Form Of Chronic Liver Disease Research Articles

Exploring the Regulatory Role of ncRNA in NAFLD: A Particular Focus on PPARs.

Liver diseases are responsible for global mortality and morbidity and are a significant cause of death worldwide. Consequently, the advancement of new liver disease targets is of great interest. Non-coding RNA (ncRNA), such as microRNA (miRNA) and long ncRNA (lncRNA), has been proven to play a significant role in the pathogenesis of virtually all acute and chronic liver disorders. Recent studies demonstrated the medical applications of miRNA in various phases of hepatic pathology. PPARs play a major role in regulating many signaling pathways involved in various metabolic disorders. Non-alcoholic fatty liver disease (NAFLD) is the most prevalent form of chronic liver disease in the world, encompassing a spectrum spanning from mild steatosis to severe non-alcoholic steatohepatitis (NASH). PPARs were found to be one of the major regulators in the progression of NAFLD. There is no recognized treatment for NAFLD, even though numerous clinical trials are now underway. NAFLD is a major risk factor for developing hepatocellular carcinoma (HCC), and its frequency increases as obesity and diabetes become more prevalent. Reprogramming anti-diabetic and anti-obesity drugs is an effective therapy option for NAFLD and NASH. Several studies have also focused on the role of ncRNAs in the pathophysiology of NAFLD. The regulatory effects of these ncRNAs make them a primary target for treatments and as early biomarkers. In this study, the main focus will be to understand the regulation of PPARs through ncRNAs and their role in NAFLD.

Transplantation of chemically-induced liver progenitor cells ameliorates hepatic fibrosis in mice with diet-induced nonalcoholic steatohepatitis.

Primary mature hepatocytes were isolated from 7-week-old male Wistar rats. To establish CLiPs, isolated hepatocytes were cultured in differentiation medium composed of Y-27632, A-83-01, and CHIR99021 (YAC medium). As an animal model that reproduces NASH pathophysiology, 6-week-old severe combined immunodeficient (SCID) mice were carefully selected and prepared and fed with choline-deficient, L-amino acid-defined, high-fat diet (HFD). After 12 weeks' HFD feeding, the mice were assigned to continue HFD with or without the administration of rat CLiPs (HFD+CLiPs and HFD-CLiPs, respectively). Rat CLiPs were administered from the spleen. Hepatic fibrosis was semi-quantitatively evaluated according to histology. Liver parenchyma and blood samples were collected for biochemical analyses. Rat CLiPs were positive for CK19 and EpCAM were successfully delivered to the liver. At 8 weeks after CLiPs transplantation, the HFD+CLiPs group showed significantly less positive staining than the HFD-CLiPs group. Alanine aminotransferase significantly improved in the HFD+CLiPs group, as demonstrated by Azan staining and αSMA immunostaining. RT qPCR showed that the liver expression of MMP2 and 9 tended to be higher in the HFD+CLiPs group. The anti-fibrotic effect of CLiPs was demonstrated in the immunodeficient NASH animal model and may have therapeutic applications in humans.

Androgen dysfunction in non-alcoholic fatty liver disease: Role of sex hormone binding globulin.

Non-alcoholic fatty liver disease (NAFLD) is the most common form of chronic liver disease in the world. It is linked mainly to insulin resistance and metabolic syndrome including obesity and dyslipidemia. In addition, various endocrine dysfunctions including polycystic ovary syndrome (PCOS) and hypogonadism are involved in the development and progression of NAFLD. We need to know the disease pathophysiology more accurately due to the heterogeneity of clinical presentation of fatty liver disease. The liver is the major metabolic organ with sexual dimorphism. Sexual dimorphism is associated not only with behavioral differences between men and women, but also with physiological differences reflected in liver metabolism. In men, normal androgen levels prevent hepatic fat accumulation, whereas androgen deficiency induce hepatic steatosis. In women, higher androgens can increase the risk of NAFLD in PCOS. Sex hormone binding globulin (SHBG) is involved in androgen regulation. Recently, SHBG may be reported as a surrogate marker for NAFLD. Therefore, this review will focus on the mechanism of androgen dysfunction in the regulation of hepatic metabolism, the risk of developing NAFLD, and the potential role of SHBG in the course of NAFLD.; Keywords: Non-alcoholic fatty liver disease, insulin resistance, sexual dimorphism, androgen, sex hormone binding globulin.

The Correlation Between Serum Collagen III Levels and APRI in Liver Fibrotic HCV Patients

Abstract Introduction/Objective Noninvasive Markers (NIM) of Liver Fibrosis help evaluate the stage of fibrosis in patients with no clear indication for a liver biopsy, such as patients with chronic hepatitis C who need monitoring of the stage of fibrosis during or after treatment. The perfect NIM for hepatic fibrosis should be inexpensive, safe, simple, reliable, and well-validated in different forms of chronic liver disease. Aim of the work Find if there is a correlation between serum collagen III and APRI as noninvasive markers in patients with HCV-induced liver fibrosis. Methods/Case Report 118 patients with HCV induced liver fibrosis (60 males and 58 females) and 50 healthy comparable control subjects (27 males and 23 females) were enrolled in the study. Collagen III was identified in serum samples of HCV-induced liver fibrosis patients at 70 kDa using collagen III polyclonal antibody and western blot analysis techniques. Collagen III was purified using the electroelution technique and then quantified using the ELISA technique. AST, ALT, albumin, and total bilirubin were measured. The APRI was calculated as [AST/ (upper limits of normal)/ platelets count 109/L]×100. The AST-ALT ratio was calculated as [AST/ ALT]. Results (if a Case Study enter NA) There was a statistically significant difference between the diseased and control groups (P<0.0001) regarding collagen III and APRI. Also, significant positive correlation between serum collagen III, APRI, and ALT levels (r=0.3 and p=0.02). However, there were no correlations between serum collagen III levels and AST, Albumin, Total Bilirubin, and AST/ALT ratio (r=0.15, -0.26, 0.22, and -0.027), respectively. Conclusion Collagen III and APRI is a promising diagnostic and prognostic potential in the noninvasive assessment of liver fibrosis as their levels elevate with each other. So, we can powerfully depend on them in liver fibrosis diagnosis in chronic HCV patients.

Stellate cell expression of SPARC-related modular calcium-binding protein 2 is associated with human non-alcoholic fatty liver disease severity

Histological assessment of liver biopsies is the gold standard for diagnosis of non-alcoholic steatohepatitis (NASH), the progressive form of non-alcoholic fatty liver disease (NAFLD), despite its well-established limitations. Therefore, non-invasive biomarkers that can offer an integrated view of the liver are needed to improve diagnosis and reduce sampling bias. Hepatic stellate cells (HSCs) are central in the development of hepatic fibrosis, a hallmark of NASH. Secreted HSC-specific proteins may, therefore, reflect disease state in the NASH liver and serve as non-invasive diagnostic biomarkers. We performed RNA-sequencing on liver biopsies from a histologically characterised cohort of obese patients (n= 30, BMI >35kg/m2) to identify and evaluate HSC-specific genes encoding secreted proteins. Bioinformatics was used to identify potential biomarkers and their expression at single-cell resolution. We validated our findings using single-molecule fluorescence in situ hybridisation (smFISH) and ELISA to detect mRNA in liver tissue and protein levels in plasma, respectively. Hepatic expression of SPARC-related modular calcium-binding protein 2 (SMOC2) was increased in NASH compared to no-NAFLD (p.adj <0.001). Single-cell RNA-sequencing data indicated that SMOC2 was primarily expressed by HSCs, which was validated using smFISH. Finally, plasma SMOC2 was elevated in NASH compared to no-NAFLD (p <0.001), with a predictive accuracy of AUROC 0.88. Increased SMOC2 in plasma appears to reflect HSC activation, a key cellular event associated with NASH progression, and may serve as a non-invasive biomarker of NASH. Non-alcoholic fatty liver disease (NAFLD) and its progressive form, non-alcoholic steatohepatitis (NASH), are the most common forms of chronic liver diseases. Currently, liver biopsies are the gold standard for diagnosing NAFLD. Blood-based biomarkers to complement liver biopsies for diagnosis of NAFLD are required. We found that activated hepatic stellate cells, a cell type central to NAFLD pathogenesis, upregulate expression of the secreted protein SPARC-related modular calcium-binding protein 2 (SMOC2). SMOC2 was elevated in blood samples from patients with NASH and may hold promise as a blood-based biomarker for the diagnosis of NAFLD.

Non-cirrhotic portal hypertension (obliterative portal venopathy) is the predominant form of chronic liver disease in cystic fibrosis.

Cystic fibrosis (CF)-associated liver disease commonly manifests as portal hypertension and its complications. We investigated the proposal that the pathophysiology is of non-cirrhotic rather than cirrhotic portal hypertension. This distinction may have important implications for treatment. We compared liver transplant explants from cystic fibrosis patients with explants from patients with classical cholestatic diseases, primary biliary cholangitis and primary sclerosing cholangitis. Presence of cirrhosis, fibrosis, nodular regenerative hyperplasia, biliary and portal venous pathology were recorded. Quantitation of portal venules in representative section was performed. Nine patients with cystic fibrosis liver disease, 7 primary biliary cholangitis (PBC) and 7 primary sclerosing cholangitis (PSC) were evaluated. Cirrhosis was present in 0/9 of CF patients and 11/14 of the PBC and PSC controls (p < 0.01). Nodular regenerative hyperplasia was present in 8/9 of the CF patients but none of the controls (p < 0.01). Portal venule numbers per 15 mm2 section were significantly lower in the CF patients 52 (20-72) compared to the primary biliary cholangitis 78 (47-110) and primary sclerosing cholangitis patients, 79 (41-134) (p < 0.05). Portal sclerotic nodules were found in all the CF patients but in only one of the controls (9/9 vs 1/14 p < 0.01). This study demonstrates that non-cirrhotic portal hypertension or obliterative portal venopathy is the predominant hepatic pathophysiology in adult CF patients requiring liver transplantation. It suggests that treatments directed at the hepatic portal venous system may be more effective than current treatment directed at the biliary system in cystic fibrosis.

Rosavin Ameliorates Hepatic Inflammation and Fibrosis in the NASH Rat Model via Targeting Hepatic Cell Death

Background: Non-alcoholic fatty liver disease (NAFLD) represents the most common form of chronic liver disease that urgently needs effective therapy. Rosavin, a major constituent of the Rhodiola Rosea plant of the family Crassulaceae, is believed to exhibit multiple pharmacological effects on diverse diseases. However, its effect on non-alcoholic steatohepatitis (NASH), the progressive form of NAFLD, and the underlying mechanisms are not fully illustrated. Aim: Investigate the pharmacological activity and potential mechanism of rosavin treatment on NASH management via targeting hepatic cell death-related (HSPD1/TNF/MMP14/ITGB1) mRNAs and their upstream noncoding RNA regulators (miRNA-6881-5P and lnc-SPARCL1-1:2) in NASH rats. Results: High sucrose high fat (HSHF) diet-induced NASH rats were treated with different concentrations of rosavin (10, 20, and 30 mg/kg/day) for the last four weeks of dietary manipulation. The data revealed that rosavin had the ability to modulate the expression of the hepatic cell death-related RNA panel through the upregulation of both (HSPD1/TNF/MMP14/ITGB1) mRNAs and their epigenetic regulators (miRNA-6881-5P and lnc-SPARCL1-1:2). Moreover, rosavin ameliorated the deterioration in both liver functions and lipid profile, and thereby improved the hepatic inflammation, fibrosis, and apoptosis, as evidenced by the decreased protein levels of IL6, TNF-α, and caspase-3 in liver sections of treated animals compared to the untreated NASH rats. Conclusion: Rosavin has demonstrated a potential ability to attenuate disease progression and inhibit hepatic cell death in the NASH animal model. The produced effect was correlated with upregulation of the hepatic cell death-related (HSPD1, TNF, MMP14, and ITGB1) mRNAs—(miRNA-6881-5P—(lnc-SPARCL1-1:2) RNA panel.

SLAMF1 is expressed and secreted by hepatocytes and the liver in nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) is one of the most prevalent forms of chronic liver disease in the United States and worldwide. Nonalcoholic steatohepatitis (NASH), the most advanced form of NAFLD, is characterized by hepatic steatosis associated with inflammation and hepatocyte death. No treatments are currently available for NASH other than lifestyle changes, and the disease lacks specific biomarkers. The signaling lymphocytic activation molecule family 1 (SLAMF1) protein is a self-ligand receptor that plays a role in orchestrating an immune response to some pathogens and cancers. We found that livers from humans and mice with NASH showed a more prominent immunohistochemistry staining for SLAMF1 than non-NASH controls. Furthermore, SLAMF1 levels are significantly increased in NASH plasma samples from mice and humans compared with their respective controls. In mice, the levels of SLAMF1 correlated significantly with the severity of the NASH phenotype. To test whether SLAMF 1 is expressed by hepatocytes, HepG2 cells and primary murine hepatocytes were treated with palmitic acid (PA) to induce a state of lipotoxicity mimicking NASH. We found that PA treatments of HepG2 cells and primary hepatocytes lead to significant increases in SLAMF1 levels. The downregulation of SLAMF1 in HepG2 cells improved the cell viability and reduced cytotoxicity. The in vivo data using mouse and human NASH samples suggests a potential role for this protein as a noninvasive biomarker for NASH. The in vitro data suggest a role for SLAMF1 as a potential therapeutic target to prevent hepatocyte death in response to lipotoxicity.NEW & NOTEWORTHY This study identified for the first time SLAMF1 as a mediator of hepatocyte death in nonalcoholic fatty liver disease (NASH) and as a marker of NASH in humans. There are no pharmacological treatments available for NASH, and diagnostic tools are limited to invasive liver biopsies. Therefore, since SLAMF1 levels correlate with disease progression and SLAMF1 mediates cytotoxic effects, this protein can be used as a therapeutic target and a clinical biomarker of NASH.

Lipidomic profiling of the hepatic esterified fatty acid composition in diet-induced nonalcoholic fatty liver disease in genetically diverse Collaborative Cross mice

Non-alcoholic fatty liver disease (NAFLD), one of the most common forms of chronic liver disease, is characterized by the excessive accumulation of lipid species in hepatocytes. Recent studies have indicated that in addition to the total lipid quantities, changes in lipid composition are a determining factor in hepatic lipotoxicity. Using ultra-high performance liquid chromatography coupled with electrospray tandem mass spectrometry, we analyzed the esterified fatty acid composition in 24 strains of male and female Collaborative Cross (CC) mice fed a high fat/high sucrose (HF/HS) diet for 12 weeks. Changes in lipid composition were found in all strains after the HF/HS diet, most notably characterized by increases in monounsaturated fatty acids (MUFA) and decreases in polyunsaturated fatty acids (PUFA). Similar changes in MUFA and PUFA were observed in a choline- and folate-deficient (CFD) mouse model of NAFLD, as well as in hepatocytes treated in vitro with free fatty acids. Analysis of fatty acid composition revealed that alterations were accompanied by an increase in the estimated activity of MUFA generating SCD1 enzyme and an estimated decrease in the activity of PUFA generating FADS1 and FADS2 enzymes. PUFA/MUFA ratios were inversely correlated with lipid accumulation in male and female CC mice fed the HF/HS diet and with morphological markers of hepatic injury in CFD diet-fed mouse model of NAFLD. These results demonstrate that different models of NAFLD are characterized by similar changes in the esterified fatty acid composition and that alterations in PUFA/MUFA ratios may serve as a diagnostic marker for NAFLD severity.

Sonoelastography in Nonalcoholic Fatty Liver Disease

Background of the Study: It is an imaging technology sensitive to tissue stiffness that was first described in the 1990s. Nonalcoholic fatty liver disease (NAFLD) is increasingly common in Western nations of the world. It is the most common form of chronic liver disease, affecting about one-quarter of the population, in the United States. Materials and Methods: Prospective studies of 100 patients with clinical impression of alcoholic were examined by Philips ultrasound imaging. Results: A total of 100 patients satisfying the inclusion criteria were included in the study. The age range of patients was from 18 years to elderly with male predominance, male 64 (64%), and female 36 (36%). Conclusion: In this study, a non-invasive and cost-effective technique, without any radiation hazards, to measure the elastic property of liver tissue using ultrasound imaging modality called as sonoelastography in Indian population for assessment of disease severity and grading of NAFLD.

Efficacy and safety of Jian-Pi Huo-Xue granule for non-alcoholic fatty liver disease: study protocol for a randomized, double-blind, placebo-controlled trial

BackgroundNon-alcoholic fatty liver disease (NAFLD) has become the most prevalent form of chronic liver disease, with a global prevalence of 25% worldwide, but a consensus treatment is still lacking. Previous studies have shown that Jian-Pi Huo-Xue granules (JPHX) can reduce hepatic steatosis in ultrasound images, but lacked quantitative observation in imagined liver fat content. This study aimed to refine the efficacy and safety assessment of JPHX for NAFLD with magnetic resonance imaging-proton density fat fraction (MRI-PDFF) as the primary outcome.MethodsThis is a randomized, double-blind, placebo-controlled clinical trial. The trial will enrol 84 NAFLD participants who will be equally randomized to receive either JPHX or a placebo for 24 weeks. Follow-up will be performed 12 weeks after the intervention. The primary outcome will be the change from baseline to week 24 in MRI-PDFF. Secondary outcomes will be the body weight, body mass index (BMI), waist circumference, waist-to-hip ratio (WHR), serum liver function, blood lipids and glucose-related indicators, quality of life measurement health survey, and traditional Chinese medicine (TCM) syndrome scale. Outcomes will be monitored at baseline, 12 weeks and 24 weeks after enrolment. Adverse events occurring in this trial will be managed and recorded promptly.DiscussionWe designed a clinical trial for the treatment of NAFLD using JPHX, a TCM formulation that has been shown to have a positive effect on hepatic steatosis in a previous self-controlled trial. This trial will use a more recognized and quantitative imaging approach to demonstrate the efficacy of JPHX in the treatment of NAFLD and observe its safety to provide clinical evidence for its translational applications.Trial registrationChinese Clinical Trial Registry ChiCTR2100046132. Registered on 4 May 2021.

The Effects of High Fat Diet on the Liver of the White Rat Model Obesity

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is the most common form of chronic liver disease with the manifestation of over-accumulation of fat in the liver. AIM: The purpose of this study was to assess the degree of occurrence of steatosis in rats induced by a standard diet, a high-fat diet, and a modified high-fat diet. METHODS: This study used 18 white rats of the Wistar strain, divided into three groups, and fed for 9 weeks. Before feeding, all rats were measured their body weight, abdominal circumference, and body length. We measured body weight every week, while body length and waist circumference were measured every 2 weeks. After 9 weeks of diet, all rats were subjected to injection of Ketamine and examined for metabolic markers and histopathological examination of liver organs. RESULT: There was an increase in body weight of rats in the three groups with the average percentage increase in body weight in the three groups of rats before and after being fed a diet for 9 weeks found in Group 1 29.19% 1 (187−264.40 g), Group 2 by 19.12% (219.33−275 g), and Group 3 24.53% (213.33−275 g). Steatosis in Group 1 was 57.50% of hepatocytes containing macrovesicular fat droplets and called Grade 2 (moderate). In contrast, with a high-fat diet, steatosis occurred around 93.33%−95% of hepatocytes containing macrovesicular fat droplets and called steatosis Grade 3 (severe). CONCLUSION: The percentage of hepatocytes that had steatosis in obese rats induced by a high-fat diet was more significant than in obese models induced by a standard diet.

Mitochondria and the NLRP3 Inflammasome in Alcoholic and Nonalcoholic Steatohepatitis.

Alcoholic (ASH) and nonalcoholic steatohepatitis (NASH) are advanced stages of fatty liver disease and two of the most prevalent forms of chronic liver disease. ASH and NASH are associated with significant risk of further progression to cirrhosis and hepatocellular carcinoma (HCC), the most common type of liver cancer, and a major cause of cancer-related mortality. Despite extensive research and progress in the last decades to elucidate the mechanisms of the development of ASH and NASH, the pathogenesis of both diseases is still poorly understood. Mitochondrial damage and activation of inflammasome complexes have a role in inducing and sustaining liver damage. Mitochondrial dysfunction produces inflammatory factors that activate the inflammasome complexes. NLRP3 inflammasome (nucleotide-binding oligomerization domain-like receptor protein 3) is a multiprotein complex that activates caspase 1 and the release of pro-inflammatory cytokines, including interleukin-1β (IL-1β) and interleukin-18 (IL-18), and contributes to inflammatory pyroptotic cell death. The present review, which is part of the issue “Mitochondria in Liver Pathobiology”, provides an overview of the role of mitochondrial dysfunction and NLRP3 activation in ASH and NASH.

Oleuropein prevents liver damage in NAFL mice by modulating copper-catalyzed dicarbonyl stress

Introduction: The Nonalcoholic Fatty Liver Disease (NAFLD) is one of the major forms of chronic liver disease. NAFLD is considered the hepatic manifestation of the metabolic syndrome, thus, a new and more appropriate nomenclature has been suggested: Metabolic Associated Fatty Liver Disease (MAFLD). An imbalance of copper homeostasis has been described in the progression of NAFLD/MAFLD toward Nonalcoholic steatohepatitis (NASH), or Metabolic-associated Steatohepatitis (MASH).

Platelet–neutrophil hybrid membrane-coated gelatin nanoparticles for enhanced targeting ability and intelligent release in the treatment of non-alcoholic steatohepatitis

Non-alcoholic steatohepatitis (NASH) is the major form of chronic liver disease in adults; however, there are no approved drugs for NASH. In this study, we designed the PNM-G-PV method, in which gelatin nanoparticles (G) are loaded with pioglitazone and vitamin E (G-PV) and then encapsulated by the surfaces of platelet–neutrophil hybrid membranes (PNM). Inherited from the natural source cells, the PNM show immune evading ability due to the surface marker comprising a number of “do not eat me” signals and has dual inflammatory enrichment capabilities due to specific surface adhesion molecules. By functionalizing the gelatin nanoparticle biomimetic surfaces, PNM-G can enhance the targeting to inflammatory sites and enrich liver tissue. The high expression of matrix metalloproteinase-9 (MMP-9) at the NASH site enables the gelatin nanoparticles to intelligently respond to degradation and then release vitamin E and pioglitazone for drug treatment. We performed an in vivo analysis of these nanoparticles to monitor changes in triacylglycerol metabolism in liver tissues and assessed the therapeutic efficacy of PNM-G-PV in a NASH rat model. The results showed that PNM-G-PV exhibited better therapeutic efficacy than therapies using G-PV or PV alone. This work explores a new biomedical use of PNM-G-PV and a promising NASH treatment protocol based on a new drug delivery system.

Protective Effect of Leisure-Time Physical Activity and Resistance Training on Nonalcoholic Fatty Liver Disease: A Nationwide Cross-Sectional Study.

Background: Nonalcoholic fatty liver disease (NAFLD) is the most common form of chronic liver disease. The present study aimed to investigate the association of NAFLD with leisure-time physical activity (PA) levels and resistance training (RT). Methods: We used data from large nationwide cohorts in Korea. NAFLD was defined based on the Framingham steatosis index. Participants were categorized into four groups based on RT frequency and adherence to PA guidelines (≥150 min/week of moderate-intensity PA): Low-PA, Low-PA+RT, High-PA, and High-PA+RT. Multiple logistic regression models were used to assess the risk of NAFLD according to leisure-time PA levels and regularity of RT. Results: When compared with Low-PA, High-PA decreased the risk of NAFLD by 17%, and High-PA+RT further decreased the risk by 30%. However, the additional reduction in risk associated with the addition of RT was observed in men (19%), but not in women. In the High-PA group, men had a significantly higher training frequency and period for RT than women. Conclusions: Following the PA guideline may confer protective effects against NAFLD, while adding RT to High-PA can further decrease the risk of NAFLD. Sex-based differences in NAFLD risk in the High-PA+RT group may be due to the differences in the frequency and period of RT.

Discovery of JND003 as a New Selective Estrogen-Related Receptor α Agonist Alleviating Nonalcoholic Fatty Liver Disease and Insulin Resistance.

Nonalcoholic fatty liver disease (NAFLD) is one of the most prevalent forms of chronic liver diseases and is causally linked to hepatic insulin resistance and reduced fatty acid oxidation. Therapeutic treatments targeting both hepatic insulin resistance and lipid oxidative metabolism are considered as feasible strategies to alleviate this disease. Emerging evidence suggests Estrogen-Related Receptor alpha (ERRα), the first orphan nuclear receptor identified, as a master regulator in energy homeostasis by controlling glucose and lipid metabolism. Small molecules improving the functions of ERRα may provide a new option for management of NAFLD. In the present study, by using liver-specific Errα knockout mouse (Errα-LKO), we showed that liver-specific deletion of ERRα exacerbated diet-evoked fatty liver, hepatic and systemic insulin resistance in mice. A potent and selective ERRα agonist JND003 (7) was also discovered. In vitro and in vivo investigation demonstrated that the compound enhanced the transactivation of ERRα downstream target genes, which was accompanied by improved insulin sensitivity and fatty liver symptoms. Furthermore, the therapeutic effects were completely abolished in Errα-LKO mice, indicative of its on-target efficacy. Our study thus suggests that hepatic ERRα is a viable target for NAFLD and that ERRα agonist may serve as an intriguing pharmacological option for management of metabolic diseases.

Gut microbiome in non-alcoholic fatty liver disease

Abstract The human gut microbiome is composed of communities of bacteria, viruses and fungi. Bacteria live in each part of digestive tract, increasing their density and changing composition in distal parts. The composition of gut microbiome mainly depends on method of childbirth, age, gender, diet, stress, infections, alcohol intake, diurnal variation, smoking, drugs (antibiotics), physical activity. Dysbiosis is defined as an imbalance or maladaptation in the gut microbial community. This imbalance favors many pathological states and it could be due to some diseases. Non-alcoholic fatty liver disease (NAFLD) has become increasingly common in parallel with the increasing prevalence of obesity and other components of the metabolic syndrome. In year 2020, a more comprehensive new definition of NAFLD was proposed – fatty liver disease associated with metabolic dysfunction (MAFLD). NAFLD/MALFD will become the major form of chronic liver disease in adults and children and could become the leading indication for liver transplantation within a decade. An increased level of Bacteroidetes and decreased level of Firmicutes is observed in fatty liver disease. This imbalance favors the collection of energy and insulin resistance. The prevention and treatment of dysbiosis in NAFLD/MAFLD is essential. The purpose of this review is an understanding related to the dysbiosis and non-alcoholic fatty liver disease in order to help physicians of different specialties in their clinical practice because of growing in population patients with metabolic syndrome and liver steatosis.

An Observational Study showing Dipeptidyl Peptidase-4 (DPP-4) Activity and Gene Expression Variation in Chronic Liver Disease (CLD) Patients from a Tertiary Care Hospital of Eastern India.

Introduction:The studies in animal models of cirrhosis suggest that dipeptidyl peptidase type 4 (DPP-4) enzymes play a crucial role in disease pathogenesis. In this clinical observational study, activity of DPP-4 and related gene expression were analysed in chronic liver disease patients.Objectives:To understand the DPP-4 enzyme activity variation in the common types of chronic liver disease by assessing plasma and peripheral blood mononuclear cell (PBMC) DPP-4 activity and comparing with healthy controls and to explore DPP-4 gene expression in PBMC.Methods:We recruited 130 study subjects in four cohorts—46 nonalcoholic fatty liver disease (NAFLD), 23 non-alcoholic cirrhosis (NAC) excluding viral aetiology, 21 alcoholic liver disease (ALC), and 40 control subjects. Blood samples were analysed for relevant biochemical parameters and plasma DPP-4 activity. PBMC fraction was used for the DPP-4 activity assay and gene expression analysis.Results:We found that lower plasma DPP-4 activity among patient cohorts but this was not statistically significant. The PBMC DPP-4 activity was significantly lower in NAFLD cohort. In the same cohort, DPP-4 gene expression in PBMC fraction was significantly increased (P < 0.05). There was significant correlation between plasma DPP-4 activity and liver injury marker alanine aminotransferase (ALT) among NAFLD (rho = 0.459, P < 0.01), NAC (rho = 0.475, P < 0.05), and ALC (rho = –0.572, P < 0.01) patients. Plasma DPP-4 activity modestly predicted ALT plasma level (beta coefficient = 0.489, P < 0.01).Conclusions:The PBMC DPP-4 activity and DPP-4 gene expression gets significantly altered in NAFLD patients. Plasma DPP-4 activity also shows correlation with ALT levels in CLD patients. The role of DPP-4 in disease pathology in NAFLD and other forms of CLD needs to be explored.

Metabolic Fatty Liver Disease in Children: A Growing Public Health Problem.

Metabolic-associated fatty liver disease (MAFLD), previously called nonalcoholic fatty liver diseases (NAFLD), is one of the most important causes of chronic liver disease worldwide and will likely become the leading cause of end-stage liver disease in the decades ahead. MAFLD covers a continuum of liver diseases from fatty liver to nonalcoholic steatohepatitis (NASH), liver fibrosis/cirrhosis and hepatocellular cancer. Importantly, the growing incidence of overweight and obesity in childhood, 4% in 1975 to 18% in 2016, with persisting obesity complications into adulthood, is likely to be harmful by increasing the incidence of severe MAFLD at an earlier age. Currently, MAFLD is the leading form of chronic liver disease in children and adolescents, with a global prevalence of 3 to 10%, pointing out that early diagnosis is therefore crucial. In this review, we highlight the current knowledge concerning the epidemiology, risk factors and potential pathogenic mechanisms, as well as diagnostic and therapeutic approaches, of pediatric MAFLD.