scholarly journals From NAFLD to MAFLD: Aligning Translational In Vitro Research to Clinical Insights

Biomedicines ◽  
2022 ◽  
Vol 10 (1) ◽  
pp. 161
Author(s):  
Alexandra Gatzios ◽  
Matthias Rombaut ◽  
Karolien Buyl ◽  
Joery De Kock ◽  
Robim M. Rodrigues ◽  
...  
Keyword(s):  
Liver Disease ◽  
Drug Development ◽  
Fatty Liver ◽  
Fatty Liver Disease ◽  
Drug Testing ◽  
Disease Modeling ◽  
In Vitro Models ◽  
Alcoholic Fatty Liver ◽  
Short Term Exposure

Although most same-stage non-alcoholic fatty liver disease (NAFLD) patients exhibit similar histologic sequelae, the underlying mechanisms appear to be highly heterogeneous. Therefore, it was recently proposed to redefine NAFLD to metabolic dysfunction-associated fatty liver disease (MAFLD) in which other known causes of liver disease such as alcohol consumption or viral hepatitis do not need to be excluded. Revised nomenclature envisions speeding up and facilitating anti-MAFLD drug development by means of patient stratification whereby each subgroup would benefit from distinct pharmacological interventions. As human-based in vitro research fulfils an irrefutable step in drug development, action should be taken as well in this stadium of the translational path. Indeed, most established in vitro NAFLD models rely on short-term exposure to fatty acids and use lipid accumulation as a phenotypic benchmark. This general approach to a seemingly ambiguous disease such as NAFLD therefore no longer seems applicable. Human-based in vitro models that accurately reflect distinct disease subgroups of MAFLD should thus be adopted in early preclinical disease modeling and drug testing. In this review article, we outline considerations for setting up translational in vitro experiments in the MAFLD era and allude to potential strategies to implement MAFLD heterogeneity into an in vitro setting so as to better align early drug development with future clinical trial designs.

scholarly journals Studying non-alcoholic fatty liver disease: the ins and outs of in vivo, ex vivo and in vitro human models

2018 ◽  
Vol 0 (0) ◽  
Author(s):  
Charlotte J. Green ◽  
Siôn A. Parry ◽  
Pippa J. Gunn ◽  
Carlo D.L. Ceresa ◽  
Fredrik Rosqvist ◽  
...  
Keyword(s):  
Liver Disease ◽  
Fatty Liver ◽  
Fatty Liver Disease ◽  
In Vitro Models ◽  
Ex Situ ◽  
Whole Body ◽  
Alcoholic Fatty Liver ◽  
Alcoholic Fatty Liver Disease

AbstractThe prevalence of non-alcoholic fatty liver disease (NAFLD) is increasing. Determining the pathogenesis and pathophysiology of human NAFLD will allow for evidence-based prevention strategies, and more targeted mechanistic investigations. Various in vivo, ex situ and in vitro models may be utilised to study NAFLD; but all come with their own specific caveats. Here, we review the human-based models and discuss their advantages and limitations in regards to studying the development and progression of NAFLD. Overall, in vivo whole-body human studies are advantageous in that they allow for investigation within the physiological setting, however, limited accessibility to the liver makes direct investigations challenging. Non-invasive imaging techniques are able to somewhat overcome this challenge, whilst the use of stable-isotope tracers enables mechanistic insight to be obtained. Recent technological advances (i.e. normothermic machine perfusion) have opened new opportunities to investigate whole-organ metabolism, thus ex situ livers can be investigated directly. Therefore, investigations that cannot be performed in vivo in humans have the potential to be undertaken. In vitro models offer the ability to perform investigations at a cellular level, aiding in elucidating the molecular mechanisms of NAFLD. However, a number of current models do not closely resemble the human condition and work is ongoing to optimise culturing parameters in order to recapitulate this. In summary, no single model currently provides insight into the development, pathophysiology and progression across the NAFLD spectrum, each experimental model has limitations, which need to be taken into consideration to ensure appropriate conclusions and extrapolation of findings are made.

scholarly journals In vitro models for non-alcoholic fatty liver disease: emerging platforms and their applications

iScience ◽  
2021 ◽  
pp. 103549
Author(s):  
Maria Jimenez Ramos ◽  
Lucia Bandiera ◽  
Filippo Menolascina ◽  
Jonathan Andrew Fallowfield
Keyword(s):  
Liver Disease ◽  
Fatty Liver ◽  
Fatty Liver Disease ◽  
In Vitro Models ◽  
Alcoholic Fatty Liver ◽  
Alcoholic Fatty Liver Disease

scholarly journals Activation of TAF9 via Danshensu-Induced Upregulation of HDAC1 Expression Alleviates Non-alcoholic Fatty Liver Disease

2021 ◽  
Vol 12 ◽  
Author(s):  
Ruiwen Wang ◽  
Zhecheng Wang ◽  
Ruimin Sun ◽  
Rong Fu ◽  
Yu Sun ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Liver Disease ◽  
Fatty Liver ◽  
Protective Effect ◽  
Fatty Liver Disease ◽  
Cell Model ◽  
Signaling Mechanism ◽  
Alcoholic Fatty Liver

Fatty acid β-oxidation is an essential pathogenic mechanism in nonalcoholic fatty liver disease (NAFLD), and TATA-box binding protein associated factor 9 (TAF9) has been reported to be involved in the regulation of fatty acid β-oxidation. However, the function of TAF9 in NAFLD, as well as the mechanism by which TAF9 is regulated, remains unclear. In this study, we aimed to investigate the signaling mechanism underlying the involvement of TAF9 in NAFLD and the protective effect of the natural phenolic compound Danshensu (DSS) against NAFLD via the HDAC1/TAF9 pathway. An in vivo model of high-fat diet (HFD)-induced NAFLD and a palmitic acid (PA)-treated AML-12 cell model were developed. Pharmacological treatment with DSS significantly increased fatty acid β-oxidation and reduced lipid droplet (LD) accumulation in NAFLD. TAF9 overexpression had the same effects on these processes both in vivo and in vitro. Interestingly, the protective effect of DSS was markedly blocked by TAF9 knockdown. Mechanistically, TAF9 was shown to be deacetylated by HDAC1, which regulates the capacity of TAF9 to mediate fatty acid β-oxidation and LD accumulation during NAFLD. In conclusion, TAF9 is a key regulator in the treatment of NAFLD that acts by increasing fatty acid β-oxidation and reducing LD accumulation, and DSS confers protection against NAFLD through the HDAC1/TAF9 pathway.

scholarly journals Naringin protects against non-alcoholic fatty liver disease by promoting autophagic flux and lipophagy

2021 ◽  
Author(s):  
Lingling Guan ◽  
Lan Guo ◽  
Heng Zhang ◽  
Hao Liu ◽  
Yuan Qiao ◽  
...  
Keyword(s):  
Liver Disease ◽  
Fatty Liver ◽  
Hepatic Steatosis ◽  
Fatty Liver Disease ◽  
Autophagic Flux ◽  
Mechanism Study ◽  
Alcoholic Fatty Liver ◽  
Alcoholic Fatty Liver Disease

Abstract Background and Purpose: The autophagic degradation of lipid droplets (LDs), termed lipophagy, is the main mechanism contributing to lipid consumption in hepatocytes. The identification of effective and safe natural compounds that target lipophagy to eliminate excess lipids may be a potential therapeutic strategy for non-alcoholic fatty liver disease (NAFLD). Here, we investigated the effects of naringin on NAFLD and the underlying mechanism. Experimental Approach: The role of naringin was investigated in mice fed a high-fat diet (HFD) to induce NAFLD, as well as in AML12 cells and primary hepatocytes stimulated by palmitate (PA). Transcription factor EB (TFEB)-knockdown AML12 cells and hepatocyte-specific TFEB-knockout mice were also used for the mechanism study. In vivo and in vitro studies were conducted using transmission electron microscopy, immunofluorescence techniques and western blot analysis. Key Results: We found that naringin treatment effectively relieved HFD-induced hepatic steatosis in mice and inhibited palmitate (PA)-induced lipid accumulation in hepatocytes. The increased p62 and LC3-II levels observed with excess lipid-support autophagosome accumulation and impaired autophagic flux. Treatment with naringin restored TFEB-mediated lysosomal biogenesis, thereby promoting the fusion of autophagosomes and lysosomes, restoring impaired autophagic flux and further inducing lipophagy. However, the knockdown of TFEB in hepatocytes or the hepatocyte-specific knockout of TFEB in mice abrogated naringin-induced lipophagy, which eliminated the therapeutic effect of naringin on hepatic steatosis. Conclusion and Implications: These results demonstrate that TFEB-mediated lysosomal biogenesis and subsequent lipophagy play essential roles in the ability of naringin to mitigate hepatic steatosis and suggest that naringin is a promising drug for treating or relieving NAFLD.

scholarly journals Integrated gut–liver-on-a-chip platform as an in vitro human model of non-alcoholic fatty liver disease

2020 ◽  
Author(s):  
Jiandong Yang ◽  
Yoshikazu Hirai ◽  
Kei Iida ◽  
Shinji Ito ◽  
Marika Trumm ◽  
...  
Keyword(s):  
Liver Disease ◽  
Fatty Liver ◽  
Fatty Liver Disease ◽  
Cellular Response ◽  
Liver Cells ◽  
Human Model ◽  
Gene Expressions ◽  
Alcoholic Fatty Liver ◽  
Alcoholic Fatty Liver Disease

AbstractNon-alcoholic fatty liver disease (NAFLD) afflicts a large percentage of the population, but no effective treatments have been established so far because of the unsuitability of in vitro assays and experimental models using animals. By co-culturing human gut and liver cell lines interconnected via microfluidics for a closed circulation loop, we created a gut–liver-on-a-chip (iGLC) platform as an in vitro human model of the gut–liver axis (GLA) for the initiation and progression of NAFLD. Microscopic high-content analysis followed by mRNA sequencing showed that co-culturing the gut and liver cells significantly affected each cell type compared to culturing them separately. NAFLD-inducing free fatty acids (FFAs) accumulated in the gut cells and elevated gene expressions associated with retinol metabolism and glucuronidation. The FFA-treated liver cells accumulated intracellular lipid droplets and showed an increase in gene expressions associated with a cellular response to copper ions and endoplasmic reticulum stress. As an in vitro human GLA model, the iGLC platform may serve as an alternative to animal experiments for investigating NAFLD mechanisms.

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