Abstract
Non-alcoholic fatty liver disease (NAFLD) is currently the most common chronic liver disease in the Western world, affecting about 20-30% of the population. The hallmark of NAFLD is fat accumulation in the hepatocytes (steatosis), which is not triggered by well-established causes of steatosis like alcohol or hepatotoxic substances. The concomitant presence of inflammation and degenerative injury of hepatocytes is labelled non-alcoholic steatohepatitis (NASH). Up to 30% of the patients with NAFLD have NASH, which potentially leads to progressive liver fibrosis, liver cirrhosis and hepatocellular carcinoma. Currently no approved pharmacotherapy exists to counter the progression of the disease. From a pathophysiological point of view, multiple mechanisms, which are currently still poorly understood, are involved in the onset of NALFD and involve different organs, including the adipose tissue, that cross talk to generate metabolic and organ-specific damage, probably in genetically predisposed subjects. Adipose tissue impairment, e.g. hypoxia, inflammation and dysfunction, results via altered secretion of adipokines and a plethora of inflammatory and immunological mechanisms in an impact on other organs. Furthermore, accumulating data, including from our research group, show that insulin resistance at the level of the adipose tissue has itself a tight link to liver damage. Interestingly, the clinical course of the disease is extremely dynamic and can be reversed. The general concept is that the degree of activity of NASH fluctuates over time, probably in relation to changes in the metabolic drivers of the disease, and that also fibrosis progression follows an undulant course. However, we recently challenged this concept of reversibility, since we demonstrated in a high-fat-high-fructose model (where we investigated T-cell related immunological mechanisms in NAFLD pathogenesis) that, after reversal of the diet to a normal chow diet, and despite most HFHFD-induced metabolic and histological reverted to normal, T-cell subset alterations persisted. We were hereby the first to demonstrate this persisting immune disruption at the level of multiple T-cell subsets in liver and adipose tissue. These findings challenge our current understanding of the reversibility of NASH upon weight loss and raise the question whether rechallenge might elicit an enhanced response (and hence accelerated disease progression). Currently no approved pharmacotherapy exists to counter the progression of the disease. One of the most promising drug classes are the peroxisome proliferator-activated receptor (PPARs) agonists. The 3 PPAR isotypes are key regulators of metabolism, inflammation and fibrogenesis. We demonstrated the role of liver PPARalpha expression in pre-clinical models and in NASH patients. We recently reported significant beneficial effects of the panPPAR agonist lanifibranor on steatohepatitis and fibrosis severity in a Phase2b study of non-cirrhotic NASH patients. Moreover, an improvement in the metabolic profile was demonstrated. In the current project, we aim first at elucidating the mechanisms underlying the cross talk between liver and dysfunctional adipose tissue in NAFLD, integrating extensive data obtained in a well characterized NAFLD cohort, including extensive metabolic profile and gene expression data. Secondly, we will explore the reversibility of the alterations of the adipose tissue-liver axis and, third, the effect on the disease course of the exposure to repetitive insults (rechallenge). Finally, we will evaluate the effect of the modulation of the PPAR pathways in preventing an enhanced disease progression upon repeated insults.
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