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Transcriptomics analysis of in vitro NASH models unveils potential adverse effect of elafibranor

ABSTRACT: Non-alcoholic steatohepatitis (NASH) is a life-threatening liver disease for which no drug has been approved. We have previously shown that human-derived hepatic in vitro models can be used to mimic key cellular mechanisms involved in the progression of NASH. In the present study, we first assess the predictive capacity of different in vitro models and then investigate how the reduction of NASH-specific parameters upon treatment with elafibranor, a PPAR-α/δ agonist, correlates with clinical NASH-resolution obtained through bariatric surgery. Whole genome transcriptomics analyses revealed that in vitro NASH models based on primary human hepatocytes (PHH), HepaRG and human skin stem cell-derived hepatic progenitors (hSKP-HPC) exhibit up to 35% overlap with publicly available datasets of liver biopsies of 4 cohorts of NASH patients. Exposure of the in vitro NASH models to elafibranor partially reverses these human-specific transcriptional NASH signatures, with the hSKP-HPC-derived NASH model showing the most sensitive response. NASH-specific transcriptomic changes observed in patients that underwent bariatric surgery correlated with the changes observed in the in vitro NASH models exposed to the PPAR-α/δ agonist. PPARGC1A, PPARA and SIRT1 are shared upstream regulators in the PHH-, HepaRG- and hSKP-HPC NASH models exposed to elafibranor. Activation of these upstream regulators increases the expression of ANGPTL4, PDK4 and PLIN2, while this does not occur in patients that underwent bariatric surgery, suggesting an adverse effect on lipid metabolism. In conclusion, pathologic and therapeutic (anti-)NASH-specific transcriptional responses can be mimicked in PHH, HepaRG and hSKP-HPC, while the latter most sensitively responds to drug testing. PPAR-α/δ agonism adversely modulates pro-steatogenic genes which deserves attention in further studies.

ORGANISM(S): Homo sapiens

PROVIDER: GSE166186 | GEO | 2022/03/16

REPOSITORIES: GEO

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Project description:Background & Aims: Bariatric surgery is associated with improved outcomes in subjects with severe obesity. We aimed to determine the prognostic relevance of liver histology in a large cohort of obese patients undergoing bariatric surgery. Methods: In a single center cohort of 492 subjects undergoing Roux-en-Y gastric bypass bariatric surgery with routine perioperative liver biopsy at Geneva University Hospital between January 1997 to December 2004, clinical and histopathological variables were analyzed for association with overall survival. Survival of the cohort was compared to age- and sex-matched life tables from the Swiss general population and propensity score-matched subjects from the third National Health and Nutrition Examination Survey (NHANES III). A 32-gene signature was evaluated in the liver tissue of 47 non-alcoholic steatohepatitis (NASH) subjects. Results: Median body mass index was 43.6 kg/m2. Twenty-one patients (4.2%) died during a median follow-up of 10.3 years. At baseline liver histology, 12% and 16% of subjects had NASH, and fibrosis, respectively. In multivariable Cox regression, presence of NASH (hazard ratio [HR] 3.4, p=0.0087), age greater than 50 years (HR 2.7, p=0.044), hypertension (HR 3.8, p=0.021), and short-term postoperative complications (HR 2.8, p=0.048) were associated with overall survival. Compared to matched NHANES III subjects, bariatric surgery improved long-term survival (HR 0.54, p=0.035), although this benefit was not observed in the subgroup of NASH patients (HR 0.97, p=0.94). A 32-gene poor prognosis signature prediction was associated with worse overall survival within NASH subjects (n=47, HR = 7.7, p=0.03 ). Conclusions Histologically proven NASH was associated with increased long-term mortality in subjects undergoing bariatric surgery. Although survival benefit of bariatric surgery may be limited in obese patients with NASH, a 32-gene expression signature appears to predict long term mortality in these patients.

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.

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Transcriptomics analysis of in vitro NASH models unveils potential adverse effect of elafibranor

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