Abstract
Nonalcoholic steatohepatitis (NASH) is defined as a progressive form of nonalcoholic fatty liver disease (NAFLD) and is a common chronic liver disease that causes significant worldwide morbidity and mortality, and has no approved pharmacotherapy. Nevertheless, growing understanding of the molecular mechanisms underlying the development and progression of NASH has suggested multiple potential therapeutic targets and strategies to treat this disease. Here, we review this progress, with emphasis on the functional role of secretory proteins in the development and progression of NASH, in addition to the change of expression of various secretory proteins in mouse NASH models and human NASH subjects. We also highlight secretory protein-based therapeutic approaches that influence obesity-associated insulin resistance, liver steatosis, inflammation, and fibrosis, as well as the gut–liver and adipose–liver axes in the treatment of NASH.
Highlights
Nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH) are chronic liver diseases with significant worldwide health implications [1]
Despite the significant clinical impact of NAFLD/NASH, no therapeutic drugs are approved for its treatment
Most therapeutic strategies have focused on monotherapy targeting one among four main pathogenic processes
Summary
Nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH) are chronic liver diseases with significant worldwide health implications [1]. ApoB100 and microsomal triglyceride transfer protein (MTP), key components in hepatic VLDL secretion, are negatively regulated by insulin [18]; selective insulin resistance in NAFLD patients allows insulin to stimulate DNL without suppressing VLDL production [19] Overall, these pathways lead to intracellular lipid accumulation in hepatocytes. Preclinical animal studies using a small molecule NLR family pyrin domain containing 3 (NLRP3) inhibitor (MCC950) or mice with deletion of Il-1β or Il-1r have revealed that deficiency of the inflammasome results in reduced hepatic inflammation and fibrosis in mice [26,27] These data suggest that inflammasome could be a potential target for treatment of NAFLD/NASH. Galectin-3, a lectin derived from KCs/macrophages, plays an important role in transforming growth factor beta (TGFβ)-mediated activation of HSCs [49], leading to phase 3 trial for a galectin-3 inhibitor (GR-MD-02)
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