Abstract
Non-alcoholic fatty liver disease (NAFLD) is characterized by the excessive and detrimental accumulation of liver fat as a result of high-caloric intake and/or cellular and molecular abnormalities. The prevalence of this pathological event is increasing worldwide, and is intimately associated with obesity and type 2 diabetes mellitus, among other comorbidities. To date, only therapeutic strategies based on lifestyle changes have exhibited a beneficial impact on patients with NAFLD, but unfortunately this approach is often difficult to implement, and shows poor long-term adherence. For this reason, great efforts are being made to elucidate and integrate the underlying pathological molecular mechanism, and to identify novel and promising druggable targets for therapy. In this regard, a large number of clinical trials testing different potential compounds have been performed, albeit with no conclusive results yet. Importantly, many other clinical trials are currently underway with results expected in the near future. Here, we summarize the key aspects of NAFLD pathogenesis and therapeutic targets in this frequent disorder, highlighting the most recent advances in the field and future research directions.
Highlights
Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in Western countries, with an estimated global prevalence of 25%
The spectrum of NAFLD ranges from simple steatosis to non-alcoholic steatohepatitis (NASH), which is characterized by a variable grade of inflammation and hepatocellular damage [2,3] and may further progress to more severe hepatic disorders, such as fibrosis, cirrhosis, and hepatocellular carcinoma (HCC) [4]
This review is aimed at summarizing current knowledge about the pathophysiological mechanisms involved in the establishment and progression of NAFLD and their effects in the liver, the efforts in developing effective drug treatments attending to these mechanisms, and at discussing the potential stratification of patients to identify the better candidates for each treatment
Summary
Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in Western countries, with an estimated global prevalence of 25% It includes a wide spectrum of liver injuries whose distinctive feature is the accumulation of intrahepatic fat, especially triglycerides (TGs) [1]. The new definition clearly establishes this disease as a metabolic disorder; besides metabolic dysfunction, many other diseases result in hepatic steatosis, such as alcohol- and drug-induced liver injury, and chronic inflammatory diseases. Clinical trials reporting for NAFLD are suboptimal, limiting our understanding All these data suggest the existence of different phenotypes within NAFLD that differ in which molecular pathways are predominantly altered, that is inflammatory or metabolic pathways or both, and they probably have a different natural history and liver disease course. This review is aimed at summarizing current knowledge about the pathophysiological mechanisms involved in the establishment and progression of NAFLD and their effects in the liver, the efforts in developing effective drug treatments attending to these mechanisms, and at discussing the potential stratification of patients to identify the better candidates for each treatment
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