LiverSex Computational Model: Sexual Aspects in Hepatic Metabolism and Abnormalities

Abstract

The liver is to date the best example of a sexually dimorphic non-reproductive organ. Over 1,000 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 modeling can aid importantly in understanding the multifactorial liver disease etiology leading toward 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 modeling. 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.

Prevalence of prediabetes and type 2 diabetes in children with obesity and increased transaminases in European German‐speaking countries. Analysis of the APV initiative

“…Further, the role of NAFLD as a sexual dimorphic disease is also supported by animal models that demonstrate a disposition of male individuals to more advanced fatty liver disease compared to females that is linked to a state of subclinical inflammation and increased hepatic morbidity . A study applying a computational model concluded that due to sex‐specific metabolic demands, female and male livers are metabolically diverse and therefore differently regulated . In addition, a recent review stated that most published clinical and epidemiological studies fail to examine sex differences appropriately' and suggested to consider sex differences, sex hormones, age and other reproductive information in clinical investigation and gene association studies of NAFLD 'in order to fill current gaps and implement precision medicine for patients with NAFLD' …”

“…46 A study applying a computational model concluded that due to sex-specific metabolic demands, female and male livers are metabolically diverse and therefore differently regulated. 47 In addition, a recent review stated that most published clinical and epidemiological studies fail to examine sex differences appropriately' and suggested to consider sex differences, sex hormones, age and other reproductive information in clinical investigation and gene association studies of NAFLD 'in order to fill current gaps and implement precision medicine for patients with NAFLD'. 46 There are some strengths and limitations that need to be acknowledged.…”

Sex Differences in Nonalcoholic Fatty Liver Disease: State of the Art and Identification of Research Gaps

“…A recent mouse computational model concluded that female and male livers are metabolically distinct organs . Simulating transcriptional regulation of estradiol, androgen, and sex‐specific patterns of growth hormone secretion, the modeling approach identified genes which regulate sex‐specific effects on metabolism pertaining to hepatic triglyceride accumulation (e.g., triglyceride export, fatty acid [FA] oxidation): peroxisome proliferator–activated receptor gamma ( PPAR‐γ ) coactivator 1‐α, farnesoid X receptor ( FXR ), liver X receptor, and PPAR‐ α . These regulators are currently being investigated as therapeutic targets in NASH, stressing the importance of examining sex differences in the efficacy and safety of drugs that target these genes.…”

Computational Modelling of Liver Metabolism and its Applications in Research and the Clinics

“…70 Since the number of parameters that need to be incorporated into the model is small, this prevents several problems, such as parameter estimation problems as well as the problem of model overfitting. On the other hand parameters that are used at the end allow us to easily adapt the models to specific data, such as personalised or gender specific data as described in 20 .…”