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Revisiting Human Cholesterol Synthesis and Absorption: The Reciprocity Paradigm and its Key Regulators

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  • Published:
Lipids

Abstract

Hypercholesterolemia is a major risk factor for cardiovascular disease. Cholesterol homeostasis in the body is governed by the interplay between absorption, synthesis, and excretion or conversion of cholesterol into bile acids. A reciprocal relationship between cholesterol synthesis and absorption is known to regulate circulating cholesterol in response to dietary or therapeutic interventions. However, the degree to which these factors affect synthesis and absorption and the extent to which one vector shifts in response to the other are not thoroughly understood. Also, huge inter-individual variability exists in the manner in which the two systems act in response to any cholesterol-lowering treatment. Various factors are known to account for this variability and in light of recent experimental advances new players such as gene–gene interactions, gene–environmental effects, and gut microbiome hold immense potential in offering an explanation to the complex traits of inter-individual variability in human cholesterol metabolism. In this context, the objective of the present review is to provide an overview on cholesterol metabolism and discuss the role of potential factors such as genetics, epigenetics, epistasis, and gut microbiome, as well as other regulators in modulating cholesterol metabolism, especially emphasizing the reciprocal relationship between cholesterol synthesis and absorption. Furthermore, an evaluation of the implications of this push–pull mechanism on cholesterol-lowering strategies is presented.

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Abbreviations

ABC:

Adenosine triphosphate protein binding cassette transporter

ABCG5/G8:

ABC, subfamily G, members 5/8

ABCA1:

Adenosine triphosphate protein binding cassette transporter A1

ACAT2:

Acetyl-CoA acetyltransferase

apoA1:

Apolipoprotein A1

apoB48:

Apolipoprotein B48

apoE:

Apolipoprotein E

5AZA:

5-Aza-2′-deoxycytidine

CBP/p300:

Histone acetylase cyclic adenosine monophosphate responsive element binding protein 1-binding protein

CE:

Cholesteryl ester(s)

CEL:

Carboxyl ester lipase

CVD:

Cardiovascular disease

CYP7A1:

Cholesterol 7α-hydroxylase

CYP8B:

Sterol 12α-hydroxylase

DI:

Deuterium incorporation

FSR:

Fractional synthesis rate

FXR:

Farnesoid X receptor

GWAS:

Genome-wide association studies

HDAC3:

Histone deacetylase 3

HDL-C:

High density lipoprotein cholesterol

HMG-CoA:

3-Hydroxy-3-methylglutaryl-coenzyme A

HMGCS:

3-Hydroxy-3-methylglutaryl-coenzyme A synthase

HMGCR:

3-Hydroxy-3-methylglutaryl-coenzyme A reductase

LDL-C:

Low density lipoprotein cholesterol

LDLr:

Low density lipoprotein receptor

LIPC:

Hepatic triglyceride lipase

LSS:

Lanosterol synthase

LXR:

Liver X receptor(s)

MIDA:

Mass isotopomer distribution analysis

miRNA:

Micro-ribonucleic acid(s)

MTTP:

Microsomal triglyceride transfer protein

NPC1L1:

Niemann–Pick C1-like 1 protein

PARK2:

Parkin ring between ring family E3 ubiquitin protein ligase

PUFA:

Polyunsaturated fatty acids

SCAP:

SREBP cleavage-activating protein

SCF:

Skp, Cullin, F-box containing complex

SCFA:

Short chain fatty acid(s)

SFA:

Saturated fatty acid(s)

SIRT:

Sirtuin

SNP:

Single nucleotide polymorphisms

SRE:

Sterol response element

SREBP:

Sterol regulatory binding protein

TAG:

Triacylglycerols

TC:

Total cholesterol

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Authors and Affiliations

  1. Human Nutritional Sciences, University of Manitoba, Winnipeg, MB, Canada

    Peter A. S. Alphonse & Peter J. H. Jones

  2. Richardson Centre for Functional Foods and Nutraceuticals (RCFFN), University of Manitoba, 196, Innovation Drive, SmartPark, Winnipeg, MB, R3T 2N2, Canada

    Peter A. S. Alphonse & Peter J. H. Jones

  3. Food Science, University of Manitoba, Winnipeg, MB, Canada

    Peter J. H. Jones

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  1. Peter A. S. Alphonse
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  2. Peter J. H. Jones
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Correspondence to Peter A. S. Alphonse.

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Alphonse, P.A.S., Jones, P.J.H. Revisiting Human Cholesterol Synthesis and Absorption: The Reciprocity Paradigm and its Key Regulators. Lipids 51, 519–536 (2016). https://doi.org/10.1007/s11745-015-4096-7

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  • DOI: https://doi.org/10.1007/s11745-015-4096-7

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