LiverSex computational model : sexual aspects in hepatic metabolism and abnormalities
ID Cvitanović Tomaš, Tanja (Author), ID Urlep, Žiga (Author), ID Moškon, Miha (Author), ID Mraz, Miha (Author), ID Rozman, Damjana (Author)

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The liver is to date the best example of a sexually dimorphic non-reproductive organ. Over 1000 genes are differentially expressed between sexes indicating that female and male livers are two metabolically distinct organs. The spectrum of liver diseases is broad and is usually prevalent in one or the other sex, with different contributing genetic and environmental factors. It is thus difficult to predict individual's disease outcomes and treatment options. Systems approaches including mathematical modelling can aid importantly in understanding the multifactorial liver disease etiology leading towards tailored diagnostics, prognostics and therapy. The currently established computational models of hepatic metabolism that have proven to be essential for understanding of non-alcoholic fatty liver disease (NAFLD) and hepatocellular carcinoma (HCC) are limited to the description of gender-independent response or reflect solely the response of the males. Herein we present LiverSex, the first sex-based multi-tissue and multi-level liver metabolic computational model. The model was constructed based on in silico liver model SteatoNet and the object-oriented modelling. The crucial factor in adaptation of liver metabolism to the sex is the inclusion of estrogen and androgen receptor responses to respective hormones and the link to sex-differences in growth hormone release. The model was extensively validated on literature data and experimental data obtained from wild type C57BL/6 mice fed with regular chow and western diet. These experimental results show extensive sex-dependent changes and could not be reproduced in silico with the uniform model SteatoNet. LiverSex represents the first large-scale liver metabolic model, which allows a detailed insight into the sex-dependent complex liver pathologies, and how the genetic and environmental factors interact with the sex in disease appearance and progression. We used the model to identify the most important sex-dependent metabolic pathways, which are involved in accumulation of triglycerides representing initial steps of NAFLD. We identified PGC1A, PPARα, FXR, and LXR as regulatory factors that could become important in sex-dependent personalized treatment of NAFLD.

Keywords:sexual dimorphism, hepatic metabolism, systems medicine, large-scale metabolic model, NAFLD, liver
Work type:Article
Typology:1.01 - Original Scientific Article
Organization:MF - Faculty of Medicine
FRI - Faculty of Computer and Information Science
Publication status:Published
Publication version:Version of Record
Number of pages:12 str.
Numbering:Vol. 9, art. 360
PID:20.500.12556/RUL-128735 This link opens in a new window
ISSN on article:1664-042X
DOI:10.3389/fphys.2018.00360 This link opens in a new window
COBISS.SI-ID:33711833 This link opens in a new window
Publication date in RUL:26.07.2021
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Title:Frontiers in physiology
Shortened title:Front. physiol.
Publisher:Frontiers Research Foundation
COBISS.SI-ID:1218939 This link opens in a new window


License:CC BY 4.0, Creative Commons Attribution 4.0 International
Description:This is the standard Creative Commons license that gives others maximum freedom to do what they want with the work as long as they credit the author.
Licensing start date:12.04.2018

Secondary language

Keywords:spolni dimorfizem, hepatični metabolizem, sistemska medicina, obsežni presnovni model, NAFLD, jetra


Funder:EC - European Commission
Funding programme:FP7
Project number:305033
Name:Coordinating Action Systems Medicine – Implementation of Systems Medicine across Europe

Funder:ARRS - Agencija za raziskovalno dejavnost Republike Slovenije
Project number:P1-0390
Name:Funkcijska genomika in biotehnologija za zdravje

Funder:ARRS - Agencija za raziskovalno dejavnost Republike Slovenije
Project number:P2-0359
Name:Vseprisotno računalništvo

Funder:ARRS - Agencija za raziskovalno dejavnost Republike Slovenije

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