Non-alcoholic fatty liver disease (NAFLD) encompasses a spectrum of diseases ranging from non-alcoholic fatty liver, which is characterised by hepatic steatosis, to the more severe form non-alcoholic steatohepatitis (NASH), which is characterised by hepatic steatosis, inflammation and hepatocyte injury (e.g. ballooning), with or without hepatic fibrosis. NAFLD is present in ~25% of the general population and incidence is increased strikingly in obesity, with overall NAFLD prevalence of ~75%. There is also a high prevalence of NAFLD in patients with T2DM (~55-80%). Despite these close links, there is an incomplete understanding of the factors mediating the close relationship between obesity, NAFLD and diabetes, with the likelihood of multiple contributing factors.
The liver regulates local and systemic metabolism via the secretion of proteins, which are collectively termed hepatokines, that signal via autocrine/paracrine and endocrine signalling to induce changes in lipid metabolism, peripheral insulin action and glycaemic control. Our laboratory has developed a discovery platform that couples murine and human precision-cut liver slices from disease-relevant donors with proteomic approaches to identify NAFLD/NASH-inducible hepatokines. We then performed target validation of these newly identified hepatokines using metabolic phenotyping in pre-clinical models of NAFLD. These studies have provided a deeper understanding of inter-tissue communication by hepatokines and identified targets for future diagnostics and therapies for obesity-associated diseases.