Browsing by Subject "STEATOHEPATITIS"
Now showing items 1-12 of 12
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(2021)Anti-inflammatory therapies have the potential to become an effective treatment for obesity-related diseases. However, the huge gap of immune system between human and rodent leads to limitations of drug discovery. This work aims at constructing a transgenic pig model with higher risk of metabolic diseases and outlining the immune responses at the early stage of metaflammation by transcriptomic strategy. We used CRISPR/Cas9 techniques to targeted knock-in three humanized disease risk genes, GIPR(dn) , hIAPP and PNPLA3(I148M) . Transgenic effect increased the risk of metabolic disorders. Triple-transgenic pigs with short-term diet intervention showed early symptoms of type 2 diabetes, including glucose intolerance, pancreatic lipid infiltration, islet hypertrophy, hepatic lobular inflammation and adipose tissue inflammation. Molecular pathways related to CD8(+) T cell function were significantly activated in the liver and visceral adipose samples from triple-transgenic pigs, including antigen processing and presentation, T-cell receptor signaling, co-stimulation, cytotoxicity, and cytokine and chemokine secretion. The similar pro-inflammatory signaling in liver and visceral adipose tissue indicated that there might be a potential immune crosstalk between the two tissues. Moreover, genes that functionally related to liver antioxidant activity, mitochondrial function and extracellular matrix showed distinct expression between the two groups, indicating metabolic stress in transgenic pigs' liver samples. We confirmed that triple-transgenic pigs had high coincidence with human metabolic diseases, especially in the scope of inflammatory signaling at early stage metaflammation. Taken together, this study provides a valuable large animal model for the clinical study of metaflammation and metabolic diseases.
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(2022)Background & aims: Recent experimental models and epidemiological studies suggest that specific environmental contaminants (ECs) contribute to the initiation and pathology of nonalcoholic fatty liver disease (NAFLD). However, the underlying mechanisms linking EC exposure with NAFLD remain poorly understood and there is no data on their impact on the human liver metabolome. Herein, we hypothesized that exposure to ECs, particularly perfluorinated alkyl substances (PFAS), impacts liver metabolism, specifically bile acid metabolism. Methods: In a well-characterized human NAFLD cohort of 105 individuals, we investigated the effects of EC exposure on liver metabolism. We characterized the liver (via biopsy) and circulating metabolomes using 4 mass spectrometry-based analytical platforms, and measured PFAS and other ECs in serum. We subsequently compared these results with an exposure study in a PPARa-humanized mouse model. Results: PFAS exposure appears associated with perturbation of key hepatic metabolic pathways previously found altered in NAFLD, particularly those related to bile acid and lipid metabolism. We identified stronger associations between the liver metabolome, chemical exposure and NAFLD-associated clinical variables (liver fat content, HOMA-IR), in females than males. Specifically, we observed PFAS-associated upregulation of bile acids, triacylglycerols and ceramides, and association between chemical exposure and dysregulated glucose metabolism in females. The murine exposure study further corroborated our findings, vis-a-vis a sex-specific association between PFAS exposure and NAFLD-associated lipid changes. Conclusions: Females may be more sensitive to the harmful impacts of PFAS. Lipid-related changes subsequent to PFAS exposure may be secondary to the interplay between PFAS and bile acid metabolism. Lay summary: There is increasing evidence that specific environmental contaminants, such as perfluorinated alkyl substances (PFAS), contribute to the progression of non-alcoholic fatty liver disease (NAFLD). However, it is poorly understood how these chemicals impact human liver metabolism. Here we show that human exposure to PFAS impacts metabolic processes associated with NAFLD, and that the effect is different in females and males. (C) 2021 The Author(s). Published by Elsevier B.V. on behalf of European Association for the Study of the Liver.
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(2020)Carriers of the hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) gene variant (rs72613567:TA) have a reduced risk of NASH and cirrhosis but not steatosis. We determined its effect on liver histology, lipidome, and transcriptome using ultra performance liquid chromatography-mass spectrometry and RNA-seq. In carriers and noncarriers of the gene variant, we also measured pathways of hepatic fatty acids (de novo lipogenesis [ONLI and adipose tissue lipolysis [ATL] using (H2O)-H-2 and H-2-glycerol) and insulin sensitivity using H-3-glucose and euglycemic-hyperinsulinemic clamp) and plasma cytokines. Carriers and noncarriers had similar age, sex and BMI. Fibrosis was significantly less frequent while phospholipids, but not other lipids, were enriched in the liver in carriers compared with noncarriers. Expression of 274 genes was altered in carriers compared with noncarriers, consisting predominantly of downregulated inflammation-related gene sets. Plasma IL-6 concentrations were lower, but DNL, ATL and hepatic insulin sensitivity were similar between the groups. In conclusion, carriers of the HSD17B13 variant have decreased fibrosis and expression of inflammation-related genes but increased phospholipids in the liver. These changes are not secondary to steatosis, ONL, ATL, or hepatic insulin sensitivity. The increase in phospholipids and decrease in fibrosis are opposite to features of choline-deficient models of liver disease and suggest HSD17B13 as an attractive therapeutic target.
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(2022)Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths worldwide, and therapeutic options for advanced HCC are limited. Here, we observe that intestinal dysbiosis affects antitumor immune surveillance and drives liver disease progression towards cancer. Dysbiotic microbiota, as seen in Nlrp6(-/-) mice, induces a Toll-like receptor 4 dependent expansion of hepatic monocytic myeloid-derived suppressor cells (mMDSC) and suppression of T-cell abundance. This phenotype is transmissible via fecal microbiota transfer and reversible upon antibiotic treatment, pointing to the high plasticity of the tumor microenvironment. While loss of Akkermansia muciniphila correlates with mMDSC abundance, its reintroduction restores intestinal barrier function and strongly reduces liver inflammation and fibrosis. Cirrhosis patients display increased bacterial abundance in hepatic tissue, which induces pronounced transcriptional changes, including activation of fibro-inflammatory pathways as well as circuits mediating cancer immunosuppression. This study demonstrates that gut microbiota closely shapes the hepatic inflammatory microenvironment opening approaches for cancer prevention and therapy. Steatohepatitis is a chronic hepatic inflammation associated with increased risk of hepatocellular carcinoma progression. Here the authors show that intestinal dysbiosis in mice lacking the inflammasome sensor molecule NLRP6 aggravates steatohepatitis and accelerates liver cancer progression, a process that can be delayed by antibiotic treatment.
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(2018)Background & Aims Nonalcoholic fatty liver disease(NAFLD) is the second most common cause of liver transplantation in the US. Data on NAFLD as a liver transplantation indication from countries with lower prevalences of obesity are lacking. We studied the temporal trends of NAFLD as an indication for liver transplantation in the Nordic countries, and compared outcomes for patients with NAFLD to patients with other indications for liver transplantation. MethodResultsPopulation-based cohort study using data from the Nordic Liver Transplant Registry on adults listed for liver transplantation between 1994 and 2015. NAFLD as the underlying indication for liver transplantation was defined as a listing diagnosis of NAFLD/nonalcoholic steatohepatitis, or cryptogenic cirrhosis with a body mass index 25kg/m(2) and absence of other liver diseases. Waiting time for liver transplantation, mortality and withdrawal from the transplant waiting list were registered. Survival after liver transplantation was calculated using multivariable Cox regression, adjusted for age, sex, body mass index and model for end-stage liver disease. A total of 4609 patients listed for liver transplantation were included. NAFLD as the underlying indication for liver transplantation increased from 2.0% in 1994-1995 to 6.2% in 2011-2015 (P=.01) and was the second most rapidly increasing indication. NAFLD patients had higher age, model for end-stage liver disease and body mass index when listed for liver transplantation, but overall survival after liver transplantation was comparable to non--NAFLD patients (aHR 1.03, 95% CI 0.70-1.53 P=.87). ConclusionNAFLD is an increasing indication for liver transplantation in the Nordic countries. Despite more advanced liver disease, NAFLD patients have a comparable survival to other patients listed for liver transplantation.
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(2020)Understanding the importance of the gut microbiota (GM) in non-alcoholic fatty liver disease (NAFLD) has raised the hope for therapeutic microbes. We have shown that high hepatic fat content associated with low abundance of Faecalibacterium prausnitzii in humans and, further, the administration of F. prausnitzii prevented NAFLD in mice. Here, we aimed at targeting F. prausnitzii by prebiotic xylo-oligosaccharides (XOS) to treat NAFLD. First, the effect of XOS on F. prausnitzii growth was assessed in vitro. Then, XOS was supplemented or not with high (HFD, 60% of energy from fat) or low (LFD) fat diet for 12 weeks in Wistar rats (n = 10/group). XOS increased F. prausnitzii growth, having only a minor impact on the GM composition. When supplemented with HFD, XOS ameliorated hepatic steatosis. The underlying mechanisms involved enhanced hepatic beta-oxidation and mitochondrial respiration. Nuclear magnetic resonance (H-1-NMR) analysis of cecal metabolites showed that, compared to the HFD, the LFD group had a healthier cecal short-chain fatty acid profile and on the HFD, XOS reduced cecal isovalerate and tyrosine, metabolites previously linked to NAFLD. Cecal branched-chain fatty acids associated positively and butyrate negatively with hepatic triglycerides. In conclusion, XOS supplementation can ameliorate NAFLD by improving hepatic oxidative metabolism and affecting GM.
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(2022)Background and Aims The presence of advanced hepatic fibrosis is the prime marker for the prediction of liver-related complications in non-alcoholic fatty liver disease (NAFLD). Blood-based non-invasive tests (NITs) have been developed to evaluate fibrosis and identify patients at risk. Current guidelines propose monitoring the progression of NAFLD using repeated NITs at 2-3-year intervals. The aim of this study was to evaluate the association of changes in NITs measured at two time points with the progression of NAFLD. Methods We retrospectively included NAFLD patients with NIT measurements in whom the baseline hepatic fibrosis stage had been assessed by biopsy or transient elastography (TE). Subjects underwent follow-up visits at least 1 year from baseline to evaluate the progression of NAFLD. NAFLD progression was defined as the development of end-stage liver disease or fibrosis progression according to repeat biopsy or TE. The following NITs were calculated at baseline and follow-up: Fibrosis-4 (FIB-4), NAFLD fibrosis score (NFS), aspartate aminotransferase to platelet ratio index (APRI) and dynamic aspartate-to-alanine aminotransferase ratio (dAAR). Results One hundred and thirty-five patients were included with a mean follow-up of 12.6 +/- 8.5 years. During follow-up, 41 patients (30%) were diagnosed with progressive NAFLD. Change in NIT scores during follow-up was significantly associated with disease progression for all NITs tested except for NFS. However, the diagnostic precision was suboptimal with area under the receiver operating characteristics 0.56-0.64 and positive predictive values of 0.28-0.36 at sensitivity fixed at 90%. Conclusions Change of FIB-4, NFS, APRI, and dAAR scores is only weakly associated with disease progression in NAFLD. Our findings do not support repeated measurements of these NITs for monitoring the course of NAFLD.
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(2020)Background and Aims The effects of alcohol use in nonalcoholic fatty liver disease are unclear. We investigated the impact of alcohol use in fatty liver disease on incident liver, cardiovascular, and malignant disease, as well as death. Approach and Results Our study comprised 8,345 persons with hepatic steatosis (fatty liver index >60) who participated in health-examination surveys (FINRISK 1992-2012 or Health 2000), with available data on baseline alcohol intake. Main exclusions were baseline clinical liver disease, viral hepatitis, ethanol intake >50 g/day, and current abstainers. Data were linked with national registers for hospital admissions, malignancies, and death regarding liver, cardiovascular, and malignant disease, as well as all-cause death. Adjustment were for multiple confounders. Alcohol consumption showed a dose-dependent risk increase for incident advanced liver disease and malignancies. Consuming 10-19 g/day of alcohol in general or 0-9 g/day as nonwine beverages doubled the risk for advanced liver disease compared to lifetime abstainers. In contrast, alcohol intake up to 49 g/day was associated with a 22%-40% reduction of incident cardiovascular disease (CVD). We observed a J-shaped association between alcohol intake and all-cause death with a maximal risk reduction of 21% (95% confidence interval, 5%-34%) at alcohol intake of 0-9 g/day compared to lifetime abstainers. However, these benefits on CVD and mortality were only observed in never smokers. Alcohol intake >30 g/day yielded increased risk estimates for mortality compared to lifetime abstainers. In a subpopulation with longitudinal data, alcohol intake remained stable over time in >80% of subjects. Conclusions Even low alcohol intake in fatty liver disease is associated with increased risks for advanced liver disease and cancer. Low to moderate alcohol use is associated with reduced mortality and CVD risk but only among never smokers.
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(2017)Gallstone disease (GD) has been associated with low serum levels of plant sterols. We evaluated the impact of laparoscopic Roux-en-Y gastric bypass (LRYGB) and non-alcoholic fatty liver disease (NAFLD) on the association of GD with low levels of serum plant sterols. Two hundred forty-two consecutive morbidly obese patients were recruited to this prospective study. Histological analysis of liver biopsy to diagnose NAFLD was performed. Bile sample was taken during the LRYGB. Associations of GD with serum non-cholesterol sterol to cholesterol ratios, measured using gas liquid chromatography and with mRNA expression of genes participating in the cholesterol, bile, and fatty acid metabolism in the liver, were analyzed. Out of the 242 participants, 95 had GD. Lower weight (p = 0.002) and female sex (p = 0.0006) were associated with GD. Serum plant sterols, campesterol (p = 0.003), sitosterol (p = 0.002), and avenasterol (p = 0.015), were lower in patients with GD compared to those without GD. This association remained significant after adjustment for NAFLD, use of statin medication, and previous laparoscopic cholecystectomy (LCC). Levels of sitosterol (p = 0.001) and campesterol (p = 0.001) remained lower in obese individuals with GD also after obesity surgery. Liver mRNA expression of genes regulating cholesterol synthesis and bile metabolism was increased in individuals with GD. Serum plant sterols were lower in patients with GD independent of NAFLD, history of LCC, use of statin medication, and weight loss after LRYGB. Low serum plant sterols in patients with GD suggest potentially inherited alterations in sterol absorption and biliary transport in subjects susceptible for GD.
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(2020)Non-Alcoholic Fatty Liver Disease (NAFLD), a progressive liver disease that is closely associated with obesity, type 2 diabetes, hypertension and dyslipidaemia, represents an increasing global public health challenge. There is significant variability in the disease course: the majority exhibit only fat accumulation in the liver but a significant minority develop a necroinflammatory form of the disease (non-alcoholic steatohepatitis, NASH) that may progress to cirrhosis and hepatocellular carcinoma. At present our understanding of pathogenesis, disease natural history and long-term outcomes remain incomplete. There is a need for large, well characterised patient cohorts that may be used to address these knowledge gaps and to support the development of better biomarkers and novel therapies. The European NAFLD Registry is an international, prospectively recruited observational cohort study that aims to establish a large, highly-phenotyped patient cohort and linked bioresource. Here we describe the infrastructure, data management and monitoring plans, and the standard operating procedures implemented to ensure the timely and systematic collection of high-quality data and samples. Already recruiting subjects at secondary/tertiary care centres across Europe, the Registry is supporting the European Union IMI2-funded LITMUS 'Liver Investigation: Testing Marker Utility in Steatohepatitis' consortium, which is a major international effort to robustly validate biomarkers that diagnose, risk stratify and/or monitor NAFLD progression and liver fibrosis stage. The European NAFLD Registry has the demonstrable capacity to support research and biomarker development at scale and pace.
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(2022)Background & aims Non-alcoholic fatty liver disease (NAFLD) and alcohol-related liver disease frequently coexist. While several blood-based indices exist for the detection of NAFLD, few studies have examined how alcohol use possibly impacts their diagnostic performance. We analysed the effects of alcohol use on the performance of indices for detecting fatty liver disease (FLD). Methods We included participants from the Cardiovascular Risk in Young Finns Study (Finnish sample) and KORA study (German sample) who underwent abdominal ultrasound or magnetic resonance imaging, respectively, for detection of FLD and had serum analyses available for calculation of Fatty Liver Index (FLI), Hepatic Steatosis Index (HSI), Lipid Accumulation Product (LAP), and Dallas Steatosis Index (DSI). Alcohol use was estimated by questionnaires as mean daily consumption and binge drinking (Finnish sample only). Predictive performance for FLD was assessed according to alcohol consumption. Results The study included 1426 (Finnish sample) and 385 (German sample) individuals, of which 234 (16%) and 168 (44%) had FLD by imaging. When alcohol consumption was 50 g/day). AUROCs decreased to 0.74-0.80 in the highest binge-drinking category (>2 times/week). Alcohol use correlated with FLI and LAP (r-range 0.09-0.16, p-range
