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Using Bariatric Surgery to Discover Weight-Loss Independent Mechanisms Leading to the Reversal of Fatty Liver Disease

Project description

New treatment for NAFLD when lifestyle modifications fail

Strongly associated with obesity, hypertension and type 2 diabetes, non-alcoholic fatty liver disease (NAFLD) represents an increasing global public health problem worldwide. This progressive liver disease affects up to 25 % of the EU population. With no FDA-approved drugs available to treat this condition, lifestyle modification is the cornerstone of management. But what happens when lifestyle modifications fail? In this context, the EU-funded BARINAFLD project will develop novel, weight-loss independent mechanisms that can lead to NAFLD alleviation and harness them to treat this disease. Specifically, it will combine bariatric surgery in mice and humans with advanced molecular and computational analyses. By comparing livers of lean patients to those of NAFLD patients before and shortly after bariatric surgery, the project will shed light on surgery-mimetic therapies for this disease.

Objective

Non-Alcoholic Fatty Liver Disease (NAFLD), a disease characterized by accumulation of lipid droplets in the liver, is the major precursor for liver failure and liver cancer, and constitutes a global health challenge. An estimated 25% of the adult population suffers from NAFLD, but no FDA approved drugs are available to treat this condition. Obesity is a major NAFLD risk factor and weight-loss improves disease severity in obese patients. Bariatric surgeries are an effective treatment for obesity when lifestyle modifications fail and often lead to improvement in NAFLD and type 2 diabetes.
The overreaching objective of this proposal is to combine bariatric surgery in mice and humans with advanced molecular and computational analyses to discover novel, weight-loss independent mechanisms that lead to NAFLD alleviation, and harness them to treat NAFLD.
In preliminary studies, I discovered that bariatric surgery clears lipid droplets from the livers of obese db/db mice without inducing weight-loss. Using metabolic and computational analysis, I found that bariatric surgery shifts hepatic gene expression and blood metabolome of post-bariatric patients to a new trajectory, distinct from lean or sick patients. Data analysis revealed the transcription factor Egr1 and one-carbon and choline metabolism to be key drivers of weight-loss independent effects of bariatric surgery.
I will use two NAFLD mouse models that do not lose weight after bariatric surgery to characterize livers of mice post-surgery. Human patients do lose weight following surgery, therefore I will use computational methods to elucidate weight-independent pathways induced by surgery, by comparing livers of lean patients to those of NAFLD patients before and shortly after bariatric surgery. Candidate pathways will be studied by metabolic flux analysis and manipulated genetically, with the ultimate goal of reaching systems-levels understanding of NAFLD and identifying surgery-mimetic therapies for this disease.

Keywords

Host institution

THE HEBREW UNIVERSITY OF JERUSALEM
Net EU contribution
€ 1 499 354,00
Address
EDMOND J SAFRA CAMPUS GIVAT RAM
91904 Jerusalem
Israel

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Activity type
Higher or Secondary Education Establishments
Links
Total cost
€ 1 499 354,00

Beneficiaries (1)