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Sleeve-Gastrectomy results in improved metabolism and a massive stress response of the liver proteome in a mouse model of nonalcoholic steatohepatitis

ABSTRACT: Introduction: Bariatric surgery has been shown to improve the histopathological findings in patients with obesity and non-alcoholic steatohepatitis, but there are also reports about non-responder or progressive disease after bariatric interventions. Therefore, it is of utmost importance to understand the pathophysiological processes in the liver after bariatric surgery. Material and Methods: In the present study, mice were fed a Western Diet to induce non-alcoholic steatohepatitis and sleeve-gastrectomy (SG), or sham operation was performed. Mice were observed for two or eight weeks after surgery and metabolic assessment was performed throughout the experiment. Histopathology, fluorescence associated cell sorting and proteomic analysis were conducted to evaluate hepatic inflammation, liver metabolism and affected signaling pathways. Results: Weight loss was higher, and metabolism significantly improved after SG. Two weeks after SG major inflammatory and regulatory disturbances in the liver were observed, but these disturbances decreased in the long-term. Conclusion: The rapid weight loss and decrease of hepatic fat after SG lead to a proinflammatory response in the liver in the early phase after surgery, which changes to a more moderate immune response in the long-term. We suggest a preoperative risk stratification and postoperative surveillance depending on the histopathological findings.

INSTRUMENT(S): Q Exactive Plus

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Liver

DISEASE(S): Non-alcoholic Steatohepatitis

SUBMITTER: Christian Preisinger

LAB HEAD: Andreas Kroh

PROVIDER: PXD044185 | Pride | 2024-10-21

REPOSITORIES: Pride

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			Action	DRS
	MQ_data_sleeve.zip	Other
	OR2_2018_10_05_Karsten_surg_Liver_1_1.raw	Raw
	OR2_2018_10_05_Karsten_surg_Liver_1_10.raw	Raw
	OR2_2018_10_05_Karsten_surg_Liver_1_11.raw	Raw
	OR2_2018_10_05_Karsten_surg_Liver_1_12.raw	Raw

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Project description:INTRODUCTION: Bariatric surgery is known to be the most effective treatment for weight loss in obese patients and for the rapid remission of obesity-related comorbidities. These short-term improvements result from not only limited digestion or absorption but also dynamic changes in metabolism throughout the whole body. However, short-term metabolism studies associated with bariatric surgery in Asian individuals have not been reported.OBJECTIVES: The aim of this study was to investigate the short-term metabolome changes in the serum promoted by laparoscopic sleeve gastrectomy (SG) and Roux-en-Y gastric bypass (RYGB) and to determine the underlying mechanisms that affect obesity-related comorbidities.METHODS: Serum samples were collected from Korean patients who underwent RYGB or SG before and 4 weeks after the surgery. Metabolomic and lipidomic profiling was performed using UPLC-Orbitrap-MS, and data were analyzed using statistical analysis.RESULTS: Metabolites mainly related to amino acids, lipids (fatty acids, glycerophospholipids, sphingolipids, glycerolipids) and bile acids changed after surgery, and these changes were associated with the lowering of risk factors for obesity-related diseases such as nonalcoholic fatty liver disease (NAFLD), type 2 diabetes (T2D) and atherosclerosis. Interestingly, the number of significantly altered metabolites related to the lipid metabolism were greater in SG than in RYGB. Furthermore, the metabolites related to amino acid metabolism were significantly changed only after SG, whereas bile acid changed significantly only following RYGB.CONCLUSION: These differences could result from anatomical differences between the two surgeries and could be related to the gut microbiota. This study provides crucial information to expand the knowledge of the common but different molecular mechanisms involved in obesity and obesity-related comorbidities affected by each bariatric procedure.

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.

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Sleeve-Gastrectomy results in improved metabolism and a massive stress response of the liver proteome in a mouse model of nonalcoholic steatohepatitis

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