Bariatric surgery and the liver—Mechanisms, benefits, and risks

Lefere, Sander; Onghena, Louis; Vanlander, Aude; Nieuwenhove, Yves Van; Devisscher, Lindsey; Geerts, Anja

doi:10.1111/obr.13294

Cited by 32 publications

(32 citation statements)

References 137 publications

(272 reference statements)

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“…The mechanisms of BMS and improved liver health are not yet fully elucidated. Potential mechanisms include an increase in gut hormone signaling such as GLP-1, remission of hepatic and adipose tissue inflammation, lipid malabsorption, and augmentation of enterohepatic bile acid secretion and signaling [ 173 , 174 ]. BMS decreases food intake and adiposity [ 157 , 175 ], which are independent predictors of onset and progression of NAFLD/NASH to HCC [ 15 ].…”

Section: Treatment Strategies For Obesity and Their Association With ...mentioning

confidence: 99%

Obesity Management in the Primary Prevention of Hepatocellular Carcinoma

Zunica

Heintz

Axelrod

et al. 2022

Cancers

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Hepatocellular carcinoma (HCC) is the most frequent primary hepatic malignancy and a leading cause of cancer-related death globally. HCC is associated with an indolent clinical presentation, resulting in frequent advanced stage diagnoses where surgical resection or transplant therapies are not an option and medical therapies are largely ineffective at improving survival. As such, there is a critical need to identify and enhance primary prevention strategies to mitigate HCC-related morbidity and mortality. Obesity is an independent risk factor for the onset and progression of HCC. Furthermore, obesity is a leading cause of nonalcoholic steatohepatitis (NASH), the fasting growing etiological factor of HCC. Herein, we review evolving clinical and mechanistic associations between obesity and hepatocarcinogenesis with an emphasis on the therapeutic efficacy of prevailing lifestyle/behavioral, medical, and surgical treatment strategies for weight reduction and NASH reversal.

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Section: Treatment Strategies For Obesity and Their Association With ...mentioning

confidence: 99%

Obesity Management in the Primary Prevention of Hepatocellular Carcinoma

Zunica

Heintz

Axelrod

et al. 2022

Cancers

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“…By comparing the obtained results to transcriptomics datasets of liver samples from NAFLD patients after bariatric surgery, we aimed at gaining insights in the mechanisms that could possibly lay at the basis of the negative outcome of the interim analysis of the phase 3 ‘RESOLVE-IT’ trial. Bariatric surgery impacts several hepatic metabolic pathways even before weight loss occurs, leading to a reduction of liver triglyceride levels as a major cause for the reduction of NASH [ 10 , 11 ]. Therefore, it was considered as a valid reference.…”

Section: Introductionmentioning

confidence: 99%

Transcriptomics Reveals Discordant Lipid Metabolism Effects between In Vitro Models Exposed to Elafibranor and Liver Samples of NAFLD Patients after Bariatric Surgery

Boeckmans

Gatzios

Heymans

et al. 2022

Cells

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Background and aims: Non-alcoholic steatohepatitis (NASH) is a life-threatening stage of non-alcoholic fatty liver disease (NAFLD) for which no drugs have 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 characterize the transcriptome of multiple in vitro NASH models. Subsequently, we investigate how elafibranor, which is a peroxisome proliferator-activated receptor (PPAR)-α/δ agonist that has recently failed a phase 3 clinical trial as a potential anti-NASH compound, modulates the transcriptome of these models. Finally, we compare the elafibranor-induced gene expression modulation to transcriptome data of patients with improved/resolved NAFLD/NASH upon bariatric surgery, which is the only proven clinical NASH therapy. Methods: Human whole genome microarrays were used for the transcriptomics evaluation of hepatic in vitro models. Comparison to publicly available clinical datasets was conducted using multiple bioinformatic application tools. Results: Primary human hepatocytes (PHH), HepaRG, and human skin stem cell-derived hepatic progenitors (hSKP-HPC) exposed to NASH-inducing triggers exhibit up to 35% overlap with datasets of liver samples from NASH patients. Exposure of the in vitro NASH models to elafibranor partially reversed the transcriptional modulations, predicting an inhibition of toll-like receptor (TLR)-2/4/9-mediated inflammatory responses, NFκB-signaling, hepatic fibrosis, and leukocyte migration. These transcriptomic changes were also observed in the datasets of liver samples of patients with resolved NASH. Peroxisome Proliferator Activated Receptor Alpha (PPARA), PPARG Coactivator 1 Alpha (PPARGC1A), and Sirtuin 1 (SIRT1) were identified as the major common upstream regulators upon exposure to elafibranor. Analysis of the downstream mechanistic networks further revealed that angiopoietin Like 4 (ANGPTL4), pyruvate dehydrogenase kinase 4 (PDK4), and perilipin 2 (PLIN2), which are involved in the promotion of hepatic lipid accumulation, were also commonly upregulated by elafibranor in all in vitro NASH models. Contrarily, these genes were not upregulated in liver samples of patients with resolved NASH. Conclusion: Transcriptomics comparison between in vitro NASH models exposed to elafibranor and clinical datasets of NAFLD patients after bariatric surgery reveals commonly modulated anti-inflammatory responses, but discordant modulations of key factors in lipid metabolism. This discordant adverse effect of elafibranor deserves further investigation when assessing PPAR-α/δ agonism as a potential anti-NASH therapy.

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“…Adipose tissue, liver tissue and skeletal muscle are important metabolic tissues that play important roles in the progression of insulin resistance and obesity [ 6 ]. Previous studies reported that hypertrophy, inflammatory response and adipokine dysregulation of adipose tissue may affect the outcomes of BS [ 7 ] and suggested that BS could reduce hepatic fat contents and improve hepatic insulin resistance [ 8 ]. In addition, Peter H Albers et al demonstrated that the improved molecular insulin-sensitive phenotype of skeletal muscle and adipose tissue contributed to the improved whole body insulin action and substantial weight loss after BS [ 9 ].…”

Section: Introductionmentioning

confidence: 99%

Integrative analyses of hub genes and their association with immune infiltration in adipose tissue, liver tissue and skeletal muscle of obese patients after bariatric surgery

et al. 2022

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Bariatric surgery (BS) is an effective treatment for obesity. Adipose tissue, liver tissue and skeletal muscle are important metabolic tissues. This study investigated hub genes and their association with immune infiltration in these metabolic tissues of obese patients after BS by bioinformatic analysis with Gene Expression Omnibus datasets. Differentially expressed genes (DEGs) were identified, and a protein–protein interaction network was constructed to identify hub genes. As a result, 121 common DEGs were identified and mainly enriched in cytokine–cytokine receptor interactions, chemokine signaling pathway, neutrophil activation and immune responses. Immune cell infiltration analysis showed that the abundance of M1 macrophages was significantly lower in adipose and liver tissue after BS (p<0.05). Ten hub genes (TYROBP, TLR8, FGR, NCF2, HCK, CCL2, LAPTM5, MNDA and S100A9) that were all downregulated after BS were also associated with immune cells. Consistently, results in the validated dataset showed that the expression levels of these hub genes were increased in obese patients and mice, and decreased after BS. In conclusion, this study analysed the potential immune and inflammatory mechanisms of BS in three key metabolic tissues of obese patients, and revealed hub genes associated with immune cell infiltration, thus providing potential targets for obesity treatment.

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Bariatric surgery and the liver—Mechanisms, benefits, and risks

Cited by 32 publications

References 137 publications

Obesity Management in the Primary Prevention of Hepatocellular Carcinoma

Obesity Management in the Primary Prevention of Hepatocellular Carcinoma

Transcriptomics Reveals Discordant Lipid Metabolism Effects between In Vitro Models Exposed to Elafibranor and Liver Samples of NAFLD Patients after Bariatric Surgery

Integrative analyses of hub genes and their association with immune infiltration in adipose tissue, liver tissue and skeletal muscle of obese patients after bariatric surgery

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