A mathematical model of in vitro hepatocellular cholesterol and lipoprotein metabolism for hyperlipidemia therapy

Yuri Efremov; Anastasia Ermolaeva; Georgiy Vladimirov; Susanna Gordleeva; Andrey Svistunov; Alexey Zaikin; Peter Timashev

doi:10.1371/journal.pone.0264903

A mathematical model of in vitro hepatocellular cholesterol and lipoprotein metabolism for hyperlipidemia therapy

PLoS One. 2022 Jun 3;17(6):e0264903. doi: 10.1371/journal.pone.0264903. eCollection 2022.

Authors

Yuri Efremov^{1

2}, Anastasia Ermolaeva^{2

3}, Georgiy Vladimirov¹, Susanna Gordleeva^{3

4}, Andrey Svistunov⁵, Alexey Zaikin^{3

6

7

8}, Peter Timashev^{1

2

9}

Affiliations

¹ Institute for Regenerative Medicine, Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia.
² World-Class Research Center "Digital Biodesign and Personalized Healthcare", Sechenov University, Moscow, Russia.
³ Lobachevsky State University of Nizhny Novgorod, Nizhny Novgorod, Russia.
⁴ Neuroscience and Cognitive Technology Laboratory, Center for Technologies in Robotics and Mechatronics Components, Innopolis University, Innopolis, Russia.
⁵ Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia.
⁶ Department of Mathematics, University College London, London, United Kingdom.
⁷ Institute for Women's Health, University College London, London, United Kingdom.
⁸ Centre for Analysis of Complex Systems, Sechenov University, Moscow, Russia.
⁹ Chemistry Department, Lomonosov Moscow State University, Moscow, Russia.

Abstract

Cardiovascular diseases associated with high cholesterol (hypercholesterolemia) and low-density lipoproteins (LDL) levels are significant contributors to total mortality in developing and developed countries. Mathematical modeling of LDL metabolism is an important step in the development of drugs for hypercholesterolemia. The aim of this work was to develop and to analyze an integrated mathematical model of cholesterol metabolism in liver cells and its interaction with two types of drugs, statins and PCSK9 inhibitors. The model consisted of 21 ordinary differential equations (ODE) describing cholesterol biosynthesis and lipoprotein endocytosis in liver cells in vitro. The model was tested for its ability to mimic known biochemical effects of familial hypercholesterolemia, statin therapy, and PCSK9 inhibitors. The model qualitatively reproduced the well-known biology of cholesterol regulation, which confirms its potential for minimizing cellular research in initial testing of new drugs for cardiology.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antibodies, Monoclonal / therapeutic use
Anticholesteremic Agents* / therapeutic use
Carcinoma, Hepatocellular* / drug therapy
Cholesterol
Cholesterol, LDL / metabolism
Humans
Hydroxymethylglutaryl-CoA Reductase Inhibitors* / pharmacology
Hydroxymethylglutaryl-CoA Reductase Inhibitors* / therapeutic use
Hypercholesterolemia* / drug therapy
Hyperlipidemias* / drug therapy
Lipoproteins
Liver Neoplasms* / drug therapy
Models, Theoretical
PCSK9 Inhibitors
Proprotein Convertase 9 / metabolism

Substances

Antibodies, Monoclonal
Anticholesteremic Agents
Cholesterol, LDL
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Lipoproteins
PCSK9 Inhibitors
Cholesterol
PCSK9 protein, human
Proprotein Convertase 9

Associated data

figshare/10.6084/m9.figshare.c.5815217.v1

Grants and funding

This work was financed by the Ministry of Science and Higher Education of the Russian Federation within the framework of state support for the creation and development of World-Class Research Centers “Digital biodesign and personalized healthcare” No 075-15-2020-926. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.