Human-based systems: Mechanistic NASH modelling just around the corner?

Abstract

Non-alcoholic steatohepatitis (NASH) is a chronic liver disease characterized by excessive triglyceride accumulation in the liver accompanied by inflammation, cell stress and apoptosis. It is the tipping point to the life-threatening stages of non-alcoholic fatty liver disease (NAFLD). Despite the high prevalence of NASH, up to five percent of the global population, there are currently no approved drugs to treat this disease. Animal models, mostly based on specific diets and genetic modifications, are often employed in anti-NASH drug development. However, due to interspecies differences and artificial pathogenic conditions, they do not represent the human situation accurately and are inadequate for testing the efficacy and safety of potential new drugs. Human-based in vitro models provide a more legitimate representation of the human NASH pathophysiology and can be used to investigate the dysregulation of cellular functions associated with the disease. Also in silico methodologies and pathway-based approaches using human datasets, may contribute to a more accurate representation of NASH, thereby facilitating the quest for new anti-NASH drugs. In this review, we describe the molecular components of NASH and how human-based tools can contribute to unraveling the pathogenesis of this disease and be used in anti-NASH drug development. We also propose a roadmap for the development and application of human-based approaches for future investigation of NASH.

3D Primary Hepatocyte Culture Systems for Analyses of Liver Diseases, Drug Metabolism, and Toxicity: Emerging Culture Paradigms and Applications

“…[97] Modeling of NAFLD in vitro has been challenging in conventional 2D liver models due to the chronic nature of the disease, which requires long-term stable cultures; the need for adequate in vivo-like metabolic responses to hormones and nutrients, as well as the disease complexity that requires the intricate interplay between both parenchymal and nonparenchymal liver cells to mediate disease progression and inflammatory responses. [98] PHH in the MPCC model are responsive to alterations in glucose levels in the culture media. Under hyperglycemic conditions, hepatocytes developed insulin resistance and subsequent steatosis.…”

Characterization Of Human Pluripotent Stem Cell-Derived Hepatocytes With Adult Features And Potential For Modeling Metabolic Diseases

“…The long progression until clinical signs, the lack of good diagnostic tools as well as the absence of relevant preclinical models hampers the development of adequate treatments and drugs for NADFL/NASH, and highlights the need for novel translational in vitro models [36]. Several animal models have been developed, however, due to the heterogeneous pathology few or none of these models represent the human situation accurately [37]. Therefore, there is great and urgent need for an in vitro model for NAFLD/NASH.…”

“…Since the progression of NAFLD to NASH includes a contribution of inflammatory and fibrogenic response from non-parenchymal cells, hepatocytes need to be co-cultured with nonparenchymal cells, such as stellate cells and Kupffer cells, as reviewed in [37]. To date, only a limited number of attempts using primary cells or cell lines (reviewed in [42]) or hepatocytes derived from human pluripotent stem cells [11,43] have been reported in the NASH field.…”

Intestinally derived bacterial products stimulate development of nonalcoholic steatohepatitis

“…This view is supported by endotoxin signaling identified in HSCs activation (Table 2), while fibrogenic cell type in injured liver mediates key responses and inflammatory phenotype [90,91]. In-vitro models can offer mechanistic insights into how inflammation and lipotoxicity directly contribute to the development of NASH [92]. Tang et al [93] investigated the importance of LPS-induced liver injury in administration of HF diet.…”