A structured literature review of interventions used in the management of nonalcoholic steatohepatitis (<scp>NASH</scp>)

Inflammation‐driven diseases and related comorbidities, such as the metabolic syndrome, obesity, fatty liver disease, and cardiovascular diseases cause significant global burden. There is a growing body of evidence that nutrients alter inflammatory responses and can therefore make a decisive contribution to the treatment of these diseases. Recently, the inflammasome, a cytosolic multiprotein complex, has been identified as a key player in inflammation and the development of various inflammation‐mediated disorders, with nucleotide‐binding domain and leucine‐rich repeat pyrin domain (NLRP) 3 being the inflammasome of interest. Here an overview about the cellular signaling pathways underlying nuclear factor “kappa‐light‐chain‐enhancer” of activated B‐cells (NF‐κB)‐ and NLRP3‐mediated inflammatory processes, and the pathogenesis of the inflammatory diseases atherosclerosis and non‐alcoholic fatty liver disease (NAFLD) is provided; next, the current state of knowledge for drug‐based and dietary‐based interventions for treating cardiovascular diseases and NAFLD is discussed. To date, one of the most important antioxidants in the human diet is vitamin E. Various in vitro and in vivo studies suggest that the different forms of vitamin E and also their derivatives have anti‐inflammatory activity. Recent publications suggest that vitamin E—and possibly metabolites of vitamin E—are a promising therapeutic approach for treating inflammatory diseases such as NAFLD.

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“…[ 158 ] However, in patients with progressing to advanced fibrosis lifestyle interventions alone are not sufficient. [ 159 ]…”

Section: Inflammatory Diseasesmentioning

confidence: 99%

Inflammatory Diseases and Vitamin E—What Do We Know and Where Do We Go?

Wallert

Börmel

Lorkowski

2020

Molecular Nutrition Food Res

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“…Regarding VCAM-1, it has also been recently validated as an accurate biomarker of fibrosis in NASH patients. 42 Furthermore, ASK1/MAP3K5 has been largely described in the literature as a pharmacological target for NASH disease treatment [43][44][45] and, interestingly, its up-regulation is observed in our human 3D NASH model (Supplementary Table 2).…”

Section: Discussionmentioning

confidence: 57%

A 3D Human Liver Model of Nonalcoholic Steatohepatitis

Duriez

Jacquet

Hoet

et al. 2020

Journal of Clinical and Translational Hepatology

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Background and Aims: To better understand nonalcoholic steatohepatitis (NASH) disease progression and to evaluate drug targets and compound activity, we undertook the development of an in vitro 3D model to mimic liver architecture and the NASH environment. Methods: We have developed an in vitro preclinical 3D NASH model by coculturing primary human hepatocytes, human stellate cells, liver endothelial cells and Kupffer cells embedded in a hydrogel of rat collagen on a 96-well plate. A NASH-like environment was induced by addition of medium containing free fatty acids and tumor necrosis factor-a. This model was then characterized by biochemical, imaging and transcriptomics analyses. Results: We succeeded in defining suitable culture conditions to maintain the 3D coculture for up to 10 days in vitro, with the lowest level of steatosis and reproducible low level of inflammation and fibrosis. NASH disease was induced with a custom medium mimicking NASH features. The cell model exhibited the key NASH disease phenotypes of hepatocyte injury, steatosis, inflammation, and fibrosis. Hepatocyte injury was highlighted by a decrease of CYP3A4 expression and activity, without loss of viability up to day 10. Moreover, the model was able to stimulate a stable inflammatory and early fibrotic environment, with expression and secretion of several cytokines. A global gene expression analysis confirmed the NASH induction. Conclusions: This is a new in vitro model of NASH disease consisting of four human primary cell-types that exhibits most features of the disease. The 10-day cell viability and cost effectiveness of the model make it suitable for medium throughput drug screening and provide attractive avenues to better understand disease physiology and to identify and characterize new drug targets.

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“…Regarding VCAM-1, it has also been recently validated as an accurate biomarker of fibrosis in NASH patients (Lefere et al, 2017). Furthermore, apoptosis signaling kinase 1 (ASK1/MAP3K5) has been largely described in the literature as a pharmacological target for NASH disease treatment (Povsic et al, 2019, Connolly et al, 2018, Drescher et al, 2019 and, interestingly, its upregulation is observed in our human 3D NASH model (Table S2).…”

Section: Discussionmentioning

confidence: 67%

A 3D human liver model of nonalcoholic steatohepatitis

Duriez

Jacquet

Hoet

et al. 2020

Preprint

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We developed a 3D human liver model which exhibits many features of nonalcoholic steatohepatitis and that could become a platform for medium throughput drug screening. ABSTRACTWe have developed an in vitro preclinical 3D Non-Alcoholic SteatoHepatitis (NASH) model by co-culturing four human primary liver cell types: hepatocytes, stellate, endothelial and Kupffer cells. Cells were embedded in a hydrogel of rat collagen in 96-well plate and a NASH-like environment was induced with a medium containing free fatty acids (FFAs) and tumor necrosis factor  (TNF). This model was characterized by biochemical, imaging and transcriptomics analysis. On the one hand, we succeed in defining suitable culture conditions to maintain the 3D co-culture up to 10 days in vitro with the lowest level of steatosis, and reproducible low levels of inflammation and fibrosis. On the other hand, we induced NASH disease with a custom medium mimicking NASH features (hepatocyte injury, steatosis, inflammation and fibrosis). The 10-day cell viability and cost effectiveness of the model make it suitable for medium throughput drug screening and provide attractive avenues to better understand disease physiology and to identify and characterize new drug targets.

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A structured literature review of interventions used in the management of nonalcoholic steatohepatitis (NASH)

Cited by 16 publications

References 62 publications

Inflammatory Diseases and Vitamin E—What Do We Know and Where Do We Go?

Inflammatory Diseases and Vitamin E—What Do We Know and Where Do We Go?

A 3D Human Liver Model of Nonalcoholic Steatohepatitis

A 3D human liver model of nonalcoholic steatohepatitis

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