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Report

Teaser, summary, work performed and final results

Periodic Reporting for period 1 - Foie Gras (Bioenergetic Remodeling in the Pathophysiology and Treatment of Non-Alcoholic Fatty Liver Disease)

Teaser

Summary

Despite over 30 years of major progress in the knowledge and management of liver disease, approximately 29 million people in the European Union currently suffer from a chronic liver condition, with cirrhosis and primary liver cancer representing the end-stage of liver pathology.
The overall aims of FOIE GRAS are 1) to identify mechanisms and consequences of metabolic remodeling secondary to mitochondrial alterations during NAFLD, 2) to explore how the gut-liver axis is disrupted in NAFLD and how that impacts hepatic metabolism and 3) to identify related circulating biomarkers that will underpin better diagnostic tests for NAFLD and allow designing interventions that alleviate NAFLD through hepatic or gut metabolic remodelling. This training network intends to exploit complementary expertise of different partners across the EU in order to train future leaders in Europe in this important research topic, as well as creating value, employment and new societal behaviours in the EU.
The FOIE GRAS programme aims to develop 13 integrated Ph.D. research projects to investigate internal and external mediators of metabolic remodelling, including modified gut-liver crosstalk in the development of NAFLD. FOIE GRAS will intersect basic and translational research, clinical implementation, technology development and transfer, and social outreach, under a common and focused strategy. I

Work performed

The main objective of ESR1 project is the elucidation of clinical, metabolic and molecular abnormalities resulting in mitochondrial-related alterations in the development of Non-Alcoholic Fatty Liver Disease (NAFLD). All diets contributed to the accumulation of triglycerides in the liver. Interestingly, studied diets caused different patterns of fat accumulation, what may suggest that the components of each individual diet may activate different signaling pathways.
For the project ESR2 it was necessary the optimization of methodology that allows the analysis of Krebs cycle intermediates, and other compounds derived either from glycolysis or de novo lipogenesis. ESR2 has contributed to develop and optimize a method that will allow to analyze the metabolites of interest in different samples (plasma and cells).
ESR3 optimized protocol to measure H2S oxidation in mouse liver mitochondria using oxygraphy (Oroboros). Preliminary experiments were performed for in vivo H2S supplementation (for 3 weeks) to determine the donor choice and the method of administration. Results are being obtained regarding the regulation of H2S during NAFLD progression and the protective effects of H2S donors.
ESR4 is undertaking the study on the relationship between intestinal short-chain fatty acid production, intestinal permeability and hepatic bioenergetic status both in high sugar and/or high fat diet induced NAFLD mice models and cross-sectional observational human studies. The ESR is using nuclear magnetic resonance to investigate metabolic profiling of the NAFLD animal models.
Besides two long-term in vivo studies, ESR5 studied the in vitro effects of Krill oil in the HepG2 cell line. The aim was to mimic the in vivo effects of n-3 PUFA-containing diet on mitochondrial function using cultured HepG2 cells treated with different fatty acids mixtures mimicking the respective composition of fatty acids in the above high-fat diet. The results showed that Krill oil altered mitochondrial function in intact cells which may contribute to alter the response of the same cells to fatty acids mixture (assays in progress).
The main aim of ESR6 project is to investigate the impact of the gut hormones on NAFLD. ESR6 has evaluated the lipidomic profile in different groups of patients. From the area of the peaks obtained for each lipid and the corresponding standard, ESR6 has calculated the concentrations of each lipid in each sample and correlated with the severity of the disease.
The main aim of ESR 7 is explore the role of Mediterranean Diet in NAFLD progression. As of December 2018, UNIBA has already achieved the goal set for recruitment of patients (n=35), which is currently ca. 60% of the total expected number.
ESR8 aimed to evaluate the role of the depletion of a necroptosis-associated protein on restoration of the mitochondrial activity in experimental NAFLD progression from steatosis to the development of preneoplastic lesions. The ESR detected that activity of the above-mentioned protein correlates with inflammation, fibrosis and oxidative stress in experimental NAFLD.
The main objective of the ESR9 project is to investigate the potential protective effects of PEG35 and PEG40 in preserving media for livers which are subjected to warm liver Ischemia reperfusion (IR) in different strain of rats, including obese models. The current results showed a significant degree of progression with the two additives.
The objective of ESR10 research project is to determine effects of physical activity during pregnancy in reducing the risk of developing NAFLD phenotype in female rats fed with HFD, with the focus on modulation of liver mitochondrial function and structure, as well on the epigenetic alterations of the genes involved in NAFLD pathology, especially transgenerational alterations. The ESR has managed to develop the animal model which is now being used to characterize mitochondrial function and the protection by physical activity.
ESR11 was involved in partic

Final results

Given the lack of dedicated therapies for NAFLD coupled to projected further increases in incidence, there are strong societal and commercial demands for novel fundamental knowledge on NAFLD. While nutritional, lifestyle and inherent factors undoubtedly conspire in NAFLD development, hepatocyte metabolic remodelling and a disrupted gutliver axis are likely to be key central mediators in this process. However, the extent to which recovery of metabolic function is linked to improvement of the NAFLD phenotype is still under debate. Furthermore, reliable biomarkers that inform hepatocyte mitochondrial function and fitness in the NAFLD setting are missing.
Metabolic dysfunction is now considered to be an important early event in liver disease pathogenesis, and is therefore an attractive target for drug discovery and other therapeutic approaches. Metabolic dysfunction resulting from mitochondrial oxidative
damage in particular may be a critical initiating event that is common to NAFLD pathogenesis as well as a wide range of other liver diseases. The importance of understanding links between metabolism and healthy lifestyles is now increasingly recognized for many chronic diseases.