The gut microbiota plays a role in nonalcoholic fatty liver disease (NAFLD), but data about gut dysbiosis in Asians with NAFLD remains scarce. We analyzed the differences in fecal microbiota between adults with and without NAFLD. This cross-sectional study examined adults with histology-proven NAFLD (25 nonalcoholic fatty liver (NAFL) patients, 25 nonalcoholic steatohepatitis (NASH) patients, and 25 living liver donors (healthy controls)). The taxonomic composition of the gut microbiota was determined by 16S ribosomal RNA gene sequencing of stool samples. The NAFL and NASH groups showed lower total bacterial diversity and richness than the controls. NAFLD patients had higher levels of the phylum Bacteroidetes and lower levels of Firmicutes than controls. The genus Ruminococcaceae UCG-010, family Ruminococcaceae, order Clostridiales, and class Clostridia were less abundant in patients with NAFL or NASH than healthy individuals. The lipopolysaccharide biosynthesis pathway was differentially enriched in the NASH group. This study examined the largest number of Asian patients with biopsy-proven NAFL and NASH in terms of dysbiosis of the gut microbiota in NAFLD patients. NAFLD patients had higher levels of Bacteroidetes and lower levels of Firmicutes. These results are different from research from western countries and could provide different targets for therapies by region.

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.

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.

Background: Inflammatory markers are regarded as prognostic factors of the outcomes of hepatocellular carcinoma (HCC). Examples include the neutrophil-to-lymphocyte ratio (NLR); platelet to lymphocyte ratio (PLR); the albumin and lymphocyte counts used in the prognostic nutritional index (PNI); and the neutrophil, lymphocyte, and platelet counts used in the systemic immune-inflammation index (SII). This study evaluates the effects of PNI, NLR, PLR, and SII to predict recurrence and survival in patients with Barcelona Clinic Liver Cancer (BCLC) stages 0-A of HCC after hepatectomy. Methods: This retrospective study was conducted at Kaohsiung Chung-Gung Memorial Hospital, Taiwan. The study enrolled 891 patients (77.9% males; mean age 58.53 ± 11.60 years) with BCLC stage 0/A HCC undergoing hepatectomy between 2001 and 2016. PNI, NLR, PLR and SII were measured before hepatectomy. Results: High NLR (>1.8) was adversely associated with overall survival (p = 0.032). Low PNI (≤45) was adversely associated with overall survival and disease-free survival (p < 0.001). Low SII (≤45) also had an adverse association with overall survival (p = 0.008) and disease-free survival (p < 0.001). Diabetes mellitus, cirrhosis, microvascular invasion, low PNI (≤45), and low SII (≤160) were independently associated with poor overall survival in a multivariate analysis. HCV infection, diabetes mellitus, cirrhosis, microvascular invasion, low PNI, and low SII were independent prognostic factors of recurrent HCC. The combined use of PNI and SII provided improved prognostic information. Conclusions: Low PNI and low SII are significantly poor prognostic factors for overall survival and recurrence in patients with BCLC 0-A hepatocellular carcinoma after hepatectomy.

Hepatocellular carcinoma (HCC) is one of the most common and aggressive malignancies worldwide. Treatment outcomes remain poor mainly due to lack of good diagnostic/prognostic markers and limited therapeutic strategies. We previously characterized aberrant activation of the TF/FVII/PAR2 pathway, which subsequently results in decreased autophagy, as a crucial event in malignant progression of HCC. Here, we identified miR-135a as a highly upregulated miRNA in HCC in response to TF/FVII/PAR2 activation. Analyzing 103 HCC patient specimens, we confirmed that miR-135a was frequently elevated in HCC tissues with higher FVII expression compared to adjacent non-cancerous counterparts. Increased miR-135a levels in HCC were also associated with tumor staging, recurrence, microvascular invasion, and decreased disease-free survival. We subsequently identified Atg14, a key component that regulates the formation of autophagosome as a direct target of miR-135a. Ectopic expression of miR-135a suppressed Atg14 levels and inhibited the autophagic processes. Our results indicate strong positive correlations between miR-135a levels and malignant behaviors in HCC patients and also suggest novel functions of miR-135a in regulation of autophagy, which could be useful as a potential target for prognostic and therapeutic uses.

The albumin-bilirubin (ALBI) grade has been validated as a significant predictor for hepatocellular carcinoma (HCC). However, there is little information about the impact of postoperative ALBI grade in patients with HCC who are undergoing liver resection. We enrolled 525 HCC patients who received primary resection from April 2001 to March 2017. The impact of the pre- and post-operative ALBI grades on overall survival (OS) and recurrence-free survival (RFS) were analyzed by multivariate analysis. During the follow-up period (mean, 65 months), 253 (48.1%) patients experienced recurrence, and 85 (16.2%) patients died. Multivariate analysis revealed that diabetes mellitus (DM) (p = 0.011), alpha-fetoprotein levels (AFP) (p < 0.001), low platelet count (p = 0.008), liver cirrhosis (p < 0.001), and the first year of ALBI grade after resection (p < 0.001) were independent predictors for RFS. Additionally, old age (p = 0.006), DM (p = 0.002), AFP (p = 0.027), and ALBI grade at the first year after resection (p < 0.001) were independent risk factors for poor liver-related survival. Patients with post-operative ALBI grades II/III had older age (p = 0.019), hypoalbuminemia (p = 0.038), DM (p = 0.043), and high stages of pTNM (p = 0.021). The post-operative ALBI grade is better for predicting the outcomes in HCC patients after curative hepatectomy than the pre-operative ALBI grade.