 CMV colitis cases were retrospectively enrolled and divided into a non-LDLT group in 53 and an LDLT group in 2 cases. Clinical demographics, diagnostic measurement, histopathology, and anti-viral therapy were investigated. Results: There were 1630 cases undergoing LDLT in the period 2007-2021, with only 2 recipients being confirmed to have CMV colitis in 2021 (2/114, 1-year incidence: 1.75%). Comparisons between the 53 non-LDLT cases and 2 LDLT cases are as follows: Serum anti-CMV immunoglobulin M (IgM) was shown to be positive (n = 3, 5.5% vs. n = 0, p = 1.0) and negative (n = 20, 37.7% vs. n = 2, 100%, p = 0.16); anti-CMV immunoglobulin G (IgG) was positive (n = 19, 35.8% vs. n = 2, 100%, p = 0.14) and none were negative; CMV DNAemia was shown to be detectable (n = 14, 26.4% vs. n = 1, 50%, p = 0.47) and undetectable (n = 14, 26.4% vs. n = 1, 50%, p = 0.47). Among the two recipients with CMV colitis, one had CMV DNAemia and the other had no CMV DNAemia upon the development of symptoms; negative anti-CMV-IgM and positive anti-CMV-IgG were observed both pre-transplant and post-transplant; finally, CMV colitis was documented based on the presence of inclusion bodies and positive immunohistochemistry (IHC) staining in histology. Conclusion: Patients with immunocompromised status, in particular organ transplantation, may have positive serum anti-CMV IgM/IgG antibodies both before and after transplantation. This study emphasized the fact that endoscopic biopsy with IHC staining may be a more powerful tool for making an accurate diagnosis of CMV colitis in the setting of living donor liver transplantation.

HCV RNA in serum and liver samples of patients undergoing living donor liver transplantation.

OBJECTIVE: To compare hepatitis C virus (HCV) RNA levels from serum and explanted native liver samples from patients undergoing living donor liver transplantation (LDLT). METHODS: This was a prospective observational study. Serum and liver samples were collected from consecutive serum anti-HCV-positive transplant recipients between February 2016 to August 2019. HCV RNA was extracted from liver samples and subjected to one-step reverse-transcription qPCR. using the TopScript One Step qRT-PCR Probe Kit with HCV qPCR probe assay and human GAPDH qPCR probe assay on a ViiA7 Real-Time PCR System. RESULTS: Among the 80 patients, 36% (29/80) were HCV RNA positive in serum and 85% (68/80) had positive hepatic HCV RNA. Post-liver transplantation, 4% (3/80) patients were serum positive. CONCLUSIONS: Our study suggests that pre-transplant serum HCV RNA levels may give an underestimate of the number of positive HCV RNA cases and that hepatic HCV RNA data may be more accurate.

A novel evidence of serial changes of bone mineral density in chronic hepatitis B patients treated with entecavir.

BACKGROUND AND AIMS: Tenofovir disoproxil fumarate (TDF) and Entecavir (ETV) are commonly used for patients with chronic hepatitis B (CHB), and renal or bone toxicity are possible concerns. This study is to evaluate the renal and bone effect of TDF compared with ETV in CHB patients. METHODS: This is a retrospective study at Kaohsiung Chung-Gung memorial hospital, Taiwan, from June 2013 to December 2018. Patients with CHB were prescribed with TDF or ETV for 3 years or above. Renal function was assessed at 12-week intervals. Dual-energy X-ray absorptiometry scans of the spine and femurs were performed at 48-week intervals. The propensity score analysis was conducted to balance the baseline characteristics of patients in both treatment groups. RESULTS: A total of 258 patients were included in this study: TDF (n = 135) and ETV (n = 123). The prevalence of osteopenia was much higher in the TDF group at week 48 and week 96. The TDF group showed significant mean percentage decrease from baseline in bone mineral density throughout the treatment course. Logistic regression analysis adjusted for the propensity score demonstrated that the use of TDF was the only predictive factor of significant bone density loss at week 144. The mean percentage decline of estimated glomerular filtration rate was significant in the TDF group at all time points. Renal threshold phosphate concentration was similar among both treatment groups. CONCLUSIONS: This study suggested CHB patients treated with TDF may experience increased risks of bone loss and renal deficits compared to those treated with ETV.

The Perioperatively Altered Neutrophil-to-Lymphocyte Ratio Associates with Impaired DNA Damage Response in Liver Transplantation Recipients with Hepatocellular Carcinoma.

Increasing evidence has suggested that elevated systemic inflammation with a high neutrophil-lymphocyte ratio (NLR) is associated with poor prognosis after liver transplantation (LT). The ongoing molecular events involved in poor survival remain unclear. This retrospective study evaluated LT recipients whose data was collected at Kaohsiung Chang Gung Memorial Hospital between 2005 and 2014. Clinical records of 347 patients with hepatocellular carcinoma from seven days before LT to 30 days after LT illustrated that longitudinal values of lymphocytes, RBC, and hemoglobin were persistently low in patients with peritransplant high NLR (PTH-NLR, pre-LT ≥ 4 and post-LT ≥ 5), which indicated a significantly worse survival rate in association with increased RDW-CV and pancytopenia when compared to other patients (p = 0.008). We further found that PTH-NLR patients had decreased DNA damage response (DDR) genes and detoxifying enzymes of ADH and ALDH families, and increased mitochondrial stress response genes in their liver tissues. Reduced lineage markers of liver progenitor cells were also observed in PTH-NLR patients signifying the presence of unresolved impairments after LT. Our results demonstrate the association between hematopoietic deficiencies and lack of protection against DDR with PTH-NLR in LDLT recipients with HCC and may imply abnormal hematological and organismal defects in those patients.

Emerging Roles of Calcium Signaling in the Development of Non-Alcoholic Fatty Liver Disease.

The liver plays a central role in energy metabolism. Dysregulated hepatic lipid metabolism is a major cause of non-alcoholic fatty liver disease (NAFLD), a chronic liver disorder closely linked to obesity and insulin resistance. NAFLD is rapidly emerging as a global health problem with currently no approved therapy. While early stages of NAFLD are often considered benign, the disease can progress to an advanced stage that involves chronic inflammation, with increased risk for developing end-stage disease including fibrosis and liver cancer. Hence, there is an urgent need to identify potential pharmacological targets. Ca2+ is an essential signaling molecule involved in a myriad of cellular processes. Intracellular Ca2+ is intricately compartmentalized, and the Ca2+ flow is tightly controlled by a network of Ca2+ transport and buffering proteins. Impaired Ca2+ signaling is strongly associated with endoplasmic reticulum stress, mitochondrial dysfunction and autophagic defects, all of which are etiological factors of NAFLD. In this review, we describe the recent advances that underscore the critical role of dysregulated Ca2+ homeostasis in lipid metabolic abnormalities and discuss the feasibility of targeting Ca2+ signaling as a potential therapeutic approach.

MicroRNA-301a inhibition enhances the immunomodulatory functions of adipose-derived mesenchymal stem cells by induction of macrophage M2 polarization.

MicroRNAs (miRNAs) are a class of short non-coding RNAs that play a significant role in biological processes in various cell types, including mesenchymal stem cells (MSCs). However, how miRNAs regulate the immunomodulatory functions of adipose-derived MSCs (AD-MSCs) remains unknown. Here, we showed that modulation of miR-301a in AD-MSCs altered macrophage polarization. Bone marrow (BM)-derived macrophages were stimulated with LPS (1 µg/ml) and co-cultured with miRNA transfected AD-MSCs for 24 h. The expression of M1 and M2 markers in macrophages was analyzed. Inhibition of miR-301a induced M2 macrophage with arginase-1, CD163, CD206, and IL-10 upregulation. Additionally, toll-like receptor (TLR)-4 mRNA expression in macrophages was downregulated in co-cultures with AD-MSCs transfected with a miR-301a inhibitor. Nitric oxide (NO) in the supernatant of AD-MSC/macrophage co-culture was also suppressed by inhibition of miR-301a in AD-MSCs. We further found that suppression of miR-301a in AD-MSCs increased prostaglandin E2 (PGE2) concentration in the conditioned medium of the co-culture. Taken together, the results of our study indicate that miR-301a can modulate the immunoregulatory functions of AD-MSCs that favor the applicability as a potential immunotherapeutic agent.

Decreased PEDF Promotes Hepatic Fatty Acid Uptake and Lipid Droplet Formation in the Pathogenesis of NAFLD.

Non-alcoholic fatty liver disease (NAFLD), the leading cause of chronic liver diseases worldwide, ranges from simple steatosis to steatohepatitis, with the risk for progressive fibrosis or even cirrhosis. While simple steatosis is a relatively benign condition, the buildup of toxic lipid metabolites can induce chronic inflammation, ultimately triggering disease progression. Pigment epithelium-derived factor (PEDF) is a secreted, multifunctional glycoprotein with lipid metabolic activities. PEDF promotes lipolysis through binding to adipose triglyceride lipase (ATGL), a key enzyme for triglyceride breakdown. In the current study, we aimed to delineate how changes in PEDF expression affect hepatic lipid accumulation. Our data revealed that hepatic PEDF was downregulated in a mouse NAFLD model. We further showed that decreased PEDF levels in hepatocytes in vitro resulted in elevated fatty acid uptake and lipid droplet formation, with concomitant upregulation of fatty acid transport proteins CD36 and fatty acid binding protein 1 (FABP1). RNA sequencing analysis of PEDF knocked down hepatocytes revealed an alteration in gene expression profile toward lipid accumulation. Additionally, decreased PEDF promotes mobilization of fatty acids, an observation distinct from blocking ATGL activity. Taken together, our data suggest that hepatic PEDF downregulation causes molecular changes that favor triglyceride accumulation, which may further lead to NAFLD progression.

Endoscopic injection sclerotherapy for pediatric bleeding esophageal varices complicated by gastric vein, main portal vein, splenic mesenteric junction, and splenic vein occlusion: a case report.

BACKGROUND: Endoscopic injection sclerotherapy (EIS) is a life-saving procedure for pediatric patients with bleeding gastric varices (GV) associated with advanced liver cirrhosis and severe portal hypertension. Because of the lack of an endoscopic banding ligation device for pediatric patients, EIS is usually performed for bleeding esophageal varices (EV) in infants with congenital biliary atresia. CASE PRESENTATION: We present a case of a 15-month-old female infant with type I biliary atresia with jaundice (total serum bilirubin, 22.2 mg/dL), hypoalbuminemia (serum albumin level, 2.58 g/dL), coagulopathy (prothrombin time > 20 s compared with that of a normal control), ascites, splenomegaly, portal hypertension (portal vein velocity, 3.9-5.6 cm/sec of hepatopetal flow), and repeated bleeding of the varices after receiving three doses of intravascularly administered Histoacryl 1 ampoule mixed with Lipiodol UF 8 mL in the EV. Prominent GV and EV were occluded by EIS. The sclerosing agent was also present in the main portal vein, splenic mesenteric junction, and splenic vein, causing an engorged inferior mesenteric vein. The patient underwent total hepatectomy and living donor liver transplantation (LDLT) by left lateral segment graft (segments 2, 3, and 4 of the middle hepatic vein trunk) and left portal vein graft to the recipient inferior mesenteric vein anastomosis. Portal vein stent placement via segment 4 of the portal vein stump was performed from the inferior mesenteric vein to the umbilical portion of the left portal vein. The patient is still alive and doing well after the LDLT. CONCLUSIONS: EIS is a life-saving procedure in cases involving bleeding EV complicated by gastric, main portal vein, splenic mesenteric junction, and splenic vein occlusions; hence, it should be kept in mind as a treatment for EV complications in pediatric patients.

Complications of percutaneous liver biopsy in living donor liver transplantation: Two case reports.

RATIONALE: According to previously published studies, major complications arising from a percutaneous liver biopsy are rare and occur in less than 0.1% of cases. This report describes an approach to percutaneous liver biopsy that can help avoid damage to the liver in a living donor liver transplantation (LDLT) setting. PATIENT CONCERNS: Case 1: In the first case a donor percutaneous liver biopsy (PLB) of both lobes of the liver was performed for pre-LDLT evaluation. The ultrasonography (US)-guided epigastric right-angle approach and an automatic one-handed cocking disposable 18G biopsy gun was used to puncture the left liver lobe to determine the presence of fatty liver. A penetrating liver injury occurred, accompanied by massive bloody ascites (about 700 cc) and subcapsular hematoma at the left lateral segment. The bleeding was managed by bi-polar coagulation during the transplant and the following liver donation procedure proceeded smoothly without any subsequent complications. Case 2: In the second case, selective right lobe PLB for clinical assessment after LDLT was performed in the recipient. Hemorrhagic shock occurred following a puncture of the right posterior branch of the right hepatic artery when using the biopsy-gun via the right lateral intercostal approach. DIAGNOSES: Extravasation was documented by angiography and emergent transhepatic arterial embolization was performed. INTERVENTION: Extravasation was documented by angiography and emergent transhepatic arterial embolization with glue:lipiodol (1:4) was performed to stop bleeding. OUTCOMES: The recipient survived after medical management. LESSONS: To prevent complications, the right-angle approach of PLB may be changed to an oblique angle using a one-fire biopsy-gun. Use of a manual Menghini's needle should be considered for left lobe liver biopsies. Since US-guided manual Menghini's needle for PLB can be observed with the needle tip inserted in the liver, needle-mediated compromising of the major vessels or biliary tree can be prevented, and it does not penetrate the liver again. A superficial puncture less than 0.5 cm away from the liver surface should be made during right lobe liver biopsy. This approach can help to avoid damage to the hepatic artery.

Tumor microenvironment mediated by suppression of autophagic flux drives liver malignancy.

The physiological role of autophagy in the catabolic process of the body involves protein synthesis and degradation in homeostasis under normal and stressed conditions. In hepatocellular carcinoma (HCC), the role of tumor microenvironment (TME) has been concerned as the main issue in fighting against this deadly malignancy. During the last decade, the crosstalk between tumor cells and their TME in HCC extensively accumulated. However, a deeper knowledge for the actual function of autophagy in this interconnection which involved in supporting tumor development, progression and chemoresistance in HCC is needed but still largely unknown. Recent studies have shown that coagulants tissue factor (TF) and factor VII (FVII) has a pathological role in promoting tumor growth by activating protease-activated receptor 2 (PAR2). Autophagy-associated LC3A/B-II formation was selectively suppressed by FVII/PAR2 signaling which mediated by mTOR activation through Atg7 but not Atg5/Atg12 axis. The coagulant-derived autophagic suppression seemed potentiate a vicious circle of malignancy in producing more FVII and PAR2 which facilitate in vivo and in vitro tumor progression of HCC and the investigations are consistent with the clinical observations. In this review, we briefly summarize the current understanding of autophagy and discuss recent evidence for its role in HCC malignancy.

Pigment epithelium-derived factor in lipid metabolic disorders.

Pigment epithelium-derived factor (PEDF) is a secreted glycoprotein that has anti-angiogenic, anti-proliferative, neurotrophic and immunomodulatory properties. PEDF has recently emerged as a critical metabolic regulatory protein since the discovery of its modulatory activities in the lipolytic pathway by binding to adipose triglyceride lipase (ATGL). Despite being beneficial in maintaining the homeostasis of hepatic lipid accumulation, PEDF has been uncovered an unfavorable role associated with insulin resistance. The molecular events that connect these two apparent distinct observations have been controversial and remained largely unknown. Therefore in this short review, we attempt to summarize the current findings of PEDF regarding its lipid metabolic functions and provide perspectives in identifying PEDF as a potential therapeutic target in lipid disorders.

Genetic polymorphisms of the hepatic pathways of fatty liver disease after living donor liver transplantation.

BACKGROUND & AIMS: Fatty liver disease is an important complication associated with liver transplantation, and the cytochrome P-450 system of the donor liver may be involved in its pathogenesis. To explore the effects of the CYP27A1, CYP27B1, CYP2R1, and vitamin D receptor pathways on vitamin D maintenance after living donor liver transplantation, we investigated the interplay between serum 25(OH)D and common variants in 60 paired donors and recipients who underwent living donor liver transplantation. METHODS: We prospectively collected 60 donor/recipient pairs from our liver transplantation programmes and extracted serum DNA to evaluate single nucleotide polymorphisms in CYP27A1 rs4674344, CYP27B1 rs10877012, CYP2R1 rs10741657, and VDR rs2228530 alleles using real-time polymerase chain reaction. We measured serum 25(OH)D concentrations of donors (D-D0) and recipients before (R-D0) and after (R-D30) living donor liver transplantation for comparison with repeated-measures analysis of variance in generalized estimating equations analysis. RESULTS: Fatty liver disease was noted in 28.3% of the cases after living donor liver transplantation, and the graft rejection rate was 25%. There were significant differences in low serum 25(OH)D concentrations between D-D0 and R-D0 and between R-D0 and R-30 groups. Significant associations were observed for serum CYP27A1 rs4674344 in recipients and donors as well as for graft liver tissue with VDR rs2228530. There was no significant relationship with serum CYP27B1 rs10877012 in recipients and donors or with graft liver tissue with CYP2R1 rs10741657. CONCLUSIONS: Donor/recipient CYP27A1 rs4674344 and graft VDR rs2228570 may be related to low serum 25(OH)D and may play a major role in the development of fatty liver disease in recipients after living donor liver transplantation.