Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide, affecting a staggering 25% of the general population. As NAFLD is considered the hepatic manifestation of the metabolic syndrome, its prevalence is expected to rise further with an ageing and more obese world population. Hepatic fibrosis is the main determinant of outcomes in NAFLD. Accordingly, NAFLD constitutes a major cause of life-threatening sequelae such as liver cirrhosis or hepatocellular carcinoma and is expected to replace viral hepatitis as leading cause for liver transplantation. Interventions targeting the underlying metabolic risk factors, i.e. obesity and insulin resistance, through weight loss have demonstrated some efficacy, while liver-targeted therapies have been largely disappointing to date.
CLINICAL MANIFESTATION OF NAFLD
The clinical presentation and natural history of NAFLD is heterogeneous and shows a substantial inter-patient variability. NAFLD progresses in stages: Although hepatic steatosis is highly prevalent, only a minority of patients progress to develop inflammation, i.e. non-alcoholic steatohepatitis (NASH). Progression to NASH and regression back to steatosis can be highly dynamic and occur even in a short time frame. Among individuals with NASH, some show a rapid and some an inherently slow-fibrosis progression. Many factors have been proposed to explain the marked heterogeneity of NAFLD phenotypes, including age, gender and hormonal status, ethnicity, diet, genetic predisposition, the microbiome, and metabolic comorbidities. The strong impact of the metabolic status on fatty liver disease has even prompted an intense debate whether NAFLD should be “re-defined” into metabolic dysfunction-associated fatty liver disease (MAFLD). Interestingly, for the majority of patients at risk as well as for most patients with liver steatosis, NAFLD is a prognostic marker of cardio- and cerebrovascular risk, while its inflammatory progression towards NASH and fibrosis is additionally predictive of liver-specific morbidity and mortality. In these patients, liver-related complications such as fibrosis, cirrhosis or hepatocellular carcinoma (HCC) determine prognosis.
NEED FOR COORDINATED RESEARCH
The premature termination of four recent major phase III clinical trials suggests a need to rethink our concepts and to develop a deeper understanding of NAFLD pathogenesis to identify the next generation of therapeutic targets. These future therapies need to address the complexity of NAFLD in a multi-pronged approach. The necessary scientific scope and depth can only be achieved in an interdisciplinary approach at the interface of metabolism, inflammation and fibrosis that goes far beyond the capability of the individual researcher. While industry-driven drug development naturally focuses on one mechanism or target, an interdisciplinary academic consortium with broad pioneering basic and clinical expertise will provide in-depth and unbiased mechanistic understanding of this complex disease from multiple angles intersecting at metabolism, immunology and hepatology to uncover novel therapeutically targetable disease-driving events in NAFLD. We will combine innovative cutting-edge technology including single-cell and spatial transcriptomic, proteomic, lipidomic and metabolomic analyses in patients with complementary organoid, organ-on-chip, cell biology and animal modelling to understand heterogeneity in mechanisms of hepatocyte injury and inflammatory/fibrogenic responses and the underlying cell-cell crosstalk.
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