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

Periodic Reporting for period 2 - BARINAFLD (Using Bariatric Surgery to Discover Weight-Loss Independent Mechanisms Leading to the Reversal of Fatty Liver Disease)

Reporting period: 2020-05-01 to 2021-10-31

Non alcoholic fatty liver disease (NAFLD)affects over a quarter of the adult world population. This disease, which is characterised by accumulation of lipid droplets in the liver, can progress to hepatic inflammation, liver failure and liver cancer, and is associated with type 2 diabetes and cardiovascular diseases. Finding new means to treat NAFLD and understand its development are therefore of great importance to society and public health.
Obesity can cause NAFLD, and indeed the best treatment for NAFLD is weight-loss. However only a small fraction of patients manage to to lose weight and maintain weight-loss. Bariatric, or weight-loss surgeries, achieve substantial weight-loss and are associated with a dramatic improvement in NAFLD. We have shown in animal models that these surgeries can improve NAFLD even without weight-loss and can improve NAFLD to a greater extent compared with calorie restriction. Analysis of data from patients have shown that the post-bariatric metabolism is different than the hepatic metabolism of both healthy and NAFLD patients.
The hypothesis of this project is that bariatric surgeries induce a biological process that affects positively NAFLD, independent of weight-loss. Our objectives are to identify this project using animal models and patient data, and to test candidate biological pathways on animal models, as a first step towards finding new treatments for this common and grave disease.
Corresponding to aim 1A-C: We have generated five animal models of the study of the weight-loss independent effects of bariatric surgery:
1. Sleeve gastrectomy on leptin receptor deficient mice (db/db)
2. Sleeve gastrectomy on lean mice fed with a diet deficient on choline and methionine (MCD)
3. Single anastomosis bypass on mice fed on a high fat diet.
4. Sleeve gastrectomy on Cohen lean diabetic rats, that suffer from NAFLD as well
5. Sleeve gastrectomy on rats fed on high fat diet.

In all models, the liver has shown improvement independent of weight-loss.

1. (aims 1A-B)mRNA sequencing analysis has been performed on the livers of the first two mouse models. Specific enzymes affecting lipid metabolism have been identified as key elements that may mediate the improvement in hepatic disease following surgery, independent of weight-loss. These enzymes were also affected by surgery in datasets published by other groups during 2019. Thus they stand as a common response to bariatric surgery, and may affect NAFLD directly. These targets will be tested in the next reporting period. We have also performed a proteomic analysis, results will be analysed in the next period.
2. (aim 1C) We have developed the technique to collect portal, aortic and hepatic vein blood from mice and rats following sleeve gastrectomy. In mice, we have shown a reduction in hepatic gluconeogenesis and increase in hepatic inuslin uptake following surgery. These results will be published in the next reporting period. In rats, we are calibrating the experimental system for full metabolomic analysis.

Corresponding to aim 3A: We have tested the hypotheses that post-bariatric repression of the EGR1 or AP1 pathway affects NAFLD
EGR1: We have shown that repression of EGR1 does not affect NAFLD using genetic models for NAFLD (db/db mice). EGR1 ko mice and heterozygous littermates did develop NAFLD. Therefore, we rejected the hypothesis concerning a causal role for EGR1 repression in the improvement of NAFLD.
AP1. viral mediated repression of AP1 using the dominant negative JUN constructed did not affect NAFLD development in db/db mice. Hepatic JUN repression has led to a mild increase in the weight of mice on a high fat diet, with no positive effect on NAFLD. We conclude that JUN repression has no role in improvement in NAFLD.
Altogether, our experiments have shown that there is a indeed a correlation between suppression of EGR1 and the AP1 pathway in patients following bariatric surgery, but there is no causality between the repression of these factors and the improvement in NAFLD.
We have studied the Israeli Bariatric Registry, and have found evidence for weight-loss independent effects of bariatric surgery on reduction in the levels of liver enzymes. which are a proxy for hepatic disease. This results reinforces the main hypothesis underlying our study. Results will be published in the next reporting period.