https://orcid.org/0000-0002-5201-9948
In Europe, the prevalence of non-alcoholic fatty liver disease (NAFLD) is slowly increasing due to the sedentary habits of the majority of the population, associated with diets that are fat- and especially sugar-rich. Unhealthy lifestyles associate with the individual's (epi)genetic background to create a perfect storm of metabolic diseases. Data indicates that NAFLD prevalence in Europe is around 25%,1 with the numbers approaching 50–60% in diabetic and obese individuals.2,3 The problem increases when discussing how NAFLD prevalence is progressing in children.2 An increasing number of children in developed countries have bad nutritional habits, often consuming alarming amounts of sugar and performing low amounts of physical activity, a problem exacerbated by the Covid-19 pandemic and associated lockdowns.
The genesis and progression of NAFLD are multi-dimensional, with an interplay of different factors and organs such as gut dysbiosis, hepatic mitochondrial dysfunction, oxidative stress, and adipose tissue/hepatic inflammation.4,5 How non-alcoholic fatty liver progresses to steatohepatitis and subsequent stages of NAFLD is still a matter of active research.
NAFLD progression is associated with cardiac complications, including arrhythmias and sudden death, although the mechanisms that link each are still poorly understood.6 NAFLD-associated factors such as systemic insulin resistance, activation of the immune system, increased circulation of oxidative stress and pro-inflammatory markers may contribute to cardiac structural, functional, electrical, and autonomic remodeling.6 Still, per se, NAFLD is not considered a significant contributor to cardiovascular diseases (CVD). This may stem from the fact that, at least in one large study, causality between high liver fat content and ischaemic heart disease has not been fully demonstrated.7 Whether this is transposable to other CVD or represents a second hit for established cardiac risk factors is still unclear.
The lack of a clear causal association between NAFLD and CVD can result from the lack of reliable biomarkers that indicate the NAFLD stage. Until now, the most reliable technique for NAFLD staging is liver biopsy, while liver elastography, the fatty liver index, or standard serum markers are very limited for NAFLD staging.8 In association with this, there are limited therapeutic opportunities to treat NAFLD, especially at the non-alcoholic steatohepatitis stage.4 Pharmaceutical interventions target by-stander metabolic alterations as insulin resistance or dyslipidemia, and not the core of hepatic alterations that drive simple steatosis to a pro-inflammatory phenotype and beyond.
The need for further excellence in research and innovation in NAFLD led the CNC—Center for Neuroscience and Cell Biology, University of Coimbra, to submit two complementary projects, FOIE GRAS and mtFOIE GRAS, to the European Commission. Both were funded by the Marie Skłodowska Curie Actions (MSCA) program. FOIE GRAS and mtFOIE GRAS encompass an interplay of basic and clinical investigation, technology transfer, participatory research, and science outreach, and stakeholders/public engagement, representing a concerted and holistic effort for NAFLD research-innovation-awareness in Europe (Figures 1 and 2). Importantly, FOIE GRAS and mtFOIE GRAS aimed to translate scientific training and biomedical innovation into career options for doctoral graduates, namely in biotech-pharmatech-medtech companies, while contributing for innovative clinical investigation in some partners. The author of this paper coordinates both projects.
Logos of the MSCA ETN FOIE GRAS (‘Bioenergetic Remodeling in the Pathophysiology and Treatment of Non-Alcoholic Fatty Liver Disease’), left and MSCA RISE mtFOIE GRAS mtFOIE GRAS (‘Non-invasive Profiling of Mitochondrial Function in Non-Alcoholic Fatty Liver Disease’), right.
Photos from researchers and events in FOIE GRAS and mtFOIE GRAS. From top to bottom, left to right: roll-ups from both projects at the annual scientific meeting of the European Society for Clinical Investigation; three of the ESR involved in FOIE GRAS teach a young audience about their projects; one of FOIE GRAS ESR describes her project and develops activities for young kids; the FOIE GRAS consortium in the kick-off meeting at the University of Coimbra, Portugal; the coordinator of both projects and author of this paper speaking to the press during the mtFOIE GRAS kick-off meeting; one researcher performing a secondment at a company during mtFOIE GRAS; the mtFOIE GRAS consortium meeting at Esslingen am Neckar, Germany.
FOIE GRAS (‘Bioenergetic Remodeling in the Pathophysiology and Treatment of Non-Alcoholic Fatty Liver Disease’) is a European Training Network (ETN) (http://www.projectfoiegras.eu/, https://cordis.europa.eu/project/id/722619), joining 10 universities/research institutes, 2 companies, and one patient association, from 7 different European countries. The objective of the project is two-fold: (i) to train 13 early-stage researchers (ESR) and lead them to obtain a Ph.D. degree, often in inter-disciplinary and cross-sectorial projects and (ii) to increase synergies between partners to promote fundamental and clinical investigation in NAFLD. The project has different work packages related to fundamental research on the mechanisms of NAFLD progression, identification of novel biomarkers and diagnostic tools (e.g., serum markers or breath tests), development and validation of novel pharmacological (e.g., mitochondria-targeted antioxidants) and non-pharmacological (physical activity or mushroom-enriched diets) interventions, from in vitro to in vivo models, and humans. Another work package on participative research and science outreach complements the project. For example, one of the ESR is working on participative research involving innovative tools, including comics, to increase the population's awareness towards NAFLD.9
Research and Innovation Staff Exchange (RISE) action mtFOIE GRAS (‘Non-invasive Profiling of Mitochondrial Function in Non-Alcoholic Fatty Liver Disease’) aims to promote innovation through the inter-sectorial exchange of researchers and staff working on different aspects of NAFLD. RISE mtFOIE GRAS (http://www.projectrisefoiegras.eu/, https://cordis.europa.eu/project/id/734719), featuring a solid inter-disciplinary and inter-sectorial collaborative effort, joins over 60 researchers from 9 universities and research centers, 3 companies, and 1 patient association and health provider, from 7 different countries. While FOIE GRAS focuses on the training of ESR, the mtFOIE GRAS project aims towards creating innovation in a trans-sectorial manner. Researchers and staff from academic and non-academic institutions perform secondments in their trans-sectorial partners, bringing fundamental research data to industry and clinical applications. The same concept of fundamental research-biomarkers-interventions is used in this project, complemented with science outreach actions towards different stakeholders. The development of novel commercial diagnostic kits and liquid biopsy-based technologies for assessing NAFLD staging are two of the outcomes of the mtFOIE GRAS project.
The outcome of FOIE GRAS and mtFOIE GRAS projects will directly impact future research and therapies in NAFLD. A proper assessment of the NAFLD stage, plus the characterization of the metabolic remodelling occurring in the liver of patients will have a determinant effect on the relationship between NAFLD and CVD. By integrating in vitro and animal models, and human studies, the two complementary projects will impact the current research, diagnosis, and therapeutics related to NAFLD and associated complications. A new generation of young fundamental and clinician researchers is being trained, with the hope they will finally break the chain of NAFLD progression among the population.
Acknowledgements
The author received funding from the European Union's Horizon 2020 Research and Innovation program under the Marie Skłodowska-Curie Grant Agreement No. 722619 (FOIE GRAS) and Grant Agreement No. 734719 (mtFOIE GRAS).
Conflict of interest: none declared.
