Chaohui Yu

Association of serum uric acid level with non-alcoholic fatty liver disease: A cross-sectional study

BACKGROUND/AIM Serum uric acid level has been suggested to be associated with factors that contribute to the metabolic syndrome. The aim of this study was to investigate the association of serum uric acid level with non-alcoholic fatty liver disease (NAFLD). METHODS A cross-sectional study was performed among the employees of Zhenhai Refining & Chemical Company Ltd., Ningbo, China. RESULTS The study included 8925 subjects (6008 men) with a mean age of 43 years. The prevalence rates of NAFLD and hyperuricemia were 11.78% and 14.71%, respectively. NAFLD patients had significantly higher serum uric acid levels than controls (370.3+/-86.6 vs. 321.1+/-82.6 micromol/L; P<0.001). The prevalence rate of NAFLD was significantly higher in subjects with hyperuricemia than in those without hyperuricemia (24.75% vs. 9.54%; P<0.001), and the prevalence rate increased with progressively higher serum uric acid levels (P value for trend <0.001). Multiple regression analysis showed that hyperuricemia was associated with an increased risk of NAFLD (odds ratio [OR]: 1.291, 95% confidence interval [CI]: 1.067-1.564; P<0.001). CONCLUSION Serum uric acid level is significantly associated with NAFLD, and elevated serum uric acid level is an independent risk factor for NAFLD.

Effects of probiotics on nonalcoholic fatty liver disease: A meta-analysis

AIM To investigate the relationship between the gut-liver axis and nonalcoholic fatty liver disease (NAFLD), we performed a meta-analysis to evaluate the effects of probiotic therapy in NAFLD. METHODS We searched PubMed, Medline, Embase, Web of Science, the Cochrane Library and Chinese Biomedicine Database for all relevant randomized controlled trials on probiotics in patients with NAFLD/nonalcoholic steatohepatitis (NASH). A statistical analysis was performed using RevMan 5.0 software. RESULTS Four randomized trials involving 134 NAFLD/NASH patients were included. The results showed that probiotic therapy significantly decreased alanine aminotransferase (ALT), aspartate transaminase (AST), total-cholesterol (T-chol), high density lipoprotein (HDL), tumor necrosis factor (TNF)-α and homeostasis model assessment of insulin resistance (HOMA-IR) [ALT: weighted mean difference (WMD) -23.71, 95%CI: -33.46--13.95, P < 0.00001; AST: WMD -19.77, 95%CI: -32.55--7.00, P = 0.002; T-chol: WMD -0.28, 95%CI: -0.55--0.01, P = 0.04; HDL: WMD -0.09, 95%CI: -0.16-0.01, P = 0.03; TNF-α: WMD -0.32, 95%CI: -0.48--0.17, P < 0.0001; HOMA-IR: WMD -0.46, 95%CI: -0.73--0.19, P = 0.0008]. However, the use of probiotics was not associated with changes in body mass index (BMI), glucose (GLU) and low density lipoprotein (LDL) (BMI: WMD 0.05, 95%CI: -0.18-0.29, P = 0.64; GLU: WMD 0.05, 95%CI: -0.25-0.35, P = 0.76; LDL: WMD -0.38, 95%CI: -0.78-0.02, P = 0.06). CONCLUSION Probiotic therapies can reduce liver aminotransferases, total-cholesterol, TNF-α and improve insulin resistance in NAFLD patients. Modulation of the gut microbiota represents a new treatment for NAFLD.

MicroRNA expression pattern in different stages of nonalcoholic fatty liver disease

BACKGROUND/AIMS To explore the unique microRNA expression pattern of nonalcoholic fatty liver disease in a rat model, and search for targets of certain dysregulated microRNAs. METHODS Microarray and stem-loop RT-PCR were utilized to detect dysregulated microRNAs in a rat model. Significance Analysis of Microarray, Prediction Analysis of Microarray and clustering analysis were implemented to calculate significantly aberrantly expressed microRNAs. TargetScan, miRanda and PicTar were jointly used to predict targets of microRNAs. RESULTS Confirmed by Significance Analysis of Microarray and predicted by Prediction Analysis of Microarray, portfolios of 27 and 21 microRNAs were selected as an accurate molecular signature in distinguishing steatosis and steatohepatitis from normal rat liver. Besides, a panel of microRNA-target pairs that may be involved in lipid and glucose metabolism and inflammation process was delineated. CONCLUSION This is by far the first report on the dysregulated microRNAs expression pattern in nonalcoholic fatty liver disease. The successful differentiation of steatosis and steatohepatitis from normal liver hints to the potential of using lists of dysregulated microRNAs for diagnosis, though many problems need to be solved. Besides, these data will guide further studies of the contribution of microRNAs to the pathogenesis of nonalcoholic fatty liver disease while disease-specific microRNAs might become potential targets for therapeutic intervention.

Role of endoplasmic reticulum stress in the pathogenesis of nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease (NAFLD) has emerged as a common public health problem in recent decades. However, the underlying mechanisms leading to the development of NAFLD are not fully understood. The endoplasmic reticulum (ER) stress response has recently been proposed to play a crucial role in both the development of steatosis and progression to nonalcoholic steatohepatitis. ER stress is activated to regulate protein synthesis and restore homeostatic equilibrium when the cell is stressed due to the accumulation of unfolded or misfolded proteins. However, delayed or insufficient responses to ER stress may turn physiological mechanisms into pathological consequences, including fat accumulation, insulin resistance, inflammation, and apoptosis, all of which play important roles in the pathogenesis of NAFLD. Therefore, understanding the role of ER stress in the pathogenesis of NAFLD has become a topic of intense investigation. This review highlights the recent findings linking ER stress signaling pathways to the pathogenesis of NAFLD.

High Serum Uric Acid Increases the Risk for Nonalcoholic Fatty Liver Disease: A Prospective Observational Study

Nonalcoholic fatty liver disease (NAFLD) is a common form of chronic liver disease, and serum uric acid is observed to be significantly elevated in NAFLD patients. However, whether this elevation is causal, a bystander, or a consequence of NAFLD remains unclear. We performed a population-based prospective study among the employees of Zhenhai Refining & Chemical Company Ltd., Ningbo, China to investigate whether the elevation of serum uric acid has a casual role for NAFLD. A total of 6890 initially NAFLD-free subjects were followed up for 3 years. Overall, 11.80% (813/6890) subjects developed NAFLD over 3 years of follow-up. The cumulative incidence of NAFLD increased with progressively higher baseline serum uric acid levels (the cumulative incidence was 7.2%, 9.5%, 11.5%, 13.8%, and 17.2% in quintile 1, quintile 2, 3, 4 and 5, respectively; P value for trend <0.001). Cox proportional hazards regression analyses showed that serum uric acid levels were independently and positively associated with the risk for incident NAFLD; the age-, gender- and metabolic syndrome adjusted hazard ratio (95% CI) for the subjects in quintile 2, 3, 4 and 5 versus quintile 1 was 1.18 (0.91–1.54), 1.32 (1.03–1.70), 1.39 (1.09–1.78) and 1.50 (1.18–1.92), respectively. Taken together, our prospective observational study showed that elevation of serum uric acid levels independently predicts increase risk for incident NAFLD.

Prevalence and risk factors for the development of nonalcoholic fatty liver disease in a nonobese Chinese population: the Zhejiang Zhenhai Study.

OBJECTIVES:The precise prevalence and risk factors for the development of nonalcoholic fatty liver disease (NAFLD) in nonobese adults remains unclear. The objective of this study was to investigate the prevalence of NAFLD and risk factors for its development in a nonobese Chinese population.METHODS:We firstly investigated the prevalence and factors associated with the presence of NAFLD in nonobese (body mass index (BMI) <25 kg/m2) Chinese subjects via a cross-sectional study, and then analyzed the risk factors for the development of NAFLD via a subsequent prospective 5-year follow-up of the same population.RESULTS:A total of 6,905 nonobese subjects were enrolled in the cross-sectional study. Baseline evaluation revealed that the prevalence of NAFLD was 7.27%. A total of 5,562 subjects who were free of NAFLD at baseline completed the follow-up study, and 494 (8.88%) had developed NAFLD during the 5-year follow-up. Further analyses revealed that age, gender, BMI, waist circumference, triglyceride, high-density lipoprotein (HDL) cholesterol, serum uric acid, hemoglobin, and platelet count were independently associated with the presence and development of NAFLD.CONCLUSIONS:NAFLD is prevalent in the nonobese Chinese population, and a substantial proportion of subjects developed NAFLD over the 5-year follow-up period. Special attention should be paid to the factors associated with the presence and development of NAFLD in nonobese subjects, to improve prevention and management of NAFLD.

Argonaute proteins: potential biomarkers for human colon cancer.

BackgroundAlthough Argonaute proteins are considered to play important roles in stem cell self-renewal, RNA interference (RNAi) and translational regulation, relatively little is known about their functions in human disease. In this study, we investigated the expression of eight members of human Argonaute family in colon cancer and identified their potential roles in tumor development and progression.MethodsAntibodies against human Argonaute proteins were prepared by immunizing rabbits with synthetic peptides derived from the sequences of Argonaute members. Then we constructed a tissue microarray containing 75 specimens from colon cancer and 75 specimens from adjacent non-cancer tissue, and assayed eight different proteins (EIF2C1, EIF2C2, EIF2C3, EIF2C4, PIWIL1, PIWIL2, PIWIL3 and PIWIL4) by immunohistochemistry on consecutive formalin-fixed tissue microarray sections.ResultsThe expression of EIF2C1-4 and PIWIL1-4 was significantly higher in tumorous tissue than in adjacent tissue. Notably, a significant correlation was observed between the positive expression of EIF2C2, EIF2C3, EIF2C4, PIWIL4 and the presence of distant metastasis. Logistic regression analysis revealed that an increased expression of EIF2C1 and PIWIL2 was significantly associated with occurrence of colon cancer tissue compared with non-cancer tissue.ConclusionsArgonaute proteins are overexpressed in colon cancer relative to adjacent non-cancer tissue. The expression of EIF2C2-4 and PIWIL4 appears increased in advanced tumors with distant metastasis, suggesting it may promote tumor invasion. Furthermore, EIF2C1 and PIWIL2 might represent novel colon cancer markers with early diagnostic significance.

Functional proteomic analysis of nonalcoholic fatty liver disease in rat models: enoyl-coenzyme a hydratase down-regulation exacerbates hepatic steatosis.

Nonalcoholic fatty liver disease (NAFLD) has emerged as a common public health problem that can progress to end‐stage liver disease. A high‐fat diet (HFD) may promote the development of NAFLD through a mechanism that is poorly understood. We adopted a proteomic approach to examine the effect of HFD on the liver proteome during the progression of NAFLD. Male Sprague‐Dawley rats fed an HFD for 4, 12, and 24 weeks replicated the progression of human NAFLD: steatosis, nonspecific inflammation, and steatohepatitis. Using two‐dimensional difference gel electrophoresis (DIGE) combined with matrix‐assisted laser desorption ionization time of flight/time of flight analysis, 95 proteins exhibiting significant changes (ratio ≥ 1.5 or ≤−1.5, P < 0.05) during the development of NAFLD were identified. Biological functions for these proteins reflected phase‐specific characteristics during the progression of the disease. The potential role of enoyl–coenzyme A hydratase (ECHS1), an enzyme that catalyzes the second step of mitochondrial fatty acid beta‐oxidation, received further investigation. First, the reduced protein level of ECHS1 was validated both in rat models and in patients with biopsy‐proven hepatic simple steatosis via immunoblotting or immunohistochemical analysis. Then the small interfering RNA (siRNA)–mediated knockdown of ECHS1 in the murine hepatocyte cell line alpha mouse liver 12 (AML12) demonstrated increased cellular lipid accumulation induced by free fatty acid (FFA) overload. Furthermore, using a hydradynamic transfection method, the in vivo silencing effect of siRNA duplexes targeting ECHS1 was further investigated in mice. Administering ECHS1 siRNA specifically reduced the expression of ECHS1 protein in mice liver, which significantly exacerbated the hepatic steatosis induced by an HFD. Conclusion: Our results revealed that ECHS1 down‐regulation contributed to HFD‐induced hepatic steatosis, which may help clarify the pathogenesis of NAFLD and point to potential targets for therapeutic interventions. (HEPATOLOGY 2010.)

Serum proteomic analysis revealed diagnostic value of hemoglobin for nonalcoholic fatty liver disease

BACKGROUND & AIMS Nonalcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases worldwide. The two linked studies presented herein aimed to identify and verify new biomarkers for NAFLD. METHODS First, 70 serum samples were analyzed using proteomics approaches to identify potential biomarkers for NAFLD. Second, a total of 6944 initial NAFLD-free subjects were followed up for 3 years to evaluate the predictive value of hemoglobin for NAFLD. RESULTS In the first study, 20 differentially expressed protein peaks (11 up-regulated and nine down-regulated) were observed in NAFLD patients upon comparison to the controls. With the aid of bioinformatic tools, we established a biomarker pattern for NAFLD with a sensitivity of 89% and a specificity of 83%. Further analysis suggested a protein peak to be hemoglobin subunit alpha. In the second study, prospective analysis showed that subjects with higher baseline hemoglobin levels were associated with higher incidence of NAFLD. Cox proportional hazards regression analyses showed that the age, gender, and body mass index adjusted hazard ratio (95% CI) for subjects with baseline hemoglobin level in quintile 2, 3, 4, and 5 vs. quintile 1 was 1.36 (1.02-1.81), 1.66 (1.23-2.25), 1.76 (1.28-2.41), and 1.83 (1.33-2.53), respectively. CONCLUSIONS Our study showed that serum hemoglobin may have significant predictive value for NAFLD.

Effects of pentoxifylline on nonalcoholic fatty liver disease: A meta-analysis

AIM To evaluate the effects of pentoxifylline therapy in patients with nonalcoholic fatty liver disease (NAFLD). METHODS We searched PubMed, Medline, Google Scholar, Embase, Web of Science, the Cochrane Library and the Chinese Biomedicine Database for all relevant controlled trials of pentoxifylline in patients with NAFLD from 1997 to July 2013. Five studies (3 randomized, double-blind, placebo-controlled trials and 2 prospective cohort studies with concurrent controls) were included in this meta-analysis. Statistical analysis was performed using RevMan 5.0 software. RESULTS Five randomized trials of 147 patients with NAFLD/nonalcoholic steatohepatitis (NASH) were included. The results showed that compared to placebo, pentoxifylline therapy resulted in a significant decrease in body weight (P = 0.04), alanine aminotransferase (P < 0.00001), aspartate transaminase (P = 0.0006), glucose (P = 0.0008) and tumor necrosis factor-α (P = 0.007), but did not significantly affect body mass index (P = 0.28), total cholesterol (P = 0.80), triglyceride (P = 0.98), alkaline phosphatase (P = 0.29), γ-glutamyl transferase (P = 0.39) and interleukin-6 (P = 0.38). With regard to histological changes, pentoxifylline only reduced the NAFLD activity score (P < 0.00001) and improved lobular inflammation (P < 0.0001). Improvements in steatosis grade (P = 0.11), ballooning (P = 0.10) and fibrosis (P = 0.50) were not obvious. CONCLUSION Pentoxifylline therapy results in weight loss, improved liver function and histological changes in patients with NAFLD/NASH. Therefore, pentoxifylline may be a new treatment option for NAFLD.