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Biochemical Society Transactions Oct 2019The ABCG5/G8 heterodimer is the primary neutral sterol transporter in hepatobiliary and transintestinal cholesterol excretion. Inactivating mutations on either the ABCG5... (Review)
Review
The ABCG5/G8 heterodimer is the primary neutral sterol transporter in hepatobiliary and transintestinal cholesterol excretion. Inactivating mutations on either the ABCG5 or ABCG8 subunit cause Sitosterolemia, a rare genetic disorder. In 2016, a crystal structure of human ABCG5/G8 in an apo state showed the first structural information on ATP-binding cassette (ABC) sterol transporters and revealed several structural features that were observed for the first time. Over the past decade, several missense variants of ABCG5/G8 have been associated with non-Sitosterolemia lipid phenotypes. In this review, we summarize recent pathophysiological and structural findings of ABCG5/G8, interpret the structure-function relationship in disease-causing variants and describe the available evidence that allows us to build a mechanistic view of ABCG5/G8-mediated sterol transport.
Topics: ATP Binding Cassette Transporter, Subfamily G, Member 5; ATP Binding Cassette Transporter, Subfamily G, Member 8; Animals; Biliary Tract; Catalysis; Cholesterol; Homeostasis; Humans; Hypercholesterolemia; Intestinal Diseases; Lipid Metabolism, Inborn Errors; Lipoproteins; Liver; Phytosterols
PubMed: 31654053
DOI: 10.1042/BST20190130 -
Advances in Experimental Medicine and... 2020Cardiovascular disease is characterized by lipid accumulation, inflammatory response, cell death, and fibrosis in the arterial wall and is the leading cause of morbidity... (Review)
Review
Cardiovascular disease is characterized by lipid accumulation, inflammatory response, cell death, and fibrosis in the arterial wall and is the leading cause of morbidity and mortality worldwide. Cholesterol gallstone disease is caused by complex genetic and environmental factors and is one of the most prevalent and costly digestive diseases in the USA and Europe. Although sitosterolemia is a rare inherited lipid storage disease, its genetic studies led to identification of the sterol efflux transporters ABCG5/G8 that are located on chromosome 2p21 in humans and chromosome 17 in mice. Human and animal studies have clearly demonstrated that ABCG5/G8 play a critical role in regulating hepatic secretion and intestinal absorption of cholesterol and plant sterols. Sitosterolemia is caused by a mutation in either the ABCG5 or the ABCG8 gene alone, but not in both simultaneously. Polymorphisms in the ABCG5/G8 genes are associated with abnormal plasma cholesterol metabolism and may play a key role in the genetic determination of plasma cholesterol concentrations. Moreover, ABCG5/G8 is a new gallstone gene, LITH9. Gallstone-associated variants in ABCG5/G8 are involved in the pathogenesis of cholesterol gallstones in European, Asian, and South American populations. In this chapter, we summarize the latest advances in the critical role of the sterol efflux transporters ABCG5/G8 in regulating hepatic secretion of biliary cholesterol, intestinal absorption of cholesterol and plant sterols, the classical reverse cholesterol transport, and the newly established transintestinal cholesterol excretion, as well as in the pathogenesis and pathophysiology of ABCG5/G8-related metabolic diseases such as sitosterolemia, cardiovascular disease, and cholesterol gallstone disease.
Topics: ATP Binding Cassette Transporter, Subfamily G, Member 5; ATP Binding Cassette Transporter, Subfamily G, Member 8; Animals; Humans; Lipoproteins; Liver; Sterols
PubMed: 32705597
DOI: 10.1007/978-981-15-6082-8_8 -
Frontiers in Pediatrics 2021Sitosterolemia is a rare condition in children and is often misdiagnosed as familial hypercholesterolemia. Serious complications can result if not treated promptly and...
Sitosterolemia is a rare condition in children and is often misdiagnosed as familial hypercholesterolemia. Serious complications can result if not treated promptly and effectively. When pediatric patients are diagnosed with sitosterolemia, vascular, and cardiac studies are important to evaluate for the presence of atherosclerosis. Few cases of severe atherosclerotic heart disease in children with sitosterolemia have been reported, making this case worthy of presentation. Here, we report a case of sitosterolemia in an 8-year-old child. The patient presented with severe hypercholesterolemia and xanthoma. He was diagnosed two and a half years prior with familial hypercholesterolemia because his father had elevated cholesterol levels. After conventional treatment, the patient was dissatisfied with lipid level control and visited our hospital for further management. Genetic tests of the patient and parents found mutations in intron 7 (NM 022436.2, c.904+1G>A) and intron 9 (NM 022436.2, C. 1324+1de1G) of ABCG5. The 7 intron mutation was from his mother, and the 9 intron mutation was from his father. The patient was diagnosed with sitosterolemia. The child was treated with ezetimibe, a low plant sterol diet, and clopidogrel anticoagulant therapy. After 3 months of treatment, the blood lipid level was significantly lower. Genetic testing should be completed as soon as possible to avoid misdiagnosis in children with abnormally elevated hypercholesterolemia who have a family history of elevated cholesterol. In addition, clinicians should rule out great arterial lesions and be vigilant in evaluating patients for systemic arterial disease and atherosclerosis.
PubMed: 34178886
DOI: 10.3389/fped.2021.668316 -
Circulation. Genomic and Precision... Oct 2020Familial sitosterolemia is a rare Mendelian disorder characterized by hyperabsorption and decreased biliary excretion of dietary sterols. Affected individuals typically...
BACKGROUND
Familial sitosterolemia is a rare Mendelian disorder characterized by hyperabsorption and decreased biliary excretion of dietary sterols. Affected individuals typically have complete genetic deficiency-homozygous loss-of-function (LoF) variants-in the or genes and have substantially elevated plasma sitosterol and LDL (low-density lipoprotein) cholesterol (LDL-C) levels. The impact of partial genetic deficiency of or -as occurs in heterozygous carriers of LoF variants-on LDL-C and risk of coronary artery disease (CAD) has remained uncertain.
METHODS
We first recruited 9 sitosterolemia families, identified causative LoF variants in or , and evaluated the associations of these or LoF variants with plasma phytosterols and lipid levels. We next assessed for LoF variants in or in CAD cases (n=29 321) versus controls (n=357 326). We tested the association of rare LoF variants in or with blood lipids and risk for CAD. Rare LoF variants were defined as protein-truncating variants with minor allele frequency <0.1% in or .
RESULTS
In sitosterolemia families, 7 pedigrees harbored causative LoF variants in and 2 pedigrees in . Homozygous LoF variants in either or led to marked elevations in sitosterol and LDL-C. Of those sitosterolemia families, heterozygous carriers of LoF variants exhibited increased sitosterol and LDL-C levels compared with noncarriers. Within large-scale CAD case-control cohorts, prevalence of rare LoF variants in and in was ≈0.1% each. heterozygous LoF variant carriers had significantly elevated LDL-C levels (25 mg/dL [95% CI, 14-35]; =1.1×10) and were at 2-fold increased risk of CAD (odds ratio, 2.06 [95% CI, 1.27-3.35]; =0.004). By contrast, heterozygous LoF carrier status was not associated with increased LDL-C or risk of CAD.
CONCLUSIONS
Although familial sitosterolemia is traditionally considered as a recessive disorder, we observed that heterozygous carriers of an LoF variant in had significantly increased sitosterol and LDL-C levels and a 2-fold increase in risk of CAD.
Topics: ATP Binding Cassette Transporter, Subfamily G, Member 5; ATP Binding Cassette Transporter, Subfamily G, Member 8; Adult; Case-Control Studies; Cholesterol, LDL; Coronary Artery Disease; Female; Heterozygote; Humans; Hypercholesterolemia; Intestinal Diseases; Lipid Metabolism, Inborn Errors; Lipoproteins; Loss of Function Mutation; Male; Middle Aged; Odds Ratio; Phytosterols; Risk Factors; Sitosterols
PubMed: 32862661
DOI: 10.1161/CIRCGEN.119.002871 -
Journal of Oleo Science Sep 2019Cardiovascular disease (CVD) has emerged as the leading cause of dealth worldwide today. Lowering circulating total cholesterol (TC) and low density lipoprotein... (Review)
Review
Cardiovascular disease (CVD) has emerged as the leading cause of dealth worldwide today. Lowering circulating total cholesterol (TC) and low density lipoprotein cholesterol (LDL-C) is one of the most effective approaches of CVD prevention. Dietary guidelines and health organizations approved using plant sterols (PS) as the alternative to conventional method in attenuating circulating TC and LDL-C levels and risk of CVD. However, current findings apprear to be controversial on the efficacy of PS. Giving the rise of the field "Nutrigenetics", single nucleotide polymorphisms (SNPs) such as CYP7A1-rs3808607 have been identified that strongly associate with cholesterol metabolism in response to PS intake, towards causing inter-individual variations. This review article aims to discuss the efficacy of dietary PS in managing cholesterol levels based on findings from recent studies. The scope includes reviewing evidence on supporting the efficacy, the metabolic claims, inter-individual variations as well as sitosterolemia associated with PS intake.
Topics: Animals; Anticholesteremic Agents; Cardiovascular Diseases; Cholesterol; Cholesterol 7-alpha-Hydroxylase; Cholesterol, LDL; Humans; Phytosterols; Polymorphism, Single Nucleotide
PubMed: 31413246
DOI: 10.5650/jos.ess19116 -
JIMD Reports Jul 2019Familial hypercholesterolemia due to heterozygous low-density lipoprotein-receptor mutations is a common inborn errors of metabolism. Secondary hypercholesterolemia due...
Familial hypercholesterolemia due to heterozygous low-density lipoprotein-receptor mutations is a common inborn errors of metabolism. Secondary hypercholesterolemia due to a defect in phytosterol metabolism is far less common and may escape diagnosis during the work-up of patients with dyslipidemias. Here we report on two sisters with the rare, autosomal recessive condition, sitosterolemia. This disease is caused by mutations in a defective adenosine triphosphate-binding cassette sterol excretion transporter, leading to highly elevated plant sterol concentrations in tissues and to a wide range of symptoms. After a delayed diagnosis, treatment with a diet low in plant lipids plus ezetimibe to block the absorption of sterols corrected most of the clinical and biochemical signs of the disease. We followed the two patients for over 10 years and report their initial presentation and long-term response to treatment.
PubMed: 31392106
DOI: 10.1002/jmd2.12038 -
Current Opinion in Lipidology Aug 2003PURPOSE OF REVIEW This review discusses recent progress in the role of ATP-binding cassette proteins ABCG5 and G8 in dietary sterol absorption, excretion and... (Review)
Review
PURPOSE OF REVIEW This review discusses recent progress in the role of ATP-binding cassette proteins ABCG5 and G8 in dietary sterol absorption, excretion and pathogenesis of cardiovascular disease. RECENT FINDINGS Identification of the genetic defect(s) underlying sitosterolemia has led to a renewed interest in the mechanisms of sterol absorption and biliary excretion. Mutations in ABCG5 (encoding sterolin-1) or ABCG8 (encoding sterolin-2) cause this disease. These proteins are thought to function by preventing dietary noncholesterol sterols from being retained by the body and for cholesterol excretion into bile. SUMMARY Despite improvements in treatments for hypercholesterolemia with cholesterol lowering agents, cardiovascular disease still remains highly prevalent. This has prompted many to consider that molecules other than cholesterol may be better biomarkers for this disease and targeting these more directly may allow us to develop more effective therapies. Ideally, if such a biomarker were also the bioactive molecule that is key to initiating/propagating the atherosclerosis pathogenic pathway, this would allow us to develop an optimal predictor and monitor of the disease process. One source of such molecules could come from our diet, with potential candidates such as noncholesterol sterols, oxysterols, oxidized sterols or some as yet unidentified dietary bioactive molecule. Nature has evolved a protective mechanism by which such molecules are kept out of the body, thereby reducing the negative effects of these compounds. The newly identified sterolin proteins involved in the absorption and excretion of dietary sterols may fit this bill. If so, we would speculate that a better biomarker may be lurking within their substrate specificities.
Topics: ATP-Binding Cassette Transporters; Animals; Arteriosclerosis; Cardiovascular Diseases; Clinical Trials as Topic; Humans; Phytosterols
PubMed: 12865730
DOI: 10.1097/01.mol.0000083763.66245.18 -
Orphanet Journal of Rare Diseases Nov 2014Cerebrotendinous xanthomatosis (CTX) OMIM#213700 is a rare autosomal-recessive lipid storage disease caused by mutations in the CYP27A1 gene; this gene codes for the... (Review)
Review
Cerebrotendinous xanthomatosis (CTX) OMIM#213700 is a rare autosomal-recessive lipid storage disease caused by mutations in the CYP27A1 gene; this gene codes for the mitochondrial enzyme sterol 27-hydroxylase, which is involved in bile acid synthesis. The CYP27A1 gene is located on chromosome 2q33-qter and contains nine exons. A CYP27A1 mutation leads to decreased synthesis of bile acid, excess production of cholestanol, and consequent accumulation of cholestanol in tissues. Currently there is no consensus on the prevalence of CTX, one estimate being <5/100,000 worldwide. The prevalence of CTX due to the CYP27A1 mutation R362C alone is approximately 1/50,000 in Caucasians. Patients with CTX have an average age of 35 years at the time of diagnosis and a diagnostic delay of 16 years. Clinical signs and symptoms include adult-onset progressive neurological dysfunction (i.e., ataxia, dystonia, dementia, epilepsy, psychiatric disorders,peripheral neuropathy, and myopathy) and premature non-neurologic manifestations (i.e., tendon xanthomas, childhood-onset cataracts, infantile-onset diarrhea, premature atherosclerosis, osteoporosis, and respiratory insufficiency). Juvenile cataracts, progressive neurologic dysfunction, and mild pulmonary insufficiency are unique symptoms that distinguish CTX from other lipid storage disorders including familial dysbetalipoproteinemia, homozygous familial hypercholesterolemia, and sitosterolemia, all of which might also present with xanthomas and cardiovascular diseases. Brain magnetic resonance imaging (MRI) shows bilateral lesions in the dentate nucleus of the cerebellum and mild white matter lesions. The classical symptoms and signs, namely elevated levels of cholestanol and bile alcohols in serum and urine, brain MRI, and the mutation in the CYP27A1 gene confirm the diagnosis of CTX. Early diagnosis and long-term treatment with chenodeoxycholic acid (750 mg/d) improve neurological symptoms and contribute to a better prognosis.
Topics: Animals; Bile Acids and Salts; Delayed Diagnosis; Diagnostic Imaging; Disease Management; Humans; Xanthomatosis, Cerebrotendinous
PubMed: 25424010
DOI: 10.1186/s13023-014-0179-4 -
PloS One 2020Sitosterolemia is an inherited lipid disorder which presents with elevated serum sitosterol and can result in an increased risk of premature cardiovascular disease....
BACKGROUND
Sitosterolemia is an inherited lipid disorder which presents with elevated serum sitosterol and can result in an increased risk of premature cardiovascular disease. However, sitosterol cannot be accurately measured by routine diagnostic assays, meaning that sitosterolemia diagnosis can often be difficult, especially with many clinical features overlapping with familial hypercholesterolemia. With such complications resulting in increasing reports of misdiagnosis, the prevalence of sitosterolemia is predicted to be much higher than previously reported.
METHODS
Gas chromatography-mass spectrometry was utilized to measure sitosterol levels of normocholesterolemic and hypercholesterolemic children. Subsequently, an epidemiologically determined cutoff level of sitosterol was calculated and applied to estimate the prevalence of children with increased sitosterol and identify potential sitosterolemia patients. Massively parallel sequencing was used to confirm the diagnosis in suspected patients.
RESULTS
Samples from 109 normocholesterolemic and 220 hypercholesterolemic were tested for phytosterols. Sitosterol and campesterol levels were significantly increased in hypercholesterolemic children (mean 22.0±45.9 μmol/L for sitosterol and 26.0±32.8 μmol/L for campesterol) compared to normocholesterolemic children (mean 12.1±4.9 μmol/L for sistosterol and 14.8±6.7 μmol/L for campesterol). Via application of a cutoff of 35.9 μmol/L, the prevalence rates for increased and overtly increased sitosterol in hypercholesterolemic children were 6.4% and 1.4% respectively. Furthermore, 3 suspected sitosterolemia patients were identified, with 2 patients receiving molecular confirmation for sitosterolemia diagnosis.
CONCLUSIONS
Our findings reaffirm that the prevalence of sitosterolemia is probably much higher than previously reported, which also indicates the significant risk of misdiagnosis of sitosterolemia with familial hypercholesterolemia. Special lipid testing including sitosterol, especially in children with uncontrolled hypercholesterolemia, is recommended in children in order to identify potential sitosterolemia patients that would otherwise be neglected.
Topics: ATP Binding Cassette Transporter, Subfamily G, Member 5; ATP Binding Cassette Transporter, Subfamily G, Member 8; Adolescent; Child; Child, Preschool; Cholesterol; Female; Gas Chromatography-Mass Spectrometry; Humans; Hypercholesterolemia; Infant; Intestinal Diseases; Lipid Metabolism, Inborn Errors; Lipoproteins; Male; Pedigree; Phytosterols; Prevalence; Sitosterols
PubMed: 32845916
DOI: 10.1371/journal.pone.0238079 -
Journal of Atherosclerosis and... Dec 2018
Topics: Biomarkers; Cholesterol; Humans; Hypercholesterolemia; Hyperlipidemias; Intestinal Diseases; Lipid Metabolism, Inborn Errors; Lipoproteins; Phytosterols; Postprandial Period; Prognosis; Risk Factors; Triglycerides
PubMed: 30305464
DOI: 10.5551/jat.ED104