介绍谷固醇血症这种罕见的遗传性脂代谢紊乱
Sitosterolemia: A Rare Genetic Disorder Leads to Insight into an Important Physiological Process
Shailesh B. Patel, BM, ChB, FRCP
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
How is Cholesterol Absorbed?
Intestinal cell
FFA
Micelles
Bile acids
Cholesterol
FFA
Chylomicrons
Digest food
Cholesteryl ester
Cholesterol
FFA
Free cholesterol
Blood
Lymphatic channels
VLDL
Sterol Absorption
Bosner MS et al. J Lipid Res 1999;40:302-308.
Number of Subjects
1st
2nd
3rd
4th
5th
6th
7th
8th
9th
10th
Decile Percent Cholesterol Absorption
Dietary Sterols: Normal Physiology
HO
Sitosterol
HO
Stigmasterol
Sterol Structures
HO
Cholesterol
HO
Campesterol
Bhattacharyya AK et al. J Clin Invest 1974;53:1033-1043.
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
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
Plasma Sitosterol and Cholesterol in Sitosterolemia
Lee MH et al. Curr Opin Lipidol 2001;12:141-149.
Cholesterol (mg/dl)
Plasma Cholesterol
Plasma Sitosterol (mg/dl)
Plasma Sitosterol
68
58
48
38
28
18
8
3
2
1
0
Parents
Normal Siblings
Affected Individuals
Normal Controls
Parents
Normal Siblings
Affected Individuals
Normal Controls
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
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
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
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
2100
63
64
62
65
66
67
68
61
72
71
70
69
Families with Sitosterolemia
700
36
37
34
35
38
39
40
41
42
2700
105
104
103
106
107
108
109
Lee MH et al. Curr Opin Lipidol 2001;12:141-149.
55
56
59
60
90
91
94
95
98
99
102
Fine-Mapping of STSL to D2S2294–D2S2174
Lee MH et al. Eur J Hum Genet 2001;9:375-384.
?2001 Nature Publishing Group. All rights reserved.
Haldane Map Position
Multipoint LOD Score
D2S1346
GATA194B06
D2S2259
D2S4010
D2S2298
D2S4015
D2S2240
D2S2378
D2S123
D2S2153
D2S4009
Lu K et al. Am J Hum Genet 2001;69:278-290.
?2001 The American Society of Human Genetics. All Rights Reserved
Gene Structures of ABCG5 (Sterolin-1) and ABCG8 (Sterolin-2)
Centromere
1kb
ABCG8
ABCG5
Telomere
ATG
ATG
372 bp
~143 bp
12
13
11
10
89
7
6
5
34
2
1
1
Exon1 ABCG8
Exon1 ABCG5
Expression Patterns of ABCG5 and ABCG8 in Mouse Tissues
kb
6.0
5.0
4.0
3.0
2.5
2.0
1.5
6.0
5.0
4.0
3.0
2.5
2.0
1.5
3.0
2.5
2.0
1.5
ABCG5
ABCG8
?-actin
Lee MH et al. Nat Genet 2001;27:79-83. | Lu K et al. Am J Hum Genet 2001;69:278-290.
?2001 Nature Publishing Group. All rights reserved.
Mutations in ABCG5 and ABCG8 Cause Sitosterolemia
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
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
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
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.
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)
Glueck CJ et al. Metabolism 1991;40:842-848.
All values expressed as mg/dl
Rajaratnam RA et al. J Am Coll Cardiol 2000;35:1185-1191.
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
Data are mean (SD)
Values expressed as mg/dl
Liver
Fecal sterols
Bile salts Unabsorbed cholesterol
Chol
Bile salts
Bile
Duodenal/jejunal enterocyte
Diet
Luminal cholesterol
Bile salts
Ileal enterocyte
Sterol permease
Bile salts
BAS
Micellar cholesterol
Ezetimibe
Mechanism of Intestinal-Acting Agents
Chylomicron
Lymph
Chylomicron
Hepatic portal circulation
Plant stanols
ABCG5/G8
IBAT
Slide developed by The Health Science Center for
Continuing Medical Education, New York, NY
Ezetimibe Significantly Reduces Plasma Sitosterol in Patients with Sitosterolemia
Salen G et al. Circulation 2002;106:II-18