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

Hermann-Georg Holzhütter,Nikolaus Berndt

doi:10.3390/cells10030578

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.

Highlights

Non-Alcoholic Fatty Liver Disease (NAFLD) is the most common type of chronic liver disease in developed nations, where it affects around 25% of the population [1]
Materials and Methods—Mathematical Model The mathematical model used for our disease simulations consists of three modules: (1) The hemodynamic module describes the blood flow within the liver sinusoids as was previously described [27]; (2) the metabolic module describes the cellular turnover of free fatty acids (FFAs) and TAG; and (3) the damage-repair module describes the FFA-induced damage of hepatocytes and tissue repair
Simulations of FFA-induced NAFLD progression of the whole liver were performed by numerical solution of the coupled Equations (1)–(3) for each liver units (LUs)

Summary

Introduction

Non-Alcoholic Fatty Liver Disease (NAFLD) is the most common type of chronic liver disease in developed nations, where it affects around 25% of the population [1]. NAFLD starts with simple steatosis and may progress to severe liver diseases like cirrhosis or hepatocellular carcinoma (HCC). Insulin resistance of the adipose tissue increases the release of free fatty acids (FFAs) into the blood [2] and promotes the uptake of FFAs into liver, kidney, heart and other organs using FFAs as preferred energy-delivering substrates. Conversion of excess fatty acids into complex lipids serves as a detoxification mechanism [3,4,5,6] as elevated levels of FFAs and some of their reaction products may cause cell damage [7]. As shown in mice with downregulated diacyglycerol acyl transferase 2 (DGAT2), a rate-limiting enzyme of TAG synthesis, inhibition of TAG synthesis improved hepatic steatosis but exacerbated liver damage exerted by elevated levels of potentially cytotoxic FFAs [6]. If the FFA challenge persists, a quasi-stationary balance between damage and tissue regeneration is established, which over the time may slowly shift towards fewer and fewer vital hepatocytes and more and more non-functional fibrotic lesions [9]

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