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Genome-wide analysis of hepatic gene expression in patients with non-alcoholic steatohepatitis (NASH) before and after 1 year supplementation with n-3 polyunsaturated fatty acids (PUFA) from fishoil

ABSTRACT: Fishoil or n-3 PUFA supplementation has shown some beneficial effects in patients with NASH. It is known that n-3 PUFA can influence hepatic gene expression. However, the effect of n-3 PUFA supplementation on hepatic gene expression has not been examined in patients with NASH. Aim of this pilot study was to examine the effect of n-3 PUFA supplementation on liver n-3 PUFA levels, hepatic gene expression and liver histology in patients with NASH. In a single-arm pilot intervention study, the effect of a one year n-3 PUFA supplementation on hepatic gene expression (Illumina Microarray), liver histology, and liver and erythrocyte PUFA was examined in 11 adult patients with NASH. For the intervention trial, NASH patients received n-3 PUFA supplementation from fish oil (2 g fish oil per day, containing 740-840 mg eicosapentaenoic acid (EPA) and 400-440 mg docosahexaenoic acid (DHA) quantified as ethyl ester) for one year. The supplement was produced by Ocean Nutrition Canada Ltd. (Dartmouth, NS, Canada) (product code 4020PB1000CT, Lots # 21211, 24168, and 31639). The selected supplement was within the range used in previous studies, where doses of n-3 PUFA and the EPA/DHA balance varied widely. Effects of n-3 PUFA on liver steatosis were observed in other studies by ultrasound within 6 to 12 months. To increase safety and acceptance of the second liver biopsy, an intervention period of 12 months was selected. During the intervention, patients were asked to maintain their habitual diet and physical activity. Fishoil supplementation lead to increased n-3 PUFA in erythrocyte total lipids and hepatic lipids. However, there was no significant change in liver histology or hepatic gene expression between baseline and post-intervention.

ORGANISM(S): Homo sapiens

PROVIDER: GSE96971 | GEO | 2019/09/30

REPOSITORIES: GEO

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Project description:The mechanisms underlying the progression of non-alcoholic steatohepatitis (NASH) are not completely elucidated. In this study we have integrated gene expression profiling of liver biopsies of NASH patients with translational studies in a mouse model of steatohepatitis and with pharmacological interventions in isolated hepatocytes to identify a novel mechanism implicated in the pathogenesis of NASH. By using high-density oligonucleotide microarray analysis we identified a significant enrichment of known genes involved in the multi-step catalysis of long chain polyunsaturated fatty acids, including delta-5 and 6 desaturases. A combined inhibitor of delta-5 and delta-6 desaturases significantly reduced intracellular lipid accumulation and inflammatory gene expression in isolated hepatocytes. Gas chromatography analysis revealed impaired delta-5 desaturase activity toward the omega-3 pathway in livers from mice with high-fat diet (HFD)-induced NASH. Consistently, restoration of omega-3 index in transgenic fat-1 mice expressing an omega-3 desaturase, which allows the endogenous conversion of omega-6 into omega-3 fatty acids, produced a significant reduction in hepatic insulin resistance, hepatic steatosis, macrophage infiltration and necroinflammatory liver injury, accompanied by attenuated expression of genes involved in inflammation, fatty acid uptake and lipogenesis. These results were comparable to those obtained in a group of mice receiving a HFD supplemented with EPA/DHA. Of interest, hepatocytes from fat-1 mice or supplemented with EPA exhibited synergistic anti-steatotic and anti-inflammatory actions with the delta-5/ delta-6 inhibitor. Conclusion: These findings indicate that both endogenous and exogenous restoration of the hepatic balance between omega-6 and omega-3 fatty acids and/or modulation of desaturase activities exert preventive actions in NASH. The complete database comprised the expression measurements of 18185 genes for liver sample groups: 8 non-alcoholic steatohepatitis (NASH ) and 7 control samples. This dataset is part of the TransQST collection.

Project description:Non-alcoholic fatty liver disease (NAFLD) encompasses a spectrum of histological findings, from simple steatosis to steatohepatitis (NASH), the latter presenting a higher risk of cardiovascular and kidney diseases, type 2 diabetes and end-stage liver disease. NAFLD is seen as the hepatic manifestation of the metabolic syndrome and affects up to 70-80% of obese patients. There are currently no approved pharmacological therapies for NASH, thus the only option is lifestyle intervention or bariatric surgery in order to lose weight and to improve insulin resistance. Although surgical intervention has allowed collections of liver biopsies, transcriptomic data from livers are still scarce and especially follow-up data to evaluate the impact of weight loss intervention on the liver. Therefore we studied hepatic transcriptomic data in a large cohort of obese patients assessed for presence of NASH at baseline and 1 year follow-up. Patients visiting the obesity clinic of the Antwerp University Hospital for a problem of being overweight (BMI above 25 to 29.9 kg/m²) or obese (BMI above 30 kg/m²) were prospectively recruited and underwent a hepatic work-up. Patients were excluded from further analysis in case of significant alcohol consumption (>20 g/day), history of bariatric surgery, diagnosis of another liver disease, pre-existing diabetes. Patients who were, however, diagnosed with de novo diabetes at baseline or at follow-up were not excluded. If NAFLD was suspected, liver biopsy was proposed. For patients undergoing bariatric surgery (BS), a liver biopsy was proposed regardless of the criteria. Patients were reassessed after 1 year. Liver biopsy was performed percutaneously (16G Menghini) or peri-operatively (14G Tru-Cut). The different histological features of NAFLD were assessed using the NASH Clinical Research Network (NASH CRN) Scoring System. The presence of NASH was defined according to Chalasani et al. necessitating the combined presence of steatosis, ballooning and lobular inflammation.

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Genome-wide analysis of hepatic gene expression in patients with non-alcoholic steatohepatitis (NASH) before and after 1 year supplementation with n-3 polyunsaturated fatty acids (PUFA) from fishoil

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