Computational Hypothesis: How Intra-Hepatic Functional Heterogeneity May Influence the Cascading Progression of Free Fatty Acid-Induced Non-Alcoholic Fatty Liver Disease (NAFLD)

Abstract

Non-Alcoholic Fatty Liver Disease (NAFLD) is the most common type of chronic liver disease in developed nations, affecting around 25% of the population. Elucidating the factors causing NAFLD in individual patients to progress in different rates and to different degrees of severity, is a matter of active medical research. Here, we aim to provide evidence that the intra-hepatic heterogeneity of rheological, metabolic and tissue-regenerating capacities plays a central role in disease progression. We developed a generic mathematical model that constitutes the liver as ensemble of small liver units differing in their capacities to metabolize potentially cytotoxic free fatty acids (FFAs) and to repair FFA-induced cell damage. Transition from simple steatosis to more severe forms of NAFLD is described as self-amplifying process of cascading liver failure, which, to stop, depends essentially on the distribution of functional capacities across the liver. Model simulations provided the following insights: (1) A persistently high plasma level of FFAs is sufficient to drive the liver through different stages of NAFLD; (2) Presence of NAFLD amplifies the deleterious impact of additional tissue-damaging hits; and (3) Coexistence of non-steatotic and highly steatotic regions is indicative for the later occurrence of severe NAFLD stages.

Quantifying Fat Zonation in Liver Lobules: An IntegratedMultiscale In-silico Model Combining DisturbedMicroperfusion and Fat Metabolism via aContinuum-Biomechanical Bi-scale, Tri-phasic Approach

“…Furthermore, they integrated heterogeneity using areas of different metabolic capacity, as reflected by differences in perfusion distribution. Heterogeneity itself turned out to be a risk factor since metabolic underperformances must be compensated by metabolic overperformance in another area, rendering that area vulnerable to further damage (Holzhütter and Berndt, 2021). The homogenized continuum biomechanical model presented here is a further modification of the computational models reported recently.…”

Quantifying fat zonation in liver lobules: an integrated multiscale in silico model combining disturbed microperfusion and fat metabolism via a continuum biomechanical bi-scale, tri-phasic approach

“…Furthermore, they integrated heterogeneity using areas of different metabolic capacity, as reflected by differences in perfusion distribution. Heterogeneity itself turned out to be a risk factor since metabolic underperformances must be compensated by metabolic overperformance in another area, rendering that area vulnerable to further damage (Holzhütter and Berndt 2021 ).…”

Applications of Quantitative Systems Pharmacology (QSP) in Drug Development for NAFLD and NASH and Its Regulatory Application

“…Neither of these QSP models included representations of lipotoxicity, inflammation, fibrosis, or NASH biomarkers or the primary histologic endpoints of NAS and stage of fibrosis. Holzhutter and Berndt also developed a QSP model of zonal influences on hepatic steatosis ( 27 ); this model also includes hepatocellular death as a consequence of lipid accumulation. It does not, however, include representations of inflammation, fibrosis, or NASH biomarkers.…”