NASH Patients Research Articles

THU-247 - Culturomics study of gut microbiota in NASH patients and healthy controls

THU-247 - Culturomics study of gut microbiota in NASH patients and healthy controls

The prognostic relationship between donor age and infectious risk in liver transplant patients with nonalcoholic steatohepatitis: Analysis of UNOS database.

We investigate the effects of advancing donor age on the prognostic outcomes of patients with NASH who undergo liver transplant (LT), with a specialized attention toward infectious outcomes post-LT. The UNOS-STAR registry was used to select 2005 to 2019 LT recipients with NASH, who were stratified by donor age into the following categories: recipients with younger donors (less than 50 years of age-reference), quinquagenarian donors, sexagenarian donors, septuagenarian donors, and octogenarian donors. Cox regression analyses were conducted for all-cause mortality, graft failure, infectious causes of death. From a total of 8888 recipients, the quinquagenarian, septuagenarian, and octogenarian donor cohorts showed greater risk of all-cause mortality (quinquagenarian: aHR 1.16 95%CI 1.03-1.30; septuagenarian: aHR 1.20 95%CI 1.00-1.44; octogenarian: aHR 2.01 95%CI 1.40-2.88). With advancing donor age, there was an increased risk of death from sepsis (quinquagenarian: aHR 1.71 95% CI 1.24-2.36; sexagenarian: aHR 1.73 95% CI 1.21-2.48; septuagenarian: aHR 1.76 95% CI 1.07-2.90; octogenarian: aHR 3.58 95% CI 1.42-9.06) and infectious causes (quinquagenarian: aHR 1.46 95% CI 1.12-1.90; sexagenarian: aHR 1.58 95% CI 1.18-2.11; septuagenarian: aHR 1.73 95% CI 1.15-2.61; octogenarian: aHR 3.70 95% CI 1.78-7.69). NASH patients who receive grafts from elderly donors exhibit higher risk of post-LT mortality, especially due to infection.

TOP-091 - Non-invasive tests of liver injury, inflammation and fibrosis are improved by efruxifermin and correlate with histological improvements in F2-F3 NASH patients: secondary analysis of Ph2b HARMONY study

TOP-091 - Non-invasive tests of liver injury, inflammation and fibrosis are improved by efruxifermin and correlate with histological improvements in F2-F3 NASH patients: secondary analysis of Ph2b HARMONY study

SAT-347 - Recently validated non-invasive tests for liver fibrosis assessment have great performance in identifying NASH patients at risk for decompensation

SAT-347 - Recently validated non-invasive tests for liver fibrosis assessment have great performance in identifying NASH patients at risk for decompensation

Non-alcoholic steatohepatitis and hepatic fibrosis are strongly associated with estimated 10-years cardiovascular risk in people living with severe obesity

Abstract Funding Acknowledgements Type of funding sources: Public Institution(s). Main funding source(s): Cardiometabolic health, diabetes and obesity research network IUCPQ Foundation. Background Obesity (Body Mass Index [BMI] over 30 kg/m2) is associated with metabolic disturbances that promote the development and progression of cardiovascular diseases (CVD). However, the association between anthropometric indices of obesity (BMI, Waist Circumference [WC], Waist-to-Hip ratio [WHR] or Neck Circumference [NC]) and CVD risk factors has not always been observed in people living with severe obesity (BMI >35 kg/m2). Among obesity-related metabolic disorders, non-alcoholic ateatohepatitis (NASH) is associated with an increased risk of CVD and cardiac events. NASH has been shown to correlate with a degree of obesity, as defined by BMI or WC. The association between anthropometric parameters, NASH and CVD risk factors has not been explored yet in people living with severe obesity. Purpose The aim of this study was to explore the relationships between CVD risk score, anthropometric parameters and the presence of NASH (hepatic steatosis and fibrosis) in a population with severe obesity. Method A total of 2257 patients with severe obesity, who underwent bariatric surgery with concomitant liver biopsy were included. All biopsy specimens were classified according to the Brunt grading system. Pre-operative demographic and anthropometric data (age, sex, weight, height, BMI, WC, WHR, NC) were recorded. Comorbidities were assessed (type 2 diabetes, hypertension, dyslipidemia). The 10-year cardiovascular risk was calculated preoperatively in each patient using the Framingham risk score (FRS). Dependent variable FRS was compared using Kruskal Wallis H test and Chi2 exact test. Associations were tested using multivariate logistic regression analysis. Results In this specific population (mean age of 46.2 years old, mean BMI of 47.8 kg/m2, 69.1% female), FRS did not significantly increase with weight, BMI and WC, but was positively correlated with WHR and NC (p<0.05). A total of 47.3 % of patients with a histopathological diagnosis of NASH had a moderate-to-high FRS. Among NASH patients with histopathological evidence of grade-4 fibrosis, 69.3% had a moderate-to-high FRS. Presence of NASH and fibrosis were more strongly correlated with a moderate-to-high FRS (OR of 1.61 and 1.37, respectively), compared to all other anthropometric parameters (p<0.05), except WHR (OR of 1.99). Conclusion In people living with severe obesity, the presence of NASH and hepatic fibrosis is strongly associated with a high FRS but not more than WHR. Further research is needed to identify the best predictors of CVD and cardiac events in people living with NASH and severe obesity.

Carboxylesterase 2a deletion provokes hepatic steatosis and insulin resistance in mice involving impaired diacylglycerol and lysophosphatidylcholine catabolism

ObjectiveHepatic triacylglycerol accumulation and insulin resistance are key features of NAFLD. However, NAFLD development and progression are rather triggered by the aberrant generation of lipid metabolites and signaling molecules including diacylglycerol (DAG) and lysophosphatidylcholine (lysoPC). Recent studies showed decreased expression of carboxylesterase 2 (CES2) in the liver of NASH patients and hepatic DAG accumulation was linked to low CES2 activity in obese individuals. The mouse genome encodes several Ces2 genes with Ces2a showing highest expression in the liver. Herein we investigated the role of mouse Ces2a and human CES2 in lipid metabolism in vivo and in vitro. MethodsLipid metabolism and insulin signaling were investigated in mice lacking Ces2a and in a human liver cell line upon pharmacological CES2 inhibition. Lipid hydrolytic activities were determined in vivo and from recombinant proteins. ResultsCes2a deficient mice (Ces2a-ko) are obese and feeding a high-fat diet (HFD) provokes severe hepatic steatosis and insulin resistance together with elevated inflammatory and fibrotic gene expression. Lipidomic analysis revealed a marked rise in DAG and lysoPC levels in the liver of Ces2a-ko mice fed HFD. Hepatic lipid accumulation in Ces2a deficiency is linked to lower DAG and lysoPC hydrolytic activities in liver microsomal preparations. Moreover, Ces2a deficiency significantly increases hepatic expression and activity of MGAT1, a PPAR gamma target gene, suggesting aberrant lipid signaling upon Ces2a deficiency. Mechanistically, we found that recombinant Ces2a and CES2 show significant hydrolytic activity towards lysoPC (and DAG) and pharmacological inhibition of CES2 in human HepG2 cells largely phenocopies the lipid metabolic changes present in Ces2a-ko mice including reduced lysoPC and DAG hydrolysis, DAG accumulation and impaired insulin signaling. ConclusionsCes2a and CES2 are critical players in hepatic lipid signaling likely via the hydrolysis of DAG and lysoPC at the ER.

A metabolomics approach to the validation of predictive metabolites and phenotypic expression in non-alcoholic fatty liver disease

AimsNonalcoholic fatty liver disease (NAFLD) is becoming more common and severe. Individuals with NAFLD have an altered composition of gut- microbial metabolites. We used metabolomics profiling to identify microbial metabolites that could indicate gut-liver metabolic severity. Noninvasive biomarkers are required for NAFLD, especially for patients at high risk of disease progression. Main methodsWe compared the stool metabolomes, untargeted metabolomics, and clinical data of 80 patients. Patients with nonalcoholic fatty liver (NAFL: n = 16), nonalcoholic steatohepatitis (NASH: n = 26), and cirrhosis (n = 19) and healthy control individuals (HC: n = 19) were enrolled. The identified metabolites in NAFLD were evaluated by multivariate statistical analysis and metabolic pathotypic expression. Gas chromatography–mass spectrometry (GC–MS) and liquid chromatography coupled to time-of-flight–mass spectrometry (LC–TOF-MS) were used to analyze metabolites. Key findingsUntargeted metabolomics was used to identify and quantify 103 metabolites. Principal component analysis (PCA) was used to assess the metabolic discrimination of NAFL, NASH, and cirrhosis. Short-chain fatty acids (SCFA) levels were significantly lower in NAFLD patients, including those of acetate (p = 0.03), butyrate (p = 0.0008), and propionate. The stool cholic acid (p = 0.001) level was significantly increased in NAFLD patients. Palmitoylcarnitine and l-carnitine levels were significantly increased in NASH and cirrhosis patients. The phenotypic expression of these metabolites was linked to β-oxidation. SignificanceWe demonstrated a distinct metabolome profile in NAFLD patients with NAFL, NASH, and cirrhosis. We also discovered that the expression of certain metabolites and metabolic pathways was linked to NAFLD.

ATF4 suppresses hepatocarcinogenesis by inducing SLC7A11 (xCT) to block stress-related ferroptosis

Hepatocellular carcinoma (HCC), a leading cause of cancer-related death, is associated with viral hepatitis, non-alcoholic steatohepatitis (NASH), and alcohol-related steatohepatitis, all of which trigger endoplasmic reticulum (ER) stress, hepatocyte death, inflammation, and compensatory proliferation. Using ER stress-prone MUP-uPA mice, we established that ER stress and hypernutrition cooperate to cause NASH and HCC, but the contribution of individual stress effectors, such as activating transcription factor 4 (ATF4), to HCC and their underlying mechanisms of action remained unknown. Hepatocyte-specific ATF4-deficient MUP-uPA mice (MUP-uPA/Atf4Δhep) and control MUP-uPA/Atf4F/F mice were fed a high-fat diet to induce NASH-related HCC, and Atf4F/F and Atf4Δhep mice were injected with diethylnitrosamine to model carcinogen-induced HCC. Histological, biochemical, and RNA-sequencing analyses were performed to identify and define the role of ATF4-induced solute carrier family 7a member 11 (SLC7A11) expression in hepatocarcinogenesis. Reconstitution of SLC7A11 in ATF4-deficient primary hepatocytes and mouse livers was used to study its effects on ferroptosis and HCC development. Hepatocyte ATF4 ablation inhibited hepatic steatosis, but increased susceptibility to ferroptosis, resulting in accelerated HCC development. Although ATF4 activates numerous genes, ferroptosis susceptibility and hepatocarcinogenesis were reversed by ectopic expression of a single ATF4 target, Slc7a11, coding for a subunit of the cystine/glutamate antiporter xCT, which is needed for glutathione synthesis. A ferroptosis inhibitor also reduced liver damage and inflammation. ATF4 and SLC7A11 amounts were positively correlated in human HCC and livers of patients with NASH. Despite ATF4 being upregulated in established HCC, it serves an important protective function in normal hepatocytes. By maintaining glutathione production, ATF4 inhibits ferroptosis-dependent inflammatory cell death, which is known to promote compensatory proliferation and hepatocarcinogenesis. Ferroptosis inhibitors or ATF4 activators may also blunt HCC onset. Liver cancer or hepatocellular carcinoma (HCC) is associated with multiple aetiologies. Most HCC aetiologies cause hepatocyte stress and death, as well as subsequent inflammation, and compensatory proliferation, thereby accelerating HCCdevelopment. The contribution of individual stress effectors to HCC and their underlying mechanisms of action were heretofore unknown. This study shows that the stress-responsive transcription factor ATF4 blunts liver damage and cancer development by suppressing iron-dependent cell death (ferroptosis). Although ATF4 ablation prevents hepatic steatosis, it also increases susceptibility to ferroptosis, due to decreased expression of the cystine/glutamate antiporter SLC7A11, whose expression in human HCC and NASH correlates with ATF4. These findings reinforce the notion that benign steatosis may be protective and does not increase cancer risk unless accompanied by stress-induced liver damage. These results have important implications for prevention of liver damage and cancer.

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Hepatic MCPIP1 protein levels are reduced in NAFLD patients and are predominantly expressed in cholangiocytes and liver endothelium

NAFLD is characterized by the excessive accumulation of fat in hepatocytes. NAFLD can range from simple steatosis to the aggressive form called NASH, which is characterized by both fatty liver and liver inflammation. Without proper treatment, NAFLD may further progress to life-threatening complications, such as fibrosis, cirrhosis, or liver failure. Monocyte chemoattractant protein-induced protein 1 (MCPIP1, alias Regnase 1) is a negative regulator of inflammation, acting through the cleavage of transcripts coding for proinflammatory cytokines and the inhibition of NF-κB activity. In this study, we investigated MCPIP1 expression in the liver and peripheral blood mononuclear cells (PBMCs) collected from a cohort of 36 control and NAFLD patients hospitalized due to bariatric surgery or primary inguinal hernia laparoscopic repair. Based on liver histology data (hematoxylin and eosin and Oil Red-O staining), 12 patients were classified into the NAFL group, 19 into the NASH group, and 5 into the control (non-NAFLD) group. Biochemical characterization of patient plasma was followed by expression analysis of genes regulating inflammation and lipid metabolism. The MCPIP1 protein level was reduced in the livers of NAFL and NASH patients in comparison to non-NAFLD control individuals. In addition, in all groups of patients, immunohistochemical staining showed that the expression of MCPIP1 was higher in the portal fields and bile ducts in comparison to the liver parenchyma and central vein. The liver MCPIP1 protein level negatively correlated with hepatic steatosis but not with patient body mass index or any other analyte. The MCPIP1 level in PBMCs did not differ between NAFLD patients and control patients. Similarly, in patients' PBMCs there were no differences in the expression of genes regulating β-oxidation (ACOX1, CPT1A, and ACC1) and inflammation (TNF, IL1B, IL6, IL8, IL10, and CCL2), or transcription factors controlling metabolism (FAS, LCN2, CEBPB, SREBP1, PPARA, and PPARG). We have demonstrated that MCPIP1 protein levels are reduced in NAFLD patients, but further research is needed to investigate the specific role of MCPIP1 in NAFL initiation and the transition to NASH.

Progressive changes in platelet counts and Fib-4 scores precede the diagnosis of advanced fibrosis in NASH patients.

Cirrhosis and its complications develop in a subgroup of patients with non-alcoholic fatty liver disease (NASH). Early detection of liver fibrosis represents an important goal of clinical care. To test the hypothesis that the development of cirrhosis in nonalcoholic fatty liver disease patients is preceded by the long-term trends of platelet counts and Fib-4 scores. We identified all patients in our healthcare system who had undergone fibrosis staging by liver biopsy or magnetic resonance elastography (MRE) for non-alcoholic fatty liver disease during the past decade (n = 310). Platelet counts, serum glutamic-pyruvic transaminase and serum glutamic oxalacetic transaminase values preceding the staging tests were extracted from the electronic medical record system, and Fib-4 scores were calculated. Potential predictors of advanced fibrosis were evaluated using multivariate regression analysis. Significant decreases in platelet counts and increases in Fib-4 scores were observed in all fibrosis stages, particularly in patients with cirrhosis. In the liver biopsy group, the presence of cirrhosis was best predicted by the combination of the Fib-4 score at the time closest to staging (P < 0.0001), the presence of diabetes (P = 0.0001), and the correlation coefficient of the preceding time-dependent drop in platelet count (P = 0.044). In the MRE group, Fib4 score (P = 0.0025) and platelet drop (P = 0.0373) were significant predictors. In comparison, the time-dependent rise of the Fib-4 score did not contribute in a statistically significant way. Time-dependent changes in platelet counts and Fib-4 scores contribute to the prediction of cirrhosis in NASH patients with biopsy- or MRE-staged fibrosis. Their incorporation into predictive algorithms may assist in the earlier identification of high-risk patients.

Electro-acupuncture reduced steatosis on MRI-PDFF in patients with non-alcoholic steatohepatitis: a randomized controlled pilot clinical trial

BackgroundNon-alcoholic steatohepatitis (NASH) had not yet been approved therapy. Electro-acupuncture (EA) has been reported to have potential efficacy. However, high-quality clinical evidence was still lacking.MethodsNASH patients were randomized and allocated to either sham acupuncture (SA) or EA group in a 1:1 ratio, with the patient blinded. Each patient received 36 sessions of SA or EA treatment over 12 weeks, followed by additional 4 weeks. The primary outcome was the changes in relative liver fat content measured by magnetic resonance imaging proton density fat fraction (MRI-PDFF).ResultsA total of 60 patients were enrolled. From baseline to week 12, the reduction of relative liver fat content measured by MRI-PDFF in the EA group (− 33.6%, quantile range: − 52.9%, − 22.7%) was significantly more significant than that in the SA group (− 15.8%, quantile range: − 36.1%, − 2.7%) (p = 0.022). Furthermore, the EA group had more patients who achieved MRI-PDFF to 30% reduction at week 12 (53.3% vs. 25.9%, p = 0.035). EA treatment also significantly reduced body weight (− 3.0 vs. + 0.1 kg, p = 0.034) and BMI (− 1.5 vs. − 0.2 kg/m2, p = 0.013) at week 16. Except for AST (− 27.4 vs. − 16.2 U/L, p = 0.015), other biochemical varieties, including ALT, fasting-glucose, cholesterol, and triglyceride, showed no statistically significant difference. Both groups measured no significant changes in liver stiffness by magnetic resonance elastography (MRE). There were no serious adverse events in either group.ConclusionsTwelve weeks of EA effectively and safely reduces relative liver fat content in NASH patients. Further multicenter randomized controlled studies are needed.Trial registration Chinese Clinical Trial Registry, ChiCTR2100046617. Registered 23 May 2021, http://www.chictr.org.cn/edit.aspx?pid=127023&htm=4

Mapping the hepatic immune landscape identifies monocytic macrophages as key drivers of steatohepatitis and cholangiopathy progression.

The progression of chronic liver diseases towards liver cirrhosis is accompanied by drastic tissue changes. This study combines elaborate transcriptomic and histological methods aiming at spatially resolving the hepatic immune microenvironment in NAFLD (including NASH, primary sclerosing cholangitis, primary biliary cholangitis, and severe alcoholic hepatitis). Human liver samples were subjected to RNA-sequencing (n=225) and imaging cytometry (n=99) across 3 independent patient cohorts. Liver samples from alcoholic hepatitis and primary biliary cholangitis patients were used for comparison. Myeloid populations were further characterized in corresponding mouse models. Imaging, clinical, and phenotypical data were combined for multidimensional analysis. NAFLD/NASH and primary sclerosing cholangitis disease stages were associated with loss of parenchymal areas, increased ductular cell accumulation, and infiltration of immune cells. NASH patients predominantly exhibited myeloid cell accumulation, whereas primary sclerosing cholangitis patients additionally had pronounced lymphoid cell responses. Correlating to disease stage, both etiologies displayed intense IBA1 + CD16 low CD163 low macrophage aggregation in nonparenchymal areas, with a distinct spatial proximity to ductular cells. Mouse models revealed that disease-associated IBA1 + hepatic macrophages originated from bone marrow-derived monocytes. Using an unbiased, machine learning-based algorithm, IBA1 in combination with hepatocyte and ductular cell immunostaining-predicted advanced cirrhosis in human NASH, primary sclerosing cholangitis, and alcoholic hepatitis. Loss of hepatocytes and increased ductular reaction are tightly associated with monocyte-derived macrophage accumulation and represent the most prominent common immunological feature revealing the progression of NAFLD, primary sclerosing cholangitis, primary biliary cholangitis, and alcoholic hepatitis, suggesting IBA1 + CD163 low macrophages are key pathogenic drivers of human liver disease progression across diverse etiologies.

Increased Hepatic ATG7 mRNA and ATG7 Protein Expression in Nonalcoholic Steatohepatitis Associated with Obesity.

The autophagy gene ATG7 has been shown to be essential for the induction of autophagy, a process that used to be suppressed in nonalcoholic fatty liver disease (NAFLD). However, the specific role of ATG7 in NAFLD remains unclear. The aim of this study was to analyze hepatic ATG7 mRNA and ATG7 protein expression regarding obesity-associated NAFLD. Patients included women classified into normal weight (NW, n = 6) and morbid obesity (MO, n = 72). The second group was subclassified into normal liver (NL, n = 11), simple steatosis (SS, n= 29), and nonalcoholic steatohepatitis (NASH, n = 32). mRNA expression was analyzed by RT-qPCR and protein expression was evaluated by Western blotting. Our results showed that NASH patients presented higher ATG7 mRNA and ATG7 protein levels. ATG7 mRNA expression was increased in NASH compared with SS, while ATG7 protein abundance was enhanced in NASH compared with NL. ATG7 mRNA correlated negatively with the expression of some hepatic lipid metabolism-related genes and positively with endocannabinoid receptors, adiponectin hepatic expression, and omentin levels. These results suggest that ATG7-mediated autophagy may play an important role in the pathogenesis of NAFLD, especially in NASH, perhaps playing a possible protective role. However, this is a preliminary study that needs to be further studied.

Real World Experience of Obeticholic Acid in NASH Patients

Real World Experience of Obeticholic Acid in NASH Patients

Biomarkers in Determining the Risk of Liver Fibrosis in Patients with Non-Alcoholic Fatty Liver Disease and Hypertension

IntroductionNon-alcoholic steatohepatitis (NASH) affects up to 50% of patients with arterial hypertension (HT). Laboratory biomarkers are believed to help in liver fibrosis (LF) risk determination in patients with NASH and HT. PurposeTo assess the kallistatin, IL-10, IL-1β and high-sensitivity CRP (hsCRP) significance in LF risk evaluation in patients with NASH and HT. Methods. 63 patients with NASH and HT and 52 patients with isolated NASH were examined. Plasma kallistatin, IL-10, IL-1β and hsCRP levels were evaluate using ELISA. The results were statistically processed with the ROC analysis, the area under ROC curve (AUC), sensitivity (SE) and specificity (SP) were determined. ResultsKallistatin showed excellent diagnostic characteristics for LF development and progression risk determination in patients with NASH and HT (AUC=0.975, p=0.003, SE=95%, SP=100%; AUC=0.881, p<0.001; SE=95%, SP=76.9%) and isolated NASH (AUC=0.867, p<0.001); SE=76.5%, SP=81.0%; AUC=0.889, p<0.001, SE=92.3%, SP=81.3%). Interleukins showed good diagnostic characteristics for LF development risk in both groups (IL-10: AUC=0.769, p=0.012, SE=70%, SP=64.1%; AUC=0.710, p=0.009, SE=94.4%, SP=69.2%, IL 1β: AUC=0.752, p=0.02, SE=71.8%, SP=75.0%, AUC=0.788, p=0.007, SE= 84.6%, SP=66.7%), hsCRP showed diagnostical potential only in NASH and HT patients (AUC=0.849, p<0.001, SE=71.8%; SP=75.0%). Simultaneous evaluation of all biomarkers showed excellent and very good diagnostic characteristics for LF development and progression risk determination in NASH and HT patients (AUC=1.000, SE=100%, SP=100%, p=0.002; AUC=0.874, SE=82.1%, SP=85.0%, p<0.001) and isolated NASH group (AUC=0.874, SE=94.1%, SP=71.4%, p<0.001; AUC=0.889, SE=84.6%, SP=94.4%, p<0.001). ConclusionsThis allows us to offer kallistatin, IL-10, IL-1β, and hsCRP combination for LF identification in patients with NASH and HT.

Nonalcoholic Steatohepatitis: A 9-Year Follow Up Cohort Study.

Background and aim: Non-alcoholic fatty liver disease (NAFLD) may progress to severe liver fibrosis and cirrhosis. A limited number of studies with a long follow up assessed fibrosis progression and related predictors in untreated patients with a histological diagnosis of NAFLD. This study aims to investigate rate and predictors of NAFLD progression. Methods: For 9 (2–16.7) years, we followed up a cohort of patients histologically diagnosed. Disease progression was defined by a composite endpoint as evidence of cirrhosis in patients without cirrhosis at baseline, evidence of de novo occurrence of cirrhosis complications, histologically established worsening of stage 1 of fibrosis or increase of 20% in liver stiffness by transient elastography in patients rejecting a second liver biopsy. Results: A total of 91 patients were enrolled. Of them, 31 had NAFL and 60 NASH. A second liver biopsy was performed in 22 NASH patients and in 4 NAFL. Disease progression was observed in 38.5% NASH and in 12.0% NAFL (p = 0.034). Patients with portal inflammation had a higher risk of progression (66.7% vs 26%, p = 0.021). High triglycerides levels, advanced fibrosis at baseline and the duration of follow-up predict disease progression (p = 0.021; OR = 6.93, 95% CI 1.33–36.08, p = 0.43; OR 8.37; 95% CI 1.07–65.58 and p = 0.034; OR = 0.88; 95% CI 0.78–0.99, respectively). Conclusions: Our results reinforce the evidence that, in the absence of pharmacologic treatment, NASH progresses in about 40% of patients. Liver biopsy is the only mean to discriminate NAFL from NASH. The prognostic role of portal inflammation needs to be explored in larger series.

Vitamin D Status and Steatohepatitis in Obese Diabetic and Non-Diabetic Patients.

Background and Aims: The presence of steatohepatitis in obese patients can be multifactorial. The current study tries to determine the differences between diabetic and non-diabetic patients regarding the presence of steatohepatitis. We evaluated sequential liver samples and collected the times of bariatric surgery to assess the presence of NASH in patients with obesity, in the circuit of bariatric surgery. Methods: We performed a retrospective study of 49 patients presenting high-grade obesity in the circuit of bariatric surgery, with liver biopsy. The patients underwent bariatric surgery at a single center in France and were followed for 2 years. The liver biopsies were performed intraoperatively on all 49 patients before the bariatric surgery. The primary endpoint of the study was to evaluate the relationships between steatohepatitis/liver fibrosis and the presence of diabetes and to evaluate the current relationships between the biochemical work-ups. Special importance was accorded to the correlations between vitamin D levels and the presence of hepatic steatosis, due to the antifibrogenic pattern in the liver, as shown in many important papers in the field. Results: Significant correlations were found between the presence of liver fibrosis and the presence of diabetes (p = 0.022), but not regarding the antidiabetic treatment. An important correlation was found between the vitamin D levels and the presence of liver fibrosis, as well as with the levels of A1C hemoglobin and LDL cholesterol levels. Conclusions: Vitamin D deficiency presents a strong correlation with hepatic steatosis in individuals with morbid obesity. Correcting vitamin D deficiency may present a beneficial role in treating hepatic steatosis, diabetes, and cardiovascular risk in patients with morbid obesity.

The potential of mecciRNA in hepatic stellate cell to regulate progression of nonalcoholic hepatitis

BackgroundNonalcoholic steatohepatitis (NASH) occupies a substantial proportion of chronic liver disease worldwide, of which pathogenesis needs further research. Recent studies have demonstrated the significant roles of circular RNAs (circRNAs) in NASH, while the function of a novel type of circRNAs, namely mitochondria-encoded circRNAs (mecciRNAs), remains elusive. Therefore, we aimed to investigate their potential to regulate the progression of NASH in this study.MethodsGSE134146 was used to screen for differentially expressed mecciRNAs in NASH, while GSE46300 was used to identify NASH-related genes. To establish the mecciRNA-miRNA-mRNA networks, circMINE and miRNet databases were used for predicting downstream targets. Then, consensus clustering analysis was used to determine immune subtypes of NASH. Finally, we successfully validated our findings in vitro (LPS-treated hepatic stellate cells [HSCs]) and in vivo (MCD-diet mice) NASH models.ResultsWe confirmed that circRNomics balance is disrupted in HSCs of NASH, while two mecciRNAs (hsa_circ_0089761 and hsa_circ_0089763) could function as competing for endogenous RNAs (ceRNAs) to regulate fibrosis-related signals. Furthermore, we constructed two ceRNA networks based on mecciRNAs for the first time. Cell and animal NASH models validated our findings that c-MYC and SMAD2/3 were upregulated in HSCs, while THBS1 and p-STAT3 were upregulated in hepatocytes. Moreover, we identified 21 core genes by overlapping the differentially expressed genes (NASH vs. Normal) with mecciRNA-targeted genes. According to their expression profiles, NASH patients could be divided in 2 different clusters, in which proinflammatory signals (TNF and IL-17 pathways) are significantly activated in Cluster 1.ConclusionWe successfully established two novel mecciRNA-miRNA-mRNA networks in HSCs and hepatocytes, which were further confirmed by in vitro and in vivo models. Meanwhile, the novel immunotyping model revealed the heterogeneity of NASH, thereby might guiding treatment options. Altogether, our study brought a distinct perspective on the relationship between mecciRNAs and NASH.

Intrahepatic paracrine signaling by cardiotrophin-like cytokine factor 1 ameliorates diet-induced NASH in mice.

The mammalian liver harbors heterogeneous cell types that communicate via local paracrine signaling. Recent studies have delineated the transcriptomic landscape of the liver in NASH that provides insights into liver cell heterogeneity, intercellular crosstalk, and disease-associated reprogramming. However, the nature of intrahepatic signaling and its role in NASH progression remain obscure. Here, we performed transcriptomic analyses and identified cardiotrophin-like cytokine factor 1 (CLCF1), a member of the IL-6 family cytokines, as a cholangiocyte-derived paracrine factor that was elevated in the liver from diet-induced NASH mice and patients with NASH. Adenovirus-associated virus-mediated overexpression of CLCF1 in the liver ameliorated NASH pathologies in two diet-induced NASH models in mice, illustrating that CLCF1 induction may serve an adaptive and protective role during NASH pathogenesis. Unexpectedly, messenger RNA and protein levels of leukemia inhibitory factor receptor (LIFR), a subunit of the receptor complex for CLCF1, were markedly downregulated in NASH liver. Hepatocyte-specific inactivation of LIFR accelerated NASH progression in mice, supporting an important role of intrahepatic cytokine signaling in maintaining tissue homeostasis under metabolic stress conditions. Together, this study sheds light on the molecular nature of intrahepatic paracrine signaling during NASH pathogenesis and uncovers potential targets for therapeutic intervention.