Cholesterol Synthesis and Absorption Markers
Thomas Dayspring MD, FACP, FNLA1
-- Sterol Sterol Biomarker Testing Biomarker Testing --What the Practitioner What the Practitioner
Needs to KnowNeeds to Know
Thomas Dayspring, MD, Thomas Dayspring, MD, FACP, FNLA, NCMPFACP, FNLA, NCMP
DiplomateDiplomate of the American Board of of the American Board of Internal Medicine & Clinical LipidologyInternal Medicine & Clinical Lipidology
Fellow of the American College of Physicians & the National Lipid AssociationFellow of the American College of Physicians & the National Lipid Association
North American Menopause Society: Certified North American Menopause Society: Certified Menopause PractitionerMenopause Practitioner::
Thomas Dayspring, MD, Thomas Dayspring, MD, FACP, FNLA, NCMPFACP, FNLA, NCMP
DiplomateDiplomate of the American Board of of the American Board of Internal Medicine & Clinical LipidologyInternal Medicine & Clinical Lipidology
Fellow of the American College of Physicians & the National Lipid AssociationFellow of the American College of Physicians & the National Lipid Association
North American Menopause Society: Certified North American Menopause Society: Certified Menopause PractitionerMenopause Practitioner::
Director of Cardiovascular Education Director of Cardiovascular Education The The Foundation for Foundation for Health Improvement Health Improvement and Technology and Technology
RichmondRichmond, VA , VA
Disclosures (Last 12 months)Disclosures (Last 12 months)► Consultant
► AstraZeneca► Health Diagnostic Labs
►► Lecture BureauLecture Bureau►► AstraZenecaAstraZeneca►► MerckMerck
Campesterol
Sitosterol
Stigmasterol
Brassicasterol
Avenasterol
24
24
24
22
22
24
24
methyl
ethyl
ethyl
diene
diene
diene
methyl
ethyl
SsterolSsterol Aliphatic Side ChainsAliphatic Side Chains
OHOH
CHCH33
CHCH33
1122
33
44
55
991010 88
66
77
1111
12121313
1414 1515
16161717
1818
RR
1919
HydroxysterolStructure
Klaus von Bergmann et al. Am J Cardiol 2005;96 (suppl):10D–1 4D
R = Aliphatic (nonaromatic) hydrocarbon tail
24
17
2120 22
23 25
26
27Cholesterol
Aromatic
Cholesterol Synthesis and Absorption Markers
Thomas Dayspring MD, FACP, FNLA2
CholesterolCholesterol SitosterolSitosterol CampesterolCampesterol
Sterol and Stanol StructuresSterol and Stanol Structures
OHOH OHOH OHOH
Sterols have a double bond at the ∆∆5 position
CholestanolCholestanol SitostanolSitostanol CampestanolCampestanol
OHOH OHOH OHOH
Saturation of the Saturation of the ∆∆ 5 double bond of sterols by enzymes in the liver results in 5 5 double bond of sterols by enzymes in the liver results in 5 αα stanolsstanols
CycloalkanesCycloalkanes
CycloalkenesCycloalkenes
Cholesterol MoleculesCholesterol Molecules
HOH
CholesterolCholesterol
H
Cholesteryl Cholesteryl esterester
OO
OOCC
HOH
CholestanolCholestanol
►► Serum concentrations of plant sterols are from Serum concentrations of plant sterols are from 500 500 ((campesterol) to 20,000 times (stigmasterol) less campesterol) to 20,000 times (stigmasterol) less than than that of that of cholesterol cholesterol
►► Phytosterols Phytosterols are not synthesized in the human are not synthesized in the human body and are exclusively derived from the diet body and are exclusively derived from the diet in different in different amountsamounts
►► They They are absorbed to a much lesser extent are absorbed to a much lesser extent than than cholesterolcholesterol
►► They are They are not metabolized to bile not metabolized to bile acidsacids
►► They They are excreted much faster from the liver are excreted much faster from the liver into bile compared with into bile compared with cholesterolcholesterol
Klaus von Bergmann et al. Am J Cardiol 2005;96 (supp l):10D–14D
Absorption of Dietary Sterols & StanolsAbsorption of Dietary Sterols & Stanols
SterolsCholesterol Campesterol Sitosterol, Brassicasterol Stigmasterol
Stanols
Sitostanol Campestanol
236.50.474 0.326 0.047 0.011
0.012 0.003
Sterol/Stanol Serum concentrations (mg/dL)
Patients had mild hypercholesterolemia
►► These These large differences in serum large differences in serum concentrations concentrations are are due to several differences in the due to several differences in the metabolism of metabolism of plant sterols/stanols when compared with plant sterols/stanols when compared with cholesterolcholesterol
The The concentrations of plant concentrations of plant stanols are stanols are even lower than their respective sterols even lower than their respective sterols ((egeg, , campestanol is campestanol is 140 times less than 140 times less than campesterol, and sitostanol is 28 campesterol, and sitostanol is 28 times times
less less than sitosterolthan sitosterol) )
Cholesterol Synthesis and Absorption Markers
Thomas Dayspring MD, FACP, FNLA3
Cholesterol Synthesis and Cholesterol Synthesis and Absorption RelationshipsAbsorption Relationships
Relationship between absorbed dietary cholesterol a nd the rate of sterol synthesis in freshly isolated blood monocyte s
Donald J. McNamara et al, JCI 1987;79:1729-39
9876543210
Mon
onuc
lear
Cel
l Ste
rol
Syn
thes
is (
pmol
/h/1
06
cells
The rates of incorporation of [2The rates of incorporation of [2--1414C]acetate into sterols in freshly isolated blood C]acetate into sterols in freshly isolated blood mononuclear leukocytes or MNL mononuclear leukocytes or MNL ((picomolespicomoles per hour per 10per hour per 1066 cells) plotted against the cells) plotted against the
mass of absorbed dietary cholesterol (milligrams per kilogram per daymass of absorbed dietary cholesterol (milligrams per kilogram per day))
When individual data are considered rather than means of group data, the degree of suppression of MNL sterol synthesis was found to be linearly related to the mass
of cholesterol actually absorbed by
the volunteers (milligrams per
kilogram per day)
Absorbed Dietary Cholesterol (mg/kg/day)
2
4
6
8
10
Cholesterol SynthesisCholesterol Synthesis
►► Most Most cholesterol is synthesized and utilized in the cholesterol is synthesized and utilized in the extrahepatic organsextrahepatic organs
►► Under dietary conditions Under dietary conditions equivalent to those found in equivalent to those found in Western Western humans, humans, the the extrahepatic tissues probably extrahepatic tissues probably account for > 80% account for > 80% of whole of whole animal sterol synthesis animal sterol synthesis in in virtually every virtually every species that species that has been has been studiedstudied
►► The CNS contains as much as 25% of the total amount of The CNS contains as much as 25% of the total amount of unesterified cholesterol in the entire body, and that is mostly unesterified cholesterol in the entire body, and that is mostly produced produced via local de novo via local de novo synthesissynthesis
►► Most of the cholesterol carried in LDL is taken up into Most of the cholesterol carried in LDL is taken up into the the liver (liver (indirect reverse cholesterol transportindirect reverse cholesterol transport))
Dietschy JM, Turley SD & Spady DK. J Lip Res 1993;34: 1637-1659
LathosterolDesmosterol
Cholesterol
Lanosterol
Bloch Cholesterol Synthetic Pathway
Kandutsch-Russell Cholesterol Synthetic
Pathway
AcetateHMGCoAMevalonate
HMG-CoA reductase
► Cellular cholesterol precursors are also found in normal human plasma, at concentrations roughly 1:1000 of that of cholesterol
► These values are highly heritable and are used to predict individual responsiveness to the cholesterol-lowering regimen
Lusa S et al. JBC 2003;278:19844-51
It is thought that these pathways may be independently regulated but that they share many enzymes and a deficiency of one of these enzymes will seriously disrupt cholesterol synthesis
Clayton PT. Arch Dis Child 1998;78:185–189
7-dehydrocholesterol
Cholesterol Synthesis and Absorption Markers
Thomas Dayspring MD, FACP, FNLA4
Cholesterol Synthesis Markers in Cholesterol Synthesis Markers in Metabolic Syndrome PatientsMetabolic Syndrome Patients
Cofan M et al. Nutr Metab & CV Diseases 2011;21: 651e65 7
3.02.52.01.51.00.50
Odds Ratio
Met Syndrome (IDF)
Met Syndrome (ATP-III)
High FBS / Diabetes
Hypertension
Low LDL-C
Elevated TG
Visceral Obesity
Lathosterol/Cholesterol
1-SD increases in lathosterol / cholesterol
ratios increased risk between 1.5 and 2 times
DesmosterolDesmosterol
Zerenturk EJ et al. Prog Lip Res 2013 in press
►► 2424--dehydrocholesterol dehydrocholesterol reductase reductase ( DHCR24) DHCR24) and and its its substrate substrate desmosterol play a pivotal role in cholesterol desmosterol play a pivotal role in cholesterol homeostasis, and we are homeostasis, and we are only just only just beginning to appreciate the beginning to appreciate the importance of these in a variety of cellular importance of these in a variety of cellular processes and processes and disease disease settingssettings
►► Alzheimer’s DiseaseAlzheimer’s Disease
►► HHCV and other viral diseasesCV and other viral diseases
►► Prostate cancerProstate cancer
►► Arterial macrophageArterial macrophage--dependent inflammationdependent inflammation
►► Desmosterol is not a good surrogate Desmosterol is not a good surrogate for cholesterol for cholesterol in lipid rafts, in lipid rafts, which provide platforms for signaling molecules to which provide platforms for signaling molecules to interact
► Desmosterol accumulation, like cholesterol, signals sterol overload in the cell
Desmosterol Desmosterol plasma level and the plasma level and the desmosterol to desmosterol to cholesterol cholesterol ratio in the same patients was significantly ratio in the same patients was significantly decreaseddecreased in those with in those with AD and mild cognitive impairmentAD and mild cognitive impairment
Sato Y et al. J. Lipid Res. 2012. 53: 567–576
Cholesterol Synthesis and Absorption Markers
Thomas Dayspring MD, FACP, FNLA5
Intestinal Cholesterol AbsorptionIntestinal Cholesterol Absorption►► Unlike Unlike triglycerides and phospholipids which are hydrolyzed principally triglycerides and phospholipids which are hydrolyzed principally
by by colipasecolipase--dependent pancreatic lipase, dependent pancreatic lipase, ccarboxyl arboxyl ester lipase ester lipase (CEL), (CEL), previously named previously named pancreatic cholesterol pancreatic cholesterol esterase esterase and also known as and also known as bile bile saltsalt--stimulated (or stimulated (or --dependent) lipase, is a nonspecific lipolytic dependent) lipase, is a nonspecific lipolytic enzyme capable enzyme capable of hydrolyzing cholesteryl esters, triof hydrolyzing cholesteryl esters, tri--, di, di--, and , and monomono--acylglycerolsacylglycerols, phospholipids, , phospholipids, lysophospholipids, and ceramidelysophospholipids, and ceramide
Carboxyl Carboxyl ester lipaseester lipase
OH
CEL
Proximal small intestine Cholesteryl oleate
O
O
OH
O
HO
Oleic acidFree cholesterol
Only free sterols can be absorbed
Cellular Sterol Transporters Cellular Sterol Transporters Membrane Membrane Topologies & Topologies & Domains Domains
Brown JM & Yu L. Subcell Biochem. 2010 ; 51: 337–380
N
COOH
SSD
NPC1L1
Membrane
Extracellular or luminal
Cytosolic
Loop-1
NPC1L1 = Niemann Pick C1 like 1 binding protein SSD = sterol sensing domain
Expressed apically Expressed apically primarily in the liver at primarily in the liver at
the hepatobiliary the hepatobiliary surface and small surface and small
intestine at the intestine at the enterocyteenterocyte--lumen lumen
surfacesurface
ABCG5/ABCG8 ABCG5/ABCG8 are are expressed in the expressed in the
same locations and same locations and are responsible are responsible for for
preventing preventing accumulation of a accumulation of a
host of dietary host of dietary noncholesterol noncholesterol
sterols (xenosterols)sterols (xenosterols)
COOHHOOC
NH3NBDNH3NBD
ABCG5/G8 (sterolin 1 and 2)
Membrane
Cytosolic
Extracellular or luminal
ABC = ATP binding cassette transporters
INFLUXINFLUX
EFFLUXEFFLUXScience 2004;303:1201
Lacteal Plasma
Enterocyte
Steroidogenic tissue
Bile ductule
Small Intestinal Lumen
Adipocyte
Peripheral Cell De novo SynthesisFoam Cell
Hepatocyte & Enterocyte Sterol Homeostasis
NPC1L1
NPC1L1 ABCA1ABCA1
Noncholesterol sterols
LDL receptors
Cholesterol
TG
ABCG5 G8
Phytosterols
Micelle Cholesterol
ABCG5 G8
Noncholesterol sterols
Cholesterol
SR-B1
ABCB11
Bile Acids
ABCA1 = ATP binding cassette transporter A1ABCG5, ABCG8 = ATP binding cassette transporter G5 & G8ABCB11 = ATP binding cassette transporter B11NPC1L1 = Niemann Pick C1 like 1 proteinSR-B1 = Scavenger receptor B1
Phytosterols
Bile acids
Genetic Expression of NPC1L1 and ABCG5, ABCG8 help regulate
cholesterol homeostasis
Hepatocyte
Cholesterol Synthesis and Absorption Markers
Thomas Dayspring MD, FACP, FNLA6
Cholesterol AbsorptionCholesterol Absorption
Bosner MS et al. J Lipid Res 1999;40:302-308
Cholesterol absorption measured in Cholesterol absorption measured in 100 healthy patients using dual isotope 100 healthy patients using dual isotope
tracer technique. tracer technique.
While intestinal absorption of bile acids While intestinal absorption of bile acids is essentially is essentially complete under normal conditions, cholesterol complete under normal conditions, cholesterol
absorption absorption in healthy in healthy adult volunteers is variable, with adult volunteers is variable, with 2929––81% (mean 56%) 81% (mean 56%) absorbed in absorbed in the small the small intestine intestine J
Lip Res 1998;39:2415-22 ..
The majority absorb about 55% of dietary sterolsThe majority absorb about 55% of dietary sterols
Dietary Cholesterol
ES16
� There is insufficient evidence to determine whether lowering dietary cholesterol reduces LDL-C
FFramingham ramingham OOffspring ffspring SStudy (tudy ( FOSFOS) ) Cholesterol Absorption Markers are Cholesterol Absorption Markers are
Associated with Prevalent CVDAssociated with Prevalent CVD
Matthan N, et al. J Lipid Res 2009;50:1927-1935
Absorption Absorption MarkersMarkers
Synthesis Synthesis MarkersMarkersSynthsis
Absorption
Synthesis/ Absorption
-1 10 2 3 4 5 6
Cholesterol Synthesis and Absorption Markers
Thomas Dayspring MD, FACP, FNLA7
Inactivating Mutations in Inactivating Mutations in NPC1L1 NPC1L1
and Plasma Lipidsand Plasma Lipids
Sekar Kathiresan et al. N Engl J Med 2014;371:2072-82.
►► The The exons of exons of NPC1L1NPC1L1 in 7364 patients with coronary heart in 7364 patients with coronary heart disease and disease and in 14,728 controls without such disease who in 14,728 controls without such disease who were of European, African, were of European, African, or South or South Asian Asian ancestry were ancestry were sequencedsequenced
►► Carriers Carriers of of inactivating mutationsinactivating mutations (nonsense(nonsense, splice, splice--sitesite, or , or frameshiftframeshift mutationsmutations) were identified) were identified
►► In In addition, addition, a a specific specific inactivating mutation inactivating mutation (p.Arg406X) (p.Arg406X) was was genotyped in genotyped in 22,590 patients with coronary heart disease 22,590 patients with coronary heart disease and and in 68,412 controls and tested in 68,412 controls and tested the association between the association between the presence of an the presence of an inactivating mutation inactivating mutation and both plasma and both plasma lipid levels and the risk of coronary heart lipid levels and the risk of coronary heart diseasedisease
Mean difference between carriers and noncarriers p ValueVariable
Cholesterol (mg/dL)
Total
Low density lipoprotein
High density lipoprotein
Triglycerides
-13
-12
2
-12
0.03
0.04
0.29
0.11
Inactivating Mutations in Inactivating Mutations in NPC1L1 NPC1L1
and Plasma Lipidsand Plasma Lipids
Sekar Kathiresan et al. N Engl J Med 2014;371:2072-82.
-13
-12
Naturally occurring mutations that disrupt NPC1L1 Naturally occurring mutations that disrupt NPC1L1 function were function were not only found not only found to be to be associated with associated with reduced plasma reduced plasma LDLLDL--C C levels levels but also but also a a reduced reduced
risk of risk of coronary heart diseasecoronary heart disease
Carrier status was associated with a relative reduction of 53% in the risk of coronary heart disease (odds ratio for carriers, 0.47; 95% CI, 0.25 to 0.87; P = 0.008)
DDrugs and rugs and EEvidencevidence--BABAsedsed Medicine in Medicine in TThe he EElderly (lderly (DEBATEDEBATE) Study) Study
Strandberg TE, et al. J Am Coll Cardi.ol 2006;48:708 – 14
• Even with frequent metabolic syndrome and diabetes, a low cholesterol absorption was associated with fewer re current cardiovascular events, and especially with better s urvival in elderly cardiovascular patients
• This may be due to selective survival in these elde rly individuals or because cholesterol absorption is partly geneticall y determined, the mechanism may be a lower cholesterol burden during lifetime
• Cholesterol absorption may thus modulate the risk a ssociated with T2DMs and Metabolic Syndrome
Cholesterol Synthesis and Absorption Markers
Thomas Dayspring MD, FACP, FNLA8
IMPIMProvedroved RReduction of eduction of OOutcomes: utcomes: VVytorin ytorin EEfficacy fficacy IInternational nternational TTrial (rial (IMPROVE ITIMPROVE IT))
100
90
80
70
60
50
40
QE R 1 4 8 12 16 24 36 48 60 72 84 96
Time since randomization (months)
Number at risk
EZ/Simva 53.2 125.8 120.4 48.7 3.3
Simva 9009 8921 8306 7843 7289 6939 6607 61 92 5684 5267 4395 3387 2569 1068
Mea
n LD
L-C
(m
g/dL
)
Median Time average 69.5 vs. 53.7 mg/dL
Simva 69.9 145.1 137.1 48.1 3.8
∆ in mg/dL -16.7 -19.3 -16.7 +0. 6 -0.5
1 yr mean LDL-C TC TG HDL-C hs-CRP
Ez/Simva 8990 8899 8230 7701 7264 6864 6583 6256 5734 5354 4508 3484 2608 1078
Cannon C. AHA Scientific Sessions Chicago 2014
Simvastatin
Simvastatin + ezetimibe
IMPIMProvedroved RReduction of eduction of OOutcomes: utcomes: VVytorin ytorin EEfficacy fficacy IInternational nternational TTrial (rial (IMPROVE ITIMPROVE IT))
Primary and 3 Primary and 3 PPrespecifiedrespecified Secondary Endpoints Secondary Endpoints –– ITT & OTITT & OT
0.8 1.0 1.1
PrimaryCVD/MI/UA/Cor Revasc/CVA
Secondary # 1 All D/MI/UA/Cor Revasc/CVA
Secondary # 2 CHD/MI/UA/Urgent Cor Revasc
Secondary # 3 CVD/MI/UA/All Revasc/CVA
UA, documented unstable angina requiring rehospitalization; UA, documented unstable angina requiring rehospitalization; CorCor RevascRevasc, coronary revascularization (≥ 30 , coronary revascularization (≥ 30 days after randomization); All D, alldays after randomization); All D, all--cause death; CHD, coronary heart disease death; All cause death; CHD, coronary heart disease death; All RevascRevasc, coronary and , coronary and nonnon--coronary coronary revasculartizationrevasculartization (≥30 days)(≥30 days)
Ezetimibe/SimvaBetter
SimvaBetter
Simva* EZ/Simva* HR
*7-year event rates (%)
34.7 32.7 0.936
40.3 38.7 0.034
18.9 17.5 0.016
36.2 34.5 0.035
32.4 29.8 0.924
33.9 31.4 0.924
16.3 14.4 0.885
34.0 31.6 0.929
ITT OT
ITT OT
IT OT
IT OT
Cannon C. AHA Scientific Sessions Chicago 2014
http://www.cardiosource.org/Science-And-Quality/Cli nical-Trials/I/IMPROVE-IT.aspx
IMPIMProvedroved RReduction of eduction of OOutcomes: utcomes: VVytorin ytorin EEfficacy fficacy IInternational nternational TTrial (rial (IMPROVE ITIMPROVE IT))
Primary and 3 Primary and 3 PPrespecifiedrespecified Secondary Endpoints Secondary Endpoints –– ITT & OTITT & OT
Cannon C. AHA Scientific Sessions Chicago 2014
On subgroup analysis, patients with On subgroup analysis, patients with diabetes had a greater benefit with diabetes had a greater benefit with
ezetimibe/simvastatin ezetimibe/simvastatin ((HR = 0.86, p for interaction = 0.023HR = 0.86, p for interaction = 0.023) )
http://www.cardiosource.org/Science-And-Quality/Cli nical-Trials/I/IMPROVE-IT.aspx
Cholesterol Synthesis and Absorption Markers
Thomas Dayspring MD, FACP, FNLA9
SScandinavian candinavian SSimvastatin imvastatin SSurvival urvival SStudy (tudy (4S4S))Simvastatin Efficacy: Relationship to Simvastatin Efficacy: Relationship to
Cholesterol AbsorptionCholesterol Absorption
SScandinavian candinavian SSimvastatin imvastatin SSurvival urvival SStudy (tudy (4S4S))Simvastatin Efficacy: Relationship to Simvastatin Efficacy: Relationship to
Cholesterol AbsorptionCholesterol Absorption
The higher the cholesterol absorption, the less efficacious is simvastatin
Miettinen TA et al. BMJ 1998;315:1127-30
Ezetimibe & Statin Ezetimibe & Statin Cholesterol Absorption Cholesterol Absorption MarkersMarkers
Assmann G et al. Curr Med Res & Opin 2008;24:249-259
Ezetimibe monotherapy (10 mg daily) significantly l owered plasma Ezetimibe monotherapy (10 mg daily) significantly l owered plasma concentrations of both sitosterol and campesterol f rom baseline concentrations of both sitosterol and campesterol f rom baseline
compared with placebo (compared with placebo (––53.8% and 53.8% and ––58.2%, respectively 58.2%, respectively p for both < 0.001p for both < 0.001
With atorvastatin monotherapy, there was a modest n umerical With atorvastatin monotherapy, there was a modest n umerical increase in sitosterol and campesterol increase in sitosterol and campesterol
(16.1% and 10.1%, respectively(16.1% and 10.1%, respectively
Ezetimibe 10 mg plus atorvastatin (pooled across do ses) produced Ezetimibe 10 mg plus atorvastatin (pooled across do ses) produced decreases in phytosterols from baseline of a simila r magnitude: decreases in phytosterols from baseline of a simila r magnitude: ––
49.4% for sitosterol and 49.4% for sitosterol and –– 59.3% for campesterol 59.3% for campesterol (both p < 0.001 vs. placebo and atorvastatin monoth erapy) (both p < 0.001 vs. placebo and atorvastatin monoth erapy)
Overall, the decreases in phytosterol concentrations observed wit h ezetimibe coOverall, the decreases in phytosterol concentrations observed wit h ezetimibe co--administered administered with statins were of similar magnitude to those observed with ezetimibe monotherapy.with statins were of similar magnitude to those observed with ezetimibe monotherapy.
PROPROspectivespective CACArdiovascularrdiovascular MMunster Study unster Study ((PROCAMPROCAM): Elevated ): Elevated Phytosterols and CHDPhytosterols and CHDPROPROspectivespective CACArdiovascularrdiovascular MMunster Study unster Study ((PROCAMPROCAM): Elevated ): Elevated Phytosterols and CHDPhytosterols and CHD
Assmann G et al. Nutrition, Metabolism & Cardiovascu lar Diseases 2006;16:13e21
Hazard ratios for development of coronary events ac cording to sitosterol concentration (mmol/L) among men in different
categories of 10-year global coronary risk (hazard ratio of 1 = global risk < 10% and sitosterol ≥ 5.25 mmol/L). The participants in the category with low global risk ( < 10%) were div ided into groups with low ( ≤ 5.25 mmol/L, 39 cases, 140 controls) and high (> 5 .25
mmol/L, 17 cases, 46 controls) sitosterol concentr ations
At medium level of global risk (10.0 - 19.9%), low s itosterol concentrations were observed in 29 cases and 53 controls and high sitosterol lev els in 18 cases and 24 controls, while at high global risk ( ≥ 20%), low sitosterol levels occurred in 38 cases a nd 47 controls while
high sitosterol levels were measured in 18 cases an d 8 controls
Cholesterol Synthesis and Absorption Markers
Thomas Dayspring MD, FACP, FNLA10
Interpreting Serum PhytosterolsInterpreting Serum Phytosterols
►► In In interpreting the associations interpreting the associations between circulating between circulating plant plant sterols and cardiovascular diseasesterols and cardiovascular disease, it , it should again be should again be considered that considered that plant plant sterols reflect sterols reflect intestinal cholesterol intestinal cholesterol absorptionabsorption
►► The The repeatedly observed repeatedly observed positive correlation positive correlation between between circulating plant sterols circulating plant sterols and cardiovascular and cardiovascular disease is disease is accounted for by accounted for by the atherogenic the atherogenic effects of high effects of high cholesterol absorption cholesterol absorption
►► This This view is supported by the finding view is supported by the finding that circulating that circulating cholestanol was increased in cholestanol was increased in people with people with cardiovascular cardiovascular disease and also predictive disease and also predictive of future of future cardiovascular cardiovascular events events
►► Thus, Thus, a a raised phytosterol concentration may be a raised phytosterol concentration may be a marker marker of of disturbed cholesterol metabolism and not disturbed cholesterol metabolism and not itself causally itself causally related to related to atherosclerosisatherosclerosis
Silbernagel et al Curr Opin Lipidol 2013, 24:12–17
►► Why did humans evolve the ABCG5 and ABCG8 Why did humans evolve the ABCG5 and ABCG8 nonesterified sterol (phytosterol) efflux transporters ?nonesterified sterol (phytosterol) efflux transporters ?
►► Why are these sterol efflux transporters expressed at the Why are these sterol efflux transporters expressed at the two critical locations: gut lumen/enterocyte interface and two critical locations: gut lumen/enterocyte interface and hepatobiliary interface?hepatobiliary interface?
►► Why is cholesterol the preferred substrate and why are Why is cholesterol the preferred substrate and why are phytosterols poor substrates for esterification by ACAT and phytosterols poor substrates for esterification by ACAT and LCAT?LCAT?
Enigma: Are Phytosterols “Good or Evil”Enigma: Are Phytosterols “Good or Evil”
Consider ------
Fenofibrate Decreases Sterol AbsorptionFenofibrate Decreases Sterol AbsorptionFenofibrate Decreases Sterol AbsorptionFenofibrate Decreases Sterol Absorption
Valasek MA J Lipid Res 2007;48:2725-35
Specific activation of PPARSpecific activation of PPARαα by fenofibrate decreases cholesterol absorption by fenofibrate decreases cholesterol absorption via an inhibitory effect on NPC1L1 expression in the proximal small via an inhibitory effect on NPC1L1 expression in the proximal small intestineintestine
Cholesterol Synthesis and Absorption Markers
Thomas Dayspring MD, FACP, FNLA11
Cholesterol lowering and inhibition of sterol Cholesterol lowering and inhibition of sterol absorption absorption by Lactobacillus by Lactobacillus reuterireuteri NCIMB 30242NCIMB 30242
Jones ML et al. European Journal of Clinical Nutrit ion 2012;66:1234–1241
Individual changes in plasma deconjugated bile Individual changes in plasma deconjugated bile acids (acids (DBAs) and associated changes in serum DBAs) and associated changes in serum
LDLLDL--C over the C over the intervention periodintervention period
A A significant association was observed in significant association was observed in subjects subjects taking taking L. L. reuterireuteri NCIMB 30242 (NCIMB 30242 (r=0.369r=0.369, ,
P=0.003P=0.003), whereas ), whereas no association no association was observed was observed in subjects taking in subjects taking placeboplacebo