1. Sitosterolemia: A Rare Genetic Disorder Leads to Insight into an Important Physiological Process
Shailesh B. Patel, BM, ChB, FRCP
Sitosterolemia: a rare genetic disorder leads to insight into an important physiological process

2. Evidence for Regulation of Dietary Cholesterol Absorption
Interindividual variation in cholesterol absorption rates
Absorption rates affected by dietary cholesterol levels
High degree of specificity for sterol absorbed, e.g., cholesterol >> sitosterol
Genetic disease in humans, phytosterolemia
Cholesterol excreted into bile by the liver, but mechanism/transporters not identified
Evidence for regulation of dietary cholesterol absorption
The absorption of dietary cholesterol is variable, affected by the diet, and it has been recognized for more than 80 years that this absorption process is also highly selective. Rudolf Schoenheimer demonstrated more than 80 years ago that plant sterols were not retained by mammals, even in animals such as herbivores, which do not eat cholesterol but eat exclusively plant sterols. This mechanism is so exclusive that humans do not retain any plant sterols, a process that is disrupted in the genetic disorder of sitosterolemia.
In addition to regulation at the intestinal level, such "xenobiotic" sterols are preferentially excreted by the liver into bile, and this process may also be important for excreting cholesterol into bile. The latter is also an important feature not only for the maintenance of whole body cholesterol balance, but also for enabling appropriate bile constituent secretion to enable dietary cholesterol to be absorbed.

3. How is Cholesterol Absorbed?
FFA
Free cholesterol
FFA
Digest food
Cholesteryl ester
Cholesterol
Micelles
Bile acids
Intestinal cell
Liver
VLDL
Cholesterol
How is cholesterol absorbed?
To be absorbed, dietary cholesterol needs to be de-esterified by esterases, primarily secreted by the pancreatic exocrine glands. Free cholesterol is then incorporated into micelles, a physical process that is absolutely required for cholesterol absorption. Micelles are formed by the interaction of bile salts, phospholipids (some biliary cholesterol), and dietary cholesterol.
In a dynamic process, the micelles interact with the enterocyte apical membrane, and its contents are transferred into the enterocyte, though the bile salts are not absorbed at this stage. The cholesterol is transferred to the enterocyte, esterified, and packaged into chylomicrons to be secreted into the lymphatic channels; chylomicrons are progressively digested and off-loaded in the periphery before the remnants are cleared by the liver. The liver uses some of the remnant cholesterol for bile acid synthesis, to be excreted, together with cholesterol, into bile and made available for the next round of dietary sterol absorption. Note that the bile salts are reabsorbed by the terminal ileum and, after circulation in the bloodstream, taken up by the liver and re-excreted into bile, completing the enterohepatic circulation.
Blood
FFA
Lymphatic channels
Chylomicrons

4. Decile Percent Cholesterol Absorption
Number of Subjects
Sterol absorption
To determine how much cholesterol is absorbed under normal conditions, Ostlund and his colleagues measured rates of absorption in 100 healthy individuals, using the dual isotope tracer technique. The majority of individuals absorb about 55% of dietary sterols, with only a few individuals who hyperabsorb or hypoabsorb.
Reference:
Bosner MS, Lange LG, Stenson WF, Ostlund RE Jr. Percent cholesterol absorption in normal women and men quantified with dual stable isotopic tracers and negative ion mass spectrometry. J Lipid Res 1999;40:
1st
2nd
3rd
4th
5th
6th
7th
8th
9th
10th
Decile Percent Cholesterol Absorption
Bosner MS et al. J Lipid Res 1999;40:

5. Dietary Sterols: Normal Physiology
On a daily basis, we eat about 500 mg cholesterol and an almost equal amount of plant sterols. However, while we may absorb about 55% of dietary cholesterol, almost none of the plant sterols are absorbed, and the latter are excreted in the feces. Indeed, on a daily basis, we excrete more cholesterol or cholesterol equivalents (bile salts) than we eat. This "extra" cholesterol is derived from our bodies. On a daily basis, we synthesize more cholesterol than we need. Much of this excess cholesterol comes from nonhepatic sources, and the liver takes this excess and excretes it into bile, to be lost in the feces.
What is important to note, though, is that noncholesterol sterols are not retained within our bodies and seem to be specifically excluded. Less than 1% of plant sterols are absorbed, and these are eventually also excreted, as almost none are retained by the body.

6. Sterol Structures Cholesterol Sitosterol Campesterol Stigmasterol HO
Despite the high degree of structural similarity, our bodies have evolved mechanisms that can distinguish between these different sterol species. The majority of these differences are in the "R" tail, with most plant sterols having extra methyl or ethyl groups and different levels of desaturation. The more carbon atoms and desaturation, the lower the absorption rate. Thus, campesterol is absorbed to a greater extent than sitosterol, which is absorbed to a greater extent than stigmasterol, although the absorption of all of these plant sterols is still much lower than that for cholesterol. These observations suggest that a highly sophisticated system has evolved to keep such noncholesterol sterols out and may also be responsible for restricting cholesterol absorption, since we absorb only 55% and not 100% from our diets. HO HO

7. Sitosterolemia, a.k.a. Phytosterolemia
Autosomal recessive, first described in 1974
Diagnostically elevated plasma phytosterols
Rare, <1:1,000,000 (~20 cases in US)
Associated with premature atherosclerosis
Increased dietary sterol absorption and failure to excrete sterols into bile
Need GC or HPLC to make diagnosis
Sitosterolemia, a.k.a. phytosterolemia
Bearing in mind the above physiology, Bhattacharyya and Connor described a family of two affected sisters, both of whom presented with tendon xanthomas, but who did not have any significant family history of premature coronary artery disease, and their cholesterol levels in the blood, measured by the conventional enzymatic tests, did not support a diagnosis of familial hypercholesterolemia. However, these astute clinician scientists performed sterol analyses by gas-capillary chromatography and detected in the blood of the affected sisters very large quantities of plant sterols, the major species of which was -sitosterol. The term "" is not necessary, since there is no biological ".“
Once this condition was described, a few more cases were identified, some in which the probands had died of premature coronary artery disease, and family analyses identified more cases of sitosterolemia. Since all the plant sterol species are highly elevated in this condition, the disease is better termed phytosterolemia, though perhaps the original terminology may survive this revision.
Reference:
Bhattacharyya AK, Connor WE. Beta-sitosterolemia and xanthomatosis. A newly described lipid storage disease in two sisters. J Clin Invest 1974;53:
Bhattacharyya AK et al. J Clin Invest 1974;53:

8. Sitosterolemia Biochemical abnormalities
Increased plasma phytosterols and their metabolites
Increased dietary cholesterol and plant sterol absorption
Expanded body pools of both sitosterol and cholesterol
Decreased ability to excrete any sterols into bile by the liver
Sitosterolemia
Investigation of a few newly diagnosed individuals showed that they hyperabsorbed all plant sterols and also seemed to hyperabsorb cholesterol, with an increase in plasma phytosterolemia and a resultant body pool expansion of cholesterol and phytosterols. Indeed, another defect that soon became evident was that, despite the expanded body pools of sterols, the liver seemed unable to excrete these sterols into bile. Bile samples obtained from a limited number of affected individuals showed an almost sterol-poor bile, suggesting that there were two defects, one at the level of the intestine and one at the level of the liver.

9. Plasma Sitosterol and Cholesterol in Sitosterolemia
Plasma Cholesterol
Plasma Sitosterol 68 58 48 38 28 18
Plasma Sitosterol (mg/dl) 8
Cholesterol (mg/dl) 3 2 1
Plasma sitosterol and cholesterol in sitosterolemia
Plasma cholesterol and sitosterol levels were measured by capillary gas liquid chromatography or high-performance liquid chromatography (HPLC). Only in 4 children were the plasma cholesterol levels very high (and these children were typically referred to as having "pseudohomozygous familial hypercholesterolemia"). None of the adult patients had any significant hypercholesterolemia, compared with parents, unaffected siblings, or random controls. On the other hand, plasma sitosterol levels were very elevated and are regarded as the "gold standard" for diagnosis.
References:
Lee MH, Lu K, Patel SB. Genetic basis of sitosterolemia. Curr Opin Lipidol 2001;12:
Patel SB, Salen G, Hidaka H, et al. Mapping a gene involved in regulating dietary cholesterol absorption: the sitosterolemia locus is found at chromosome 2p21. J Clin Invest 1998;102:
Parents
Parents
Normal Siblings
Affected Individuals
Normal Controls
Normal Siblings
Affected Individuals
Normal Controls
Lee MH et al. Curr Opin Lipidol 2001;12:

10. Summary of Metabolic Defect
Loss of sterol discrimination, with
Reduced bile excretion of sterols
Hyperabsorption of all sterols
Reduced sterol turnover
Abnormal regulation of cholesterol synthetic pathway
Reduced activities of HMG-CoA reductase, synthase, but increased LDL-receptor activity
Summary of metabolic defect
Thus the loss of a single locus (since sitosterolemia has an autosomal recessive pattern of inheritance) leads to a loss of sterol discrimination at the intestinal level and a loss of ability to excrete sterols into bile. In limited studies of liver biopsy samples from affected individuals, the cholesterol synthesis pathway was reduced, as was the bile salt synthesis pathway, although a discordant increase in the LDL-receptor pathway has been reported. The elucidation of this defect will lead to a greater insight into normal physiology.

11. Sitosterol and Atherosclerosis: Insight from Homozygous Sitosterolemia
Autopsy study of young sitosterolemic patient who had sudden death
~20% plant sterol content of atherosclerotic plaque
Same proportions of sterols as in LDL
Sitosterol and atherosclerosis: insight from homozygous sitosterolemia
Although the initial report of sitosterolemia did not indicate the presence of premature coronary artery disease, subsequently two probands presented with either sudden cardiac death, or angina followed by sudden cardiac death; both were less than 20 years of age.

12. Hypothesis Primary defect involves a gene product that
Regulates cholesterol absorption in the gut
Regulates cholesterol excretion in the liver
Prevents noncholesterol sterols from being retained by the body
Prevents entry in the intestine
Any small amounts that escape the intestine are rapidly excreted by the liver
Hypothesis
Thus, based upon the known physiology in healthy individuals and the observed defects in patients with sitosterolemia, we proposed that the gene defect was one that not only regulated cholesterol entry at the intestinal level and excretion at the hepatic biliary level, but also could discriminate between cholesterol and noncholesterol for these processes.

13. Genetic Analyses
Assemble pedigrees, confirm diagnosis by plasma sitosterol levels, collect DNA
Low-density genome wide-scan performed
Initially at 25 cM resolution
10–15 cM at conclusion
High-density mapping upon localization
Positionally clone the disease gene
Genetic analyses
To identify the gene defect, we assembled as many families with sitosterolemia as we could manage and, using the power of genetic analyses, localized the gene defect to a human chromosomal region such that we could undertake a positional cloning strategy.
Reference:
Patel SB, Salen G, Hidaka H, et al. Mapping a gene involved in regulating dietary cholesterol absorption: the sitosterolemia locus is found at chromosome 2p21. J Clin Invest 1998;102:

14. Families with Sitosterolemia
100 2 3 4 5 6 1
200 8 9 10 11 12 7 13 14
300 15 16 21 20 19
400 17 18
500 23 24 25 26 27 22
600 29 30 31 32 33 28
700 47 46 45
800 43 44 34 35 36 37 38 39 40 41 42 53 54
1000 57 58
2000 88 89
2300
2100
2200 75 76 73 74 77 78 79 80 81 82 83 84 85 86 87 92 93
2400 61 62 72 55 56 59 60 90 91 63 64 65 66 67 68 94 95 69 70 71 96 97
2500
100
101
2600
2700
110
111
2800
112
113
114
2900
116
115
117
3000
119
118
120
121
3100
124
125
122
123
3200
128
129
126
127
103
104 98 99
102
105
106
107
108
109
130
131
3300
132
Families with sitosterolemia
This slide shows the families we assembled. These families represent published and unpublished cases and originated worldwide, from Europe, Scandinavia, Japan, South Africa, Canada, the United States, and South America. This disease is present in Africans, as well as whites, Asians, and Latinos.
References:
Patel SB, Salen G, Hidaka H, et al. Mapping a gene involved in regulating dietary cholesterol absorption: the sitosterolemia locus is found at chromosome 2p21. J Clin Invest 1998;102:
Lee MH, Lu K, Patel SB. Genetic basis of sitosterolemia. Curr Opin Lipidol 2001;12:
135
3400
134
133
136
137
138
139
3500
140
141
142
3600
143
144
145
3700
146
3800
149
148
147
152
3900
151
150
153
154
4000
157
158
159
160
155
156
161
162
4100
163
170
171
4300
172
175
4400
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173
176
177
Lee MH et al. Curr Opin Lipidol 2001;12:

15. Fine-Mapping of STSL to D2S2294–D2S217413 11 9 7 5 3 1 -1 -3
Multipoint LOD Score
D2S1346
GATA194B06
D2S2259
D2S4010
D2S2298
D2S4015
D2S2240
D2S2378
D2S123
D2S2153
Fine-mapping of STSL to S2S2294–D2S2174
The genetic analyses allowed the mapping to human chromosome 2p21 on the short arm to a small area, which facilitated positional cloning.
Reference:
Lee MH, Gordon D, Ott J, et al. Fine mapping of a gene responsible for regulating dietary cholesterol absorption; founder effects underlie cases of phytosterolaemia in multiple communities. Eur J Hum Genet 2001;9:
D2S4009 5 10 15 20
Haldane Map Position
Lee MH et al. Eur J Hum Genet 2001;9:
©2001 Nature Publishing Group. All rights reserved.

16. Gene Structures of ABCG5 (Sterolin-1) and ABCG8 (Sterolin-2)
Centromere
Telomere 1 1 2 34 5 6 7 89 10 11 12 13
1kb
Exon1 ABCG8
Exon1 ABCG5
Gene structures of ABCG5 (sterolin-1) and ABCG8 (sterolin-2)
Using conventional positional cloning technology, we identified the sitosterolemia locus, and to our surprise, we identified not one but two genes, organized in a head-to-head configuration; complete mutations of either cause the disease. These genes are highly homologous to each other and are thought to have arisen as a result of gene duplication. They are called "ABC" proteins as they have protein motifs that share identity with the ATP-binding cassette (ABC) family of proteins.
Reference:
Lu K, Lee MH, Hazard S, et al. Two genes that map to the STSL locus cause sitosterolemia: genomic structure and spectrum of mutations involving sterolin-1 and sterolin-2, encoded by ABCG5 and ABCG8, respectively. Am J Hum Genet 2001;69:
~143 bp
372 bp
ATG
ATG
Lu K et al. Am J Hum Genet 2001;69:
©2001 The American Society of Human Genetics. All Rights Reserved

17. Expression Patterns of ABCG5 and ABCG8 in Mouse Tissueskb
6.0
5.0
4.0
3.0
2.5
2.0
1.5
ABCG5
6.0
5.0
4.0
3.0
2.5
2.0
1.5
ABCG8
3.0
2.5
2.0
1.5
Expression patterns of ABCG5 and ABCG8 in mouse tissues
As would be predicted, these genes are expressed only in the liver and intestine. Data for the mouse homologues are shown in this tissue Northern expression blot.
References:
Lee MH, Lu K, Hazard S, et al. Identification of a gene, ABCG5, important in the regulation of dietary cholesterol absorption. Nat Genet 2001;27:79-83.
Lu K, Lee MH, Hazard S, et al. Two genes that map to the STSL locus cause sitosterolemia: genomic structure and spectrum of mutations involving sterolin-1 and sterolin-2, encoded by ABCG5 and ABCG8, respectively. Am J Hum Genet 2001;69:
-actin
Brain
Kidney
Lung
Skin
Spleen
Testis
Heart
Liver
Muscle
Small Intestine
Stomach
Thymus
Lee MH et al. Nat Genet 2001;27: | Lu K et al. Am J Hum Genet 2001;69:
©2001 Nature Publishing Group. All rights reserved.

18. Mutations in ABCG5 and ABCG8 Cause Sitosterolemia
ABCG5 encodes for the protein sterolin-1, and ABCG8 encodes for the protein sterolin-2. Based upon analyses of the peptide sequences, these proteins contain 6 membrane-spanning domains and have motifs that are classic for binding ATP (and are homologous to ATP-binding family members, thus the terminology). Mutations (stop codons shown in red and missense mutations shown in green) are present in both of these proteins. Polymorphisms are also known to exist for both proteins.

19. What are ABC Proteins?
ATP-binding cassette containing membrane "transporters"
Defined by "Walker" motifs A and B
Subsequently a "C" motif defined
Large family
Present in bacteria to mammals
55 genes in Drosophila melanogaster
56 in Caenorhabditis elegans
51 in Homo sapiens
>130 in Arabidopsis thaliana
What are ABC proteins?
ABC proteins are widely dispersed and represented throughout the animal and plant kingdoms. They are grouped by virtue of having an ATP-binding cassette motif and by the number of transmembrane domains, and are defined by Walker motifs termed "A" and "B"; subsequently, a "C" motif was recognized.
Although mammals have a relatively modest number of these family members, plants have a higher number. In general, though not exclusively, these proteins frequently act as transporters, pumping toxins and molecules across the plasma membrane.

20. ABC Genes and Human Disease
Oncology
Chemotherapeutic resistance
Pulmonology
Cystic fibrosis
Cardiology/metabolic
Tangier disease
Sitosterolemia
Endocrinology
Nesidioblastosis (PHHI)
Ophthalmology
Stargardt’s macular dystrophy
Dermatology
Pseudoxanthoma elasticum
Immunology
Antigen presentation
"Bare lymphocyte"
Hematology
X-linked sideroblastic anemia
Neurology
Adrenoleukodystrophy
Hepatology
Familial cholestasis
ABC genes and human disease
Although few in number, many of these ABC family members are known to cause disease when defective. For example, cystic fibrosis, one of the best known of medical diseases, is caused by defective CFTR, an ABC family member. A few of these disorders are listed, representing a number of different systems in man.

21. Conclusions: ABCG5 and ABCG8
Mutations in ABCG5 (sterolin-1) and ABCG8 (sterolin-2) cause sitosterolemia
Affected individuals have high levels of plant sterols, but not always cholesterol
Tendon/tuberous xanthomas and accelerated atherosclerosis
Must play a key role in regulating dietary sterol absorption and excretion
? Link between diet and atherosclerosis
Do sterolins prevent the entry of toxic bioactive sterols?
Conclusions: ABCG5 and ABCG8
Clearly, ABCG5 and ABCG8 act to regulate dietary cholesterol entry, but also to prevent the entry of noncholesterol.

22. Noncholesterol Sterols
Endogenous sterols
Sterol synthesis intermediates
Desmosterol
Lathosterol
Cholestenol, etc
Metabolites
Cholestanol
Oxysterols
Exogenous sterols
Plant sterols
Sitosterol
Campesterol
Brassicasterol
Avenosterol, etc.
Yeast sterols
Ergosterol, etc.
Shellfish sterols
Desmosterol
Fucosterol, etc.
Noncholesterol sterols
There are a large number of "noncholesterol" molecules. Endogenously, these can be derived as intermediates from cholesterol synthesis, as well as intermediates from the bile acid synthesis pathway. Additionally, oxidation of cholesterol will also lead to such species. Exogenously, a large number of noncholesterol sterol species are known to be used by a variety of organisms, in some cases almost exclusively (such as plants that do not contain any cholesterol). Such sterols are not utilized by mammals, and seem to be excluded primarily by the actions of ABCG5 and ABCG8.

23. Elevated Phytosterols are a Marker of CHD
Sitosterol and campesterol concentrations were higher in subjects with personal or family history of premature CHD
42% of probands' kindred had history of premature CHD versus 19% of the cohort (P=0.13)
Hypercholesterolemics (n=595)
Hyperphytosterolemics (n=21)
Sitosterol
0.265
0.628
Campesterol
0.164
0.594
Cholesterol
261
262
Elevated phytosterols are a marker of CHD
In one of the earliest studies examining the hypothesis that plant sterol levels may be a marker of cardiovascular disease, probands who had a strong family history of coronary heart disease (CHD) had a significantly higher level of plasma plant sterol levels. These studies also indicated that plasma plant sterol levels may be strongly genetically determined. More recently, Sudhop et al. have also reported similar data. In two formal studies of plant sterol heritability, a very strong genetic basis (>70%) has been reported.
References:
Glueck CJ, Speirs J, Tracy T, Streicher P, Illig E, Vandegrift J. Relationships of serum plant sterols (phytosterols) and cholesterol in 595 hypercholesterolemic subjects, and familial aggregation of phytosterols, cholesterol, and premature coronary heart disease in hyperphytosterolemic probands and their first-degree relatives. Metabolism. 1991;40:
Sudhop T, Gottwald BM, von Bergmann K. Serum plant sterols as a potential risk factor for coronary heart disease. Metabolism 2002;51:
All values expressed as mg/dl
Glueck CJ et al. Metabolism 1991;40:

24. Sitosterol Concentrations in Postmenopausal Women with CHD
Postmenopausal women with CHD had higher levels of sitosterol and campesterol; results remained significant after adjustment for other risk factors
Cases (n=48)
Controls (n=61) P
Sitosterol
0.332 (0.22)
0.271 (0.13)
<0.05
Campesterol
0.611 (0.44)
0.493 (0.25)
Cholesterol
230 (5.41)
221 (4.64)
>0.1
Sitosterol concentrations in postmenopausal women with CHD
In a case–control study, postmenopausal women with coronary heart disease (CHD) had significantly elevated plasma plant sterol levels—campesterol and sitosterol—although their plasma cholesterol levels were not significantly different. These findings were significant, even after adjustment for conventional risk factors, suggesting that plasma plant sterol levels may be an independent risk factor for cardiovascular disease.
Reference:
Rajaratnam RA, Gylling H, Miettinen TA. Independent association of serum squalene and noncholesterol sterols with coronary artery disease in postmenopausal women. J Am Coll Cardiol 2000;35:
Data are mean (SD)
Values expressed as mg/dl
Rajaratnam RA et al. J Am Coll Cardiol 2000;35:

25. Mechanism of Intestinal-Acting Agents
Bile
Liver
Chol
Diet
Bile salts
Bile salts
Luminal cholesterol
Duodenal/jejunal enterocyte
Ezetimibe
Plant stanols
Sterol permease
Lymph
Micellar cholesterol
Chylomicron
Chylomicron
ABCG5/G8
Bile salts Unabsorbed cholesterol
Mechanism of intestinal-acting agents
Three major intestinally acting therapies are available for lowering plasma LDL-C levels.
Bile acid sequestrants inhibit bile acid reabsorption in the ileum, causing increased fecal bile acid loss, which results in upregulation of bile acid synthesis (hepatic cholesterol breakdown) and upregulation of hepatic LDL receptors. This in turn results in lowering plasma LDL-C.
Plant stanols and sterols (now commercially available as Benechol and Take Control margarines) displace cholesterol from micelles, reducing dietary cholesterol uptake at the brush border membrane and thus increasing fecal loss of cholesterol.
Ezetimibe selectively inhibits the uptake of micellar cholesterol into intestinal epithelial cells (by an as-yet-unidentified specific transporter) and substantially reduces the amount of cholesterol from the intestine that is absorbed.
Bile salts
Ileal enterocyte
BAS
Hepatic portal circulation
IBAT
Fecal sterols
Slide developed by The Health Science Center for
Continuing Medical Education, New York, NY

26. Mean % Change from Baseline
Ezetimibe Significantly Reduces Plasma Sitosterol in Patients with Sitosterolemia
Placebo
Mean % Change from Baseline
Ezetimibe significantly reduces plasma sitosterol concentrations in patients with sitosterolemia
In a study of 37 patients with homozygous sitosterolemia, randomized in a 4:1 ratio to ezetimibe 10 mg/d (n=30) or placebo (n=7), reduction in plant sterols was progressive over the course of the 8-week study. Reduction in plant sterols was consistent regardless of bile acid sequestrant therapy.
Reference:
Salen G, von Bergmann K, Kwiterovich P, Musser B, O'Grady L, Stein P, Musliner T. Ezetimibe is an effective treatment for homozygous sitosterolemia. Circulation 2002;106:II-185. Abstract.
Ezetimibe 10 mg
Baseline 2 4 6 8
Endpoint avg of wks 6 and 8
Endpoint last measure
Week
Salen G et al. Circulation 2002;106:II-185.

27. Ezetimibe Lowers Phytosterols in Patients with Mild Hypercholesterolemia
–48%
–41%
Campesterol (mg/dl)
Sitosterol (mg/dl)
Ezetimibe lowers phytosterols in patients with mild hypercholesterolemia
Ezetimibe is also effective in lowering plasma plant sterol levels in mildly hypercholesterolemic individuals. Note that these levels are 50- to 100-fold lower than those seen in patients with sitosterolemia.
Reference:
Sudhop T, Lutjohann D, Kodal A, Igel M, Tribble DL, Shah S, Perevozskaya I, von Bergmann K. Inhibition of intestinal cholesterol absorption by ezetimibe in humans. Circulation 2002;106:
Ezetimibe
Placebo
Placebo
Ezetimibe
Sudhop T et al. Circulation 2002;106:

28. Conclusions
Specific mechanisms have evolved to keep noncholesterol sterols out of our bodies (STSL locus)
Highly conserved proteins from fugu to humans
Plant sterol levels may be another indicator of cardiovascular risk
Noncholesterol sterols correlate with CHD
Plant sterol levels can be lowered by ezetimibe in both normal and sitosterolemic individuals
Conclusions