Mathematical Models for Cholesterol Metabolism and Transport

Cholesterol is an essential component of eukaryotic cellular membranes. It is also an important precursor for making other molecules needed by the body. Cholesterol homeostasis plays an essential role in human health. Having high cholesterol can increase the chances of getting heart disease. As a result of the risks associated with high cholesterol, it is imperative that studies are conducted to determine the best course of action to reduce whole body cholesterol levels. Mathematical models can provide direction on this. By examining existing models, the suitable reactions or processes for drug targeting to lower whole-body cholesterol can be determined. This paper examines existing models in the literature that, in total, cover most of the processes involving cholesterol metabolism and transport, including: the absorption of cholesterol in the intestine; the cholesterol biosynthesis in the liver; the storage and transport of cholesterol between the intestine, the liver, blood vessels, and peripheral cells. The findings presented in these models will be discussed for potential combination to form a comprehensive model of cholesterol within the entire body, which is then taken as an in-silico patient for identifying drug targets, screening drugs, and designing intervention strategies to regulate cholesterol levels in the human body.

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Abnormal brain cholesterol homeostasis in Alzheimer’s disease—a targeted metabolomic and transcriptomic study

npj Aging and Mechanisms of Disease ◽

10.1038/s41514-021-00064-9 ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Vijay R. Varma ◽

H. Büşra Lüleci ◽

Anup M. Oommen ◽

Sudhir Varma ◽

Chad T. Blackshear ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Brain Tissue ◽

Cholesterol Metabolism ◽

Cholesterol Biosynthesis ◽

Cholesterol Homeostasis ◽

Transcriptomic Data ◽

Brain Cholesterol ◽

Cholesterol Levels

AbstractThe role of brain cholesterol metabolism in Alzheimer’s disease (AD) remains unclear. Peripheral and brain cholesterol levels are largely independent due to the impermeability of the blood brain barrier (BBB), highlighting the importance of studying the role of brain cholesterol homeostasis in AD. We first tested whether metabolite markers of brain cholesterol biosynthesis and catabolism were altered in AD and associated with AD pathology using linear mixed-effects models in two brain autopsy samples from the Baltimore Longitudinal Study of Aging (BLSA) and the Religious Orders Study (ROS). We next tested whether genetic regulators of brain cholesterol biosynthesis and catabolism were altered in AD using the ANOVA test in publicly available brain tissue transcriptomic datasets. Finally, using regional brain transcriptomic data, we performed genome-scale metabolic network modeling to assess alterations in cholesterol biosynthesis and catabolism reactions in AD. We show that AD is associated with pervasive abnormalities in cholesterol biosynthesis and catabolism. Using transcriptomic data from Parkinson’s disease (PD) brain tissue samples, we found that gene expression alterations identified in AD were not observed in PD, suggesting that these changes may be specific to AD. Our results suggest that reduced de novo cholesterol biosynthesis may occur in response to impaired enzymatic cholesterol catabolism and efflux to maintain brain cholesterol levels in AD. This is accompanied by the accumulation of nonenzymatically generated cytotoxic oxysterols. Our results set the stage for experimental studies to address whether abnormalities in cholesterol metabolism are plausible therapeutic targets in AD.

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Inhibition of cholesterol biosynthesis through RNF145-dependent ubiquitination of SCAP

eLife ◽

10.7554/elife.28766 ◽

2017 ◽

Vol 6 ◽

Cited By ~ 19

Author(s):

Li Zhang ◽

Prashant Rajbhandari ◽

Christina Priest ◽

Jaspreet Sandhu ◽

Xiaohui Wu ◽

...

Keyword(s):

Ubiquitin Ligase ◽

Plasma Cholesterol ◽

Cholesterol Biosynthesis ◽

Cholesterol Homeostasis ◽

High Cholesterol Diet ◽

High Cholesterol ◽

Cholesterol Levels ◽

Expression Of Genes ◽

Lysine Residues ◽

Genetic Deletion

Cholesterol homeostasis is maintained through concerted action of the SREBPs and LXRs. Here, we report that RNF145, a previously uncharacterized ER membrane ubiquitin ligase, participates in crosstalk between these critical signaling pathways. RNF145 expression is induced in response to LXR activation and high-cholesterol diet feeding. Transduction of RNF145 into mouse liver inhibits the expression of genes involved in cholesterol biosynthesis and reduces plasma cholesterol levels. Conversely, acute suppression of RNF145 via shRNA-mediated knockdown, or chronic inactivation of RNF145 by genetic deletion, potentiates the expression of cholesterol biosynthetic genes and increases cholesterol levels both in liver and plasma. Mechanistic studies show that RNF145 triggers ubiquitination of SCAP on lysine residues within a cytoplasmic loop essential for COPII binding, potentially inhibiting its transport to Golgi and subsequent processing of SREBP-2. These findings define an additional mechanism linking hepatic sterol levels to the reciprocal actions of the SREBP-2 and LXR pathways.

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Pharmacological activation of LXR in utero directly influences ABC transporter expression and function in mice but does not affect adult cholesterol metabolism

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.90597.2008 ◽

2008 ◽

Vol 295 (6) ◽

pp. E1341-E1348 ◽

Cited By ~ 12

Author(s):

E. M. E. van Straten ◽

N. C. A. Huijkman ◽

J. F. W. Baller ◽

F. Kuipers ◽

T. Plösch

Keyword(s):

Fetal Development ◽

Cholesterol Metabolism ◽

In Utero ◽

Cholesterol Homeostasis ◽

High Cholesterol Diet ◽

Cholesterol Diet ◽

High Cholesterol ◽

High Fat ◽

Hepatic Expression ◽

Cholesterol Levels

Cholesterol is critical for several cellular functions and essential for normal fetal development. Therefore, its metabolism is tightly controlled during all life stages. The liver X receptors-α (LXRα; NR1H3) and -β (LXRβ; NR1H2) are nuclear receptors that are of key relevance in coordinating cholesterol and fatty acid metabolism. The aim of this study was to elucidate whether fetal cholesterol metabolism can be influenced in utero via pharmacological activation of LXR and whether this would have long-term effects on cholesterol homeostasis. Administration of the LXR agonist T0901317 to pregnant mice via their diet (0.015% wt/wt) led to induced fetal hepatic expression levels of the cholesterol transporter genes Abcg5/g8 and Abca1, higher plasma cholesterol levels, and lower hepatic cholesterol levels compared with controls. These profound changes during fetal development did not affect cholesterol metabolism in adulthood nor did they influence coping with a high-fat/high-cholesterol diet. This study shows that the LXR system is functional in fetal mice and susceptible to pharmacological activation. Despite massive changes in fetal cholesterol metabolism, regulatory mechanisms involved in cholesterol metabolism return to a “normal” state in offspring and allow coping with a high-fat/high-cholesterol diet.

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Impact of Cholesterol Metabolism in Immune Cell Function and Atherosclerosis

Nutrients ◽

10.3390/nu12072021 ◽

2020 ◽

Vol 12 (7) ◽

pp. 2021 ◽

Cited By ~ 1

Author(s):

María Aguilar-Ballester ◽

Andrea Herrero-Cervera ◽

Ángela Vinué ◽

Sergio Martínez-Hervás ◽

Herminia González-Navarro

Keyword(s):

Immune Cells ◽

Immune Cell ◽

De Novo ◽

Cholesterol Metabolism ◽

The Body ◽

Cholesterol Homeostasis ◽

Hematopoietic Stem ◽

Regulatory Pathways ◽

Cholesterol Levels ◽

Atherosclerosis Development

Cholesterol, the most important sterol in mammals, helps maintain plasma membrane fluidity and is a precursor of bile acids, oxysterols, and steroid hormones. Cholesterol in the body is obtained from the diet or can be de novo synthetized. Cholesterol homeostasis is mainly regulated by the liver, where cholesterol is packed in lipoproteins for transport through a tightly regulated process. Changes in circulating lipoprotein cholesterol levels lead to atherosclerosis development, which is initiated by an accumulation of modified lipoproteins in the subendothelial space; this induces significant changes in immune cell differentiation and function. Beyond lesions, cholesterol levels also play important roles in immune cells such as monocyte priming, neutrophil activation, hematopoietic stem cell mobilization, and enhanced T cell production. In addition, changes in cholesterol intracellular metabolic enzymes or transporters in immune cells affect their signaling and phenotype differentiation, which can impact on atherosclerosis development. In this review, we describe the main regulatory pathways and mechanisms of cholesterol metabolism and how these affect immune cell generation, proliferation, activation, and signaling in the context of atherosclerosis.

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TDP-43 mediates SREBF2-regulated gene expression required for oligodendrocyte myelination

The Journal of Cell Biology ◽

10.1083/jcb.201910213 ◽

2021 ◽

Vol 220 (9) ◽

Author(s):

Wan Yun Ho ◽

Jer-Cherng Chang ◽

Kenneth Lim ◽

Amaury Cazenave-Gassiot ◽

Aivi T. Nguyen ◽

...

Keyword(s):

Cholesterol Metabolism ◽

Cholesterol Biosynthesis ◽

Cholesterol Homeostasis ◽

Cholesterol Levels ◽

The Central Nervous System ◽

Cholesterol Supplementation ◽

Regulated Gene Expression ◽

Lateral Sclerosis

Cholesterol metabolism operates autonomously within the central nervous system (CNS), where the majority of cholesterol resides in myelin. We demonstrate that TDP-43, the pathological signature protein for amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), influences cholesterol metabolism in oligodendrocytes. TDP-43 binds directly to mRNA of SREBF2, the master transcription regulator for cholesterol metabolism, and multiple mRNAs encoding proteins responsible for cholesterol biosynthesis and uptake, including HMGCR, HMGCS1, and LDLR. TDP-43 depletion leads to reduced SREBF2 and LDLR expression, and cholesterol levels in vitro and in vivo. TDP-43–mediated changes in cholesterol levels can be restored by reintroducing SREBF2 or LDLR. Additionally, cholesterol supplementation rescues demyelination caused by TDP-43 deletion. Furthermore, oligodendrocytes harboring TDP-43 pathology from FTD patients show reduced HMGCR and HMGCS1, and coaggregation of LDLR and TDP-43. Collectively, our results indicate that TDP-43 plays a role in cholesterol homeostasis in oligodendrocytes, and cholesterol dysmetabolism may be implicated in TDP-43 proteinopathies–related diseases.

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Contemporary aspects of cholesterol metabolism in cattle.

Bulletin of NSAU (Novosibirsk State Agrarian University) ◽

10.31677/2072-6724-2021-59-2-91-105 ◽

2021 ◽

pp. 91-105

Author(s):

O. I. Sebezhko ◽

K. N. Narozhnykh ◽

O. S. Korotkevich ◽

D. A. Alexandrova ◽

I. N. Morozov

Keyword(s):

Cholesterol Metabolism ◽

Phenotypic Variability ◽

Cholesterol Biosynthesis ◽

Molecular Genetic ◽

Deficiency Syndrome ◽

The Body ◽

Cholesterol Homeostasis ◽

High Density Lipoproteins ◽

Nucleotide Polymorphisms ◽

Endogenous Synthesis

The literature review presents the current understanding of cholesterol metabolism occurring under physiological conditions. The homeostasis of cholesterol in the body is determined by its endogenous synthesis, the transition to the cell from plasma as part of low-densitylipoproteins( LDL), the release of their cells as part of high-density lipoproteins (HDL). The molecular-genetic mechanisms of regulation of cholesterol homeostasis are described in detail. The genes for cholesterol biosynthesis in major multicellular animals were inherited from their last common eukaryotic ancestor and are evolutionarily conserved for cholesterol biosynthesis. Non-coding variants of singlenucleotide polymorphisms can significantly contribute to the phenotypic variability of cholesterol, and missense variants that lead to the replacement of amino acids in proteins can have a significant effect on the phenotypic variability. The modern aspects of cholesterol homeostasis in cattle are formed and sufficiently fully presented. During absence of exogenous intake, the balance of cholesterol in cattle is maintained by endogenous synthesis, occurring mainly in the liver, the intake of lipoproteins, as well as reverse transport mechanisms. This review gives an idea that the stability of homeostasis can be achieved only with the complex interaction of all systems (transport, enzyme, receptor) involved in this process. The analysis of the latest scientific works concerning the problem of the content and regulation of cholesterol in cow’s milk is presented. Significant single-nucleotide polymorphisms localized in the ACAT2, LDLR, DGAT, and AGPAT1 genes involved in the exchange of cholesterol in the liver or its transport and associated with the level of cholesterol in milk are described. Part of the review is devoted to cholesterol deficiency syndrome in Holstein cattle (HCD). Modern data on the prevalence, molecular and genetic basis, clinical and laboratory manifestations of the syndrome are presented.

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Terapi Hiperkolesterol pada Mencit (Mus musculus) strain Balb/C Betina Umur 2 Bulan Menggunakan Sari Bawang Putih

Jurnal Biota ◽

10.19109/biota.v3i2.1313 ◽

2017 ◽

Vol 3 (2) ◽

pp. 71

Author(s):

Muhammad Sungging Pradana ◽

Imam Suryanto

Keyword(s):

Cardiovascular Disease ◽

Active Agent ◽

The Body ◽

Blood Cholesterol ◽

High Cholesterol ◽

Synthetic Drugs ◽

Cholesterol Levels ◽

Increase Risk ◽

Group 3 ◽

Strip Test

Cholesterol is a waxy substance which is mainly made in the body. Cholesterol can provide benefits. However, having too much cholesterol in the blood can increase risk of cardiovascular disease. Prevention and treatment of cardiovascular disease can be done by taking synthetic drugs such as statin. Due to side effects of synthetic drugs, it is necessary to substitute synthetic drugs with herbal plant and some natural component in these plants. The important ones is garlic. Garlic contain organosulphur compounds such as diallyldisulphide (DADS), dipropyldisulphide (DPDS), diallytrisulphide (DATS) and dipropyltrisulphide (DPTS) which have anti artherogenic effects. Garlic also have active agent allicin, can reduce the levels of cholesterol. This research was conducted at the Experimental Animal Enclosure Installation, Center for Veterinary Farma Surabaya with 3 experimental groups. Animals used in this research were female mice 2 months old were feeding with high cholesterol feed such as fried offal of chicken twice a day as much 0,5 cc/ day every 3 days. On the 3rd day, the levels of cholesterol in each group was examined. On the 4th day, mice in group 3 were given 1cc of garlic juice. 1 hour later mice was examined blood cholesterol using Strip Test Easy Touch GCU. The results through T-paired test on SPSS stated that (p < 0,05), it means there is influence between the 3 treatment of mice. This results it can be concluded that the provision of garlic juice can reduced blood cholesterol levels in mice after fed with high cholesterol.

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Natural Dietary Phytosterols

Journal of AOAC International ◽

10.5740/jaoacint.sgeracette ◽

2015 ◽

Vol 98 (3) ◽

pp. 679-684 ◽

Cited By ~ 26

Author(s):

Susan B Racette ◽

Xiaobo Lin ◽

Lina Ma ◽

Richard E Ostlund, Jr

Keyword(s):

Ldl Cholesterol ◽

Cholesterol Metabolism ◽

Disease Risk ◽

Cholesterol Biosynthesis ◽

Cholesterol Absorption ◽

Absorption Efficiency ◽

Whole Body ◽

Natural Diet ◽

Cholesterol Excretion ◽

Heart Disease Risk

Abstract Most clinical phytosterol studies are performed by adding purified supplements to smaller phytosterol amounts present in the natural diet. However, natural dietary phytosterols themselves may also have important effects on cholesterol metabolism. Epidemiological work using food frequency questionnaires to estimate dietary intake suggest that extremes of normal consumption may be associated with 3–14% changes in LDL cholesterol. Standardized food databases do not have enough phytosterol values to allow calculation of phytosterol intake for individuals outside of specialized studies. Natural diets contain phytosterol amounts ranging from less than 60 mg/2000 kcal to over 500 mg/2000 kcal. Physiological studies in which whole body cholesterol metabolism is investigated show large effects of natural dietary phytosterols on cholesterol absorption efficiency, cholesterol biosynthesis and cholesterol excretion which exceed the magnitude of changes in LDL cholesterol. The dual effects of natural phytosterols on both LDL-C and whole body cholesterol metabolism need to be considered in relating them to potential protection from coronary heart disease risk.

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27-Hydroxycholesterol Promotes the Transfer of Astrocyte-Derived Cholesterol to Neurons in Co-cultured SH-SY5Y Cells and C6 Cells

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2020.580599 ◽

2020 ◽

Vol 8 ◽

Author(s):

Yushan Wang ◽

Xiaona Zhang ◽

Tao Wang ◽

Wen Liu ◽

Lijing Wang ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Cholesterol Metabolism ◽

Feedback Mechanism ◽

Cholesterol Homeostasis ◽

Membrane Cholesterol ◽

C6 Cells ◽

Cholesterol Accumulation ◽

Cholesterol Levels ◽

Related Proteins ◽

The Brain

Abnormality in cholesterol homeostasis in the brain is a feature of Alzheimer’s disease (AD). 27-Hydroxycholesterol (27-OHC) has been identified as a possible biomarker of AD, but its effects on cholesterol metabolism have not been fully characterized. This study was aimed to investigate the impacts of 27-OHC on cholesterol metabolism in nerve cells. SH-SY5Y cells and C6 cells were co-cultured and treated with 5, 10, and 20 μM 27-OHC for 24 h. Results showed that 27-OHC decreased cholesterol levels and up-regulated the expression of transport-related proteins in C6 cells. In SH-SY5Y cells, 27-OHC increased cholesterol accumulation, especially on plasma membrane (PM), which was consistent with the up-regulation of expressions of cholesterol endocytosis receptors, lipid raft-related proteins, and cholesterol esterase. Simultaneously, accumulation of membrane cholesterol promoted cholesterol conversion to 24S-OHC by CYP46A1(24S-hydroxylase) transfer from the endoplasmic reticulum (ER) to PM. Besides, Aβ levels were elevated in SH-SY5Y cells after 27-OHC treatment. Our results suggest that 27-OHC motivates the transfer of astrocyte-derived cholesterol to neurons. Although there exists a feedback mechanism that excessive cholesterol promotes its conversion to 24S-OHC, the increased cholesterol induced by 27-OHC could not be wholly offset in neurons.

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Cholesterol in pregnancy: a review of knowns and unknowns

Obstetric Medicine ◽

10.1258/om.2011.110003 ◽

2011 ◽

Vol 4 (4) ◽

pp. 147-151 ◽

Cited By ~ 27

Author(s):

Änne Bartels ◽

Keelin O'Donoghue

Keyword(s):

Cardiovascular Disease ◽

Vitamin D ◽

Fetal Development ◽

Plasma Cholesterol ◽

Adult Population ◽

The Body ◽

High Cholesterol ◽

Cholesterol Levels ◽

Growing Body ◽

In Pregnancy

Cholesterol forms part of every cell in the human body, and also helps make and metabolize hormones, bile acids and vitamin D. Human plasma cholesterol levels are determined by production in the liver and by dietary intake. Lipoproteins carry cholesterol around the body, and facilitate it crossing the placenta. Cholesterol is carefully monitored in the non-pregnant adult population, where its association with atherosclerosis and cardiovascular disease is well understood. Although it is known that cholesterol rises in pregnancy, at present it is not routinely measured or treated. The effects of maternal high cholesterol on pregnancy and on fetal development are not yet fully understood. However, a growing body of evidence from animal and human studies suggests adverse consequences of high cholesterol levels in pregnancy.

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