Translating scientific discovery: the need for preclinical models of nonalcoholic steatohepatitis

Abstract

Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in the Western world, affecting about 1/3 of the US general population and remaining as a significant cause of morbidity and mortality. The hallmark of the disease is the excessive accumulation of fat within the liver cells (hepatocytes), which eventually paves the way to cellular stress, injury and apoptosis. NAFLD is strongly associated with components of the metabolic syndrome and is fast emerging as a leading cause of liver transplant in the USA. Based on clinico-pathologic classification, NAFLD may present as isolated lipid collection (steatosis) within the hepatocytes (referred to as non-alcoholic fatty liver; NAFL); or as the more aggressive phenotype (known as non-alcoholic steatohepatitis; NASH). There are currently no regulatory agency-approved medication for NAFLD, despite the enormous work and resources that have gone into the study of this condition. Therefore, there remains a huge unmet need in developing and utilizing pre-clinical models that will recapitulate the disease condition in humans. In line with progress being made in developing appropriate disease models, this review highlights the cutting-edge preclinical in vitro and animal models that try to recapitulate the human disease pathophysiology and/or clinical manifestations.

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

“…Currently, the global prevalence of NAFLD is approximately 25% with associated annual medical costs of ≈103 billion USD in the United States alone . Despite the global economic and clinical burden, no FDA‐approved drug therapies for NASH exist and the cornerstone of therapy includes lifestyle intervention and weight control …”

“…[96] Despite the global economic and clinical burden, no FDA-approved drug therapies for NASH exist and the cornerstone of therapy includes lifestyle intervention and weight control. [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.…”

A 3D human liver model of nonalcoholic steatohepatitis

“…The development of in vitro human 3D models to mimic liver architecture has been undertaken by several groups, especially for drug safety assessment (Oseini et al, 2018). It includes layered co-cultures, co-cultures on micro-patterned surfaces, spheroids and bioprinted liver tissue (Oseini et al, 2018). Many of these models are grown within specialized microfluidic devices to provide nutrients and oxygen transport (Oseini et al, 2018).…”

“…It includes layered co-cultures, co-cultures on micro-patterned surfaces, spheroids and bioprinted liver tissue (Oseini et al, 2018). Many of these models are grown within specialized microfluidic devices to provide nutrients and oxygen transport (Oseini et al, 2018). Few 3D co-culture studies were designed as NAFL or NASH disease models to display key pathogenic phenotypes.…”

Epidemiologic Profile and Predictors of Fatty Liver: A Hospital-Based Study

“…Its incidence and prevalence are rising globally parallel to the increasing rates of obesity and diabetes. It is associated with other components of the metabolic syndrome [2]. NAFLD affects about one third of the US general population.…”