ReviewThe evolution of plasma cholesterol: Direct utility or a “spandrel” of hepatic lipid metabolism?
Section snippets
The biological function of LDL cholesterol
Despite early scepticism, cholesterol is now accepted almost universally as a major contributory factor in atherogenesis [1], [2], [3] and few health issues now provoke more popular discussion, particularly amongst the “chattering classes”, than the cardiovascular risks presented by elevated concentrations of plasma cholesterol. Popular hysteria fuelled by almost endless media coverage has created a modern-day atmosphere in which fear of cholesterol, i.e. cholesterophobia, has been surpassed
VLDL and de novo hepatic lipogenesis (DNHL)
In the absence of any real quantitative information, it was believed for many years that one major function of VLDL was to transport fat, synthesized de novo from carbohydrate in the liver, to adipose tissue for storage as TAG. Thus, in this text-book version, VLDL was considered to form part of the overall process by which excess dietary carbohydrate was converted into stored fat. More recently this view has been questioned [21], [22], [23] on the basis of measurements of DNHL in vivo, and of
Evolutionary approach and animal models
If LDL cholesterol is merely a by-product of VLDL metabolism, then factors which influence hepatic VLDL secretion will obviously contribute to steady-state plasma LDL concentrations. Over the past 30 years, the molecular and physiological aspects of hepatic VLDL production have been studied intensively [8], [9], [19], [30]. Despite this wealth of information, the precise biological functions of VLDL remain unclear. Defining a physiological role for VLDL goes beyond simply stating the obvious:
The spandrel-LDL theory
In 1979, the evolutionary biologists Richard Lewontin and Stephen J. Gould used the architectural term “spandrel” to illustrate the distinction between the evolution of a phenotypic characteristic which conferred a selective advantage by its direct utility and one which merely arose as a necessary by-product of this process [334]. Therefore, the term “spandrel” refers to the adaptive use of a function selected for another purpose. A spandrel may subsequently be co-opted for highly fruitful use
Acknowledgements
We would like to thank the following colleagues for help and advice during the preparation of this manuscript: Esther Lubzens, Nick Myant, Allan Sniderman, Keith Frayn, Fredrik Karpe, Dick van der Horst and Robert Ryan.
References (336)
Thematic review series: the pathogenesis of atherosclerosis. An interpretive history of the cholesterol controversy: part I
J Lipid Res
(2004)Thematic review series: the pathogenesis of atherosclerosis: an interpretive history of the cholesterol controversy, part III: mechanistically defining the role of hyperlipidemia
J Lipid Res
(2005)Thematic review series: the pathogenesis of atherosclerosis. An interpretive history of the cholesterol controversy: part II: the early evidence linking hypercholesterolemia to coronary disease in humans
J Lipid Res
(2005)- et al.
The Oxford vegetarian study: an overview
Am J Clin Nutr
(1999) - et al.
Role of liver in the maintenance of cholesterol and low density lipoprotein homeostasis in different animal species, including humans
J Lipid Res
(1993) - et al.
Fatty acids differentially regulate hepatic cholesteryl ester formation and incorporation into lipoproteins in the liver of the mouse
J Lipid Res
(2002) - et al.
The SREBP pathway: regulation of cholesterol metabolism by proteolysis of a membrane-bound transcription factor
Cell
(1997) - et al.
SREBP in signal transduction: cholesterol metabolism and beyond
Curr Opin Cell Biol
(2007) - et al.
Delayed secretory pathway contributions to VLDL-triglycerides from plasma NEFA. Diet, and de novo lipogenesis in humans
J Lipid Res
(2006) - et al.
Human fatty acid synthesis is reduced after the substitution of dietary starch for sugar
Am J Clin Nutr
(1998)
Hepatic de novo lipogenesis in normoinsulinemic and hyperinsulinemic subjects consuming high-fat, low-carbohydrate and low-fat, high-carbohydrate isoenergetic diets
Am J Clin Nutr
“New” hepatic fat activates PPAR-alpha to maintain glucose, lipid, and cholesterol homeostasis
Cell Metab
Glucose–fatty acid interactions in health and disease
Am J Clin Nutr
Absence of stearoyl-CoA desaturase-1 ameliorates features of the metabolic syndrome in LDLR-deficient mice
J Lipid Res
Chylomicron metabolism in rats: lipolysis, recirculation of triglyceride-derived fatty acids in plasma FFA, and fate of core lipids as analyzed by compartmental modelling
J Lipid Res
Coordinated release of acylation stimulating protein (ASP) and triacylglycerol clearance by human adipose tissue in vivo in the postprandial period
J Lipid Res
Coordinated regulation of hormone-sensitive lipase and lipoprotein lipase in human adipose tissue in vivo: implications for the control of fat storage and fat mobilization
Adv Enzyme Regul
Utilisation of triacylglycerol and non-esterified fatty acid by the working rat heart: myocardial lipid substrate preference
Biochim Biophys Acta
Beneficial health effects of exercise – the role of IL-6 as a myokine
Trends Pharmacol Sci
Angiopoietin-like proteins: potential new targets for metabolic syndrome therapy
Trends Mol Med
Hepatic fibroblast growth factor 21 is regulated by PPARalpha and is a key mediator of hepatic lipid metabolism in ketotic states
Cell Metab
Endocrine regulation of the fasting response by PPARalpha-mediated induction of fibroblast growth factor 21
Cell Metab
Co-ordination of hepatic and adipose tissue lipid metabolism after oral glucose
J Lipid Res
Nicotinic acid receptor agonists differentially activate downstream effectors
J Biol Chem
(d)-β-Hydroxybutyrate inhibits adipocyte lipolysis via the nicotinic acid receptor PUMA-G
J Biol Chem
Acylation-stimulating protein (ASP)/complement C3adesArg deficiency results in increased energy expenditure in mice
J Biol Chem
Effects of infection and inflammation on lipid and lipoprotein metabolism: mechanisms and consequences to the host
J Lipid Res
Type II nuclear hormone receptors, coactivator, and target gene repression in adipose tissue in the acute-phase response
J Lipid Res
Caspase-1 activation of lipid metabolic pathways in response to bacterial pore-forming toxins promotes cell survival
Cell
Energy expenditure, insulin, and VLDL-triglyceride production in humans
J Lipid Res
Molecular diversity and evolution of the large lipid transfer protein superfamily
J Lipid Res
Identification of twenty-three mutations in fission yeast Scap that constitutively activate SREBP
J Lipid Res
The Radiata and the evolutionary origins of the bilaterian body plan
Mol Phylogenet Evol
Do sterols reduce proton and sodium leaks through lipid bilayers?
Prog Lipid Res
Regulation of fatty acid and cholesterol synthesis: co-operation or competition?
Prog Lipid Res
Cholesterol modification of proteins
Biochim Biophys Acta
Metabolism of cholesterol in the echinoderms Asterias rubens and Solaster papposus
FEBS Lett
German vegan study: diet, life-style factors, and cardiovascular risk profile
Ann Nutr Metab
The assembly and secretion of apolipoprotein B-containing lipoproteins
Curr Opin Lipidol
Very-low-density lipoprotein assembly and secretion
Curr Opin Lipidol
Synthesis and function of hepatic very-low-density lipoprotein
Biochem Soc T
Atherogenesis: a postprandial phenomenon
Circulation
Inducible inactivation of hepatic LRP gene by cre-mediated recombination confirms role of LRP in clearance of chylomicron remnants
J Clin Invest
The mammalian low-density lipoprotein receptor family
Ann Rev Nutr
A receptor-mediated pathway for cholesterol homeostasis
Science
SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver
J Clin Invest
Lipoprotein receptors and the control of plasma LDL cholesterol levels
Eur Heart J
The roles of insulin and fatty acids in the regulation of hepatic very-low-density lipoprotein assembly
J R Soc Med
Primate-specific evolution of an LDLR enhancer
Genome Biol
Regulation of hepatic de novo lipogenesis in humans
Ann Rev Nutr
Cited by (63)
Lactobacillus paracasei improves dietary fatty liver by reducing insulin resistance and inflammation in obese mice model
2022, Journal of Functional FoodsCitation Excerpt :Studies have shown that fatty acids can affect energy metabolism, thereby modifying obesity, and this process is also regulated by the gut microbiota (Zapata et al., 2022). When fatty acids exceed the liver’s ability to clear them, they are stored in the form of TG, and then promote the formation of dietary fatty liver (Babin & Gibbons, 2009; Diraison & Beylot, 1998; Sidossis, Mittendorfer, Walser, Chinkes, & Wolfe, 1998). FAS signaling in the body is related to obesity and related diseases, such as insulin resistance and type 2 diabetes.
Obesity III: Obesogen assays: Limitations, strengths, and new directions
2022, Biochemical PharmacologyOn the possible existence of a liver LDL-ostat, and its malfunctioning in familial hypercholesterolemia
2021, Medical HypothesesCitation Excerpt :In light of Dietschy and co-workers arguments', it has therefore been proposed that VLDL (not LDL) was evolutionarily selected for, in connection with the development of a closed circulatory system in chordates, while LDL arose as non-adaptive by-product (or biological “spandrel” [9]) of VLDL selection [10]. In this view, LDL is akin to a VLDL remnant who, like chylomicron remnants, the liver has to clear up from plasma [7,10]. And yet… LDL is cleared at a much slower rate than chylomicron remnants; and despite the fact that a minor increase in the concentration of its receptor would have lead to plasma LDL levels falling to almost zero [7], there is some evidence of recent selection, in primates, for higher LDL levels [10].
Established and emerging factors affecting the progression of nonalcoholic fatty liver disease
2020, Metabolism: Clinical and ExperimentalLipids
2020, Present Knowledge in Nutrition: Basic Nutrition and MetabolismDistinct vitellogenin domains differentially regulate immunological outcomes in invertebrates
2020, Journal of Biological Chemistry