Recent advances in understanding the STSL locus and ABCG5/ABCG8 biology

Patel, Shailendra B.

doi:10.1097/mol.0000000000000071

Cited by 26 publications

(20 citation statements)

References 67 publications

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“…The many clinical manifestations of sitosterolemia have been well-documented in a number of reviews (10,32,33). In summary, asymptomatic subjects (typically identified by cascade screening once a proband has been identified) can manifest no symptoms or signs to varying levels of affectations.…”

Section: Clinical Manifestationsmentioning

confidence: 99%

Thematic Review Series: Lipid Transfer Proteins ABCG5 and ABCG8: more than a defense against xenosterols

Patel

Graf

Temel

2018

Journal of Lipid Research

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The elucidation of the molecular basis of the rare disease, sitosterolemia, has revolutionized our mechanistic understanding of how dietary sterols are excreted and how cholesterol is eliminated from the body. Two proteins, ABCG5 and ABCG8, encoded by the sitosterolemia locus, work as obligate dimers to pump sterols out of hepatocytes and enterocytes. ABCG5/ABCG8 are key in regulating whole-body sterol trafficking, by eliminating sterols via the biliary tree as well as the intestinal tract. Importantly, these transporters keep xenosterols from accumulating in the body. The sitosterolemia locus has been genetically associated with lipid levels and downstream atherosclerotic disease, as well as formation of gallstones and the risk of gallbladder cancer. While polymorphic variants raise or lower the risks of these phenotypes, loss of function of this locus leads to more dramatic phenotypes, such as premature atherosclerosis, platelet dysfunction, and thrombocytopenia, and, perhaps, increased endocrine disruption and liver dysfunction. Whether small amounts of xenosterol exposure over a lifetime cause pathology in normal humans with polymorphic variants at the sitosterolemia locus remains largely unexplored. The purpose of this review will be to summarize the current state of knowledge, but also highlight key conceptual and mechanistic issues that remain to be explored.

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Section: Clinical Manifestationsmentioning

confidence: 99%

Thematic Review Series: Lipid Transfer Proteins ABCG5 and ABCG8: more than a defense against xenosterols

Patel

Graf

Temel

2018

Journal of Lipid Research

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“…For instance, sitosterolaemia sometimes resembles FH, but its management focuses on intestinal cholesterol absorption inhibition rather than statins. 27 Furthermore, patients with some dyslipidaemias do not express overt symptoms, such as atherosclerosis, until later in the disease course. When early prevention and management have been shown to delay onset of complications, there is benefit to identify and treat these individuals assertively as early as possible, as with heterozygous FH.…”

Section: Potential Benefitsmentioning

confidence: 99%

The role of genetic testing in dyslipidaemia

Berberich

Hegele

2019

Pathology

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Dyslipidaemias encompass about two dozen relatively rare monogenic disorders and syndromes for which the genetic basis has largely been defined. In addition, the complex polygenic basis of disturbed lipids and lipoproteins has been characterised in many patients, and has been shown to result from accumulation of many common polymorphisms with small effects on lipids. Genetic technologies, including dedicated genotyping and sequencing methods can detect both rare and common DNA variants underlying dyslipidaemias. Some dyslipidaemias may be clinically silent for years, but early diagnosis, including genetic diagnosis, may permit early intervention to prevent or delay deleterious downstream clinical consequences, such as premature vascular disease or acute pancreatitis. The potential clinical utility of genetic testing for familial hypercholesterolaemia, familial chylomicronaemia syndrome, lysosomal acid lipase deficiency and some others will increase demand for reliable genetic diagnostic methods. We review some current technologies, such as targeted next-generation sequencing that seem to be helpful with DNA diagnosis of dyslipidaemias. We also address technical, biological and clinical limitations of genetic testing in dyslipidaemias. Finally, genetic counselling issues, the potential impact of results on patients and health care providers, current gaps and future directions will be discussed.

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“…Some phytosterolemic patients also present with pseudo-homozygous FH, which is due to a complete failure of cholesterol efflux into bile [44,56]. Both elevated plasma cholesterol and plant sterol levels in phytosterolemia may contribute to premature vascular disease in early childhood or later in life [44], as it has been suggested that abnormal cholesterol metabolism likely contributes most strongly to the resulting atherosclerosis than plant sterol accumulation itself [32,57]. In a recent study including five phytosterolemic subjects, Hansel et al showed that, in spite of massive hypercholesterolemia and high plant sterol levels, none of the subjects had clinical symptoms of CVD or positive clinical markers of atherosclerosis [38,58].…”

Section: Cholesterol-lowering Effect Of Plant Sterols and Its Implicamentioning

confidence: 99%

Cardiovascular Disease Prevention: The Earlier the Better? A Review of Plant Sterol Metabolism and Implications of Childhood Supplementation

Scolaro

Andrade

Castro

2019

IJMS

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Atherosclerosis is the underlying cause of major cardiovascular events. The development of atherosclerotic plaques begins early in life, indicating that dietary interventions in childhood might be more effective at preventing cardiovascular disease (CVD) than treating established CVD in adulthood. Although plant sterols are considered safe and consistently effective in lowering plasma cholesterol, the health effects of early-life supplementation are unclear. Studies suggest there is an age-dependent effect on plant sterol metabolism: at a younger age, plant sterol absorption might be increased, while esterification and elimination might be decreased. Worryingly, the introduction of low-cholesterol diets in childhood may unintentionally favor a higher intake of plant sterols. Although CVD prevention should start as early as possible, more studies are needed to better elucidate the long-term effects of plant sterol accumulation and its implication on child development.

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Recent advances in understanding the STSL locus and ABCG5/ABCG8 biology

Abstract: Progress in understanding sterolin function is beginning to show that xenosterols can be toxic and are involved on pathogenesis, and the role of ABCG5/ABCG8 may extend into other metabolic processes by altering intracellular sterol metabolism.

Cited by 26 publications

References 67 publications

Thematic Review Series: Lipid Transfer Proteins ABCG5 and ABCG8: more than a defense against xenosterols

Thematic Review Series: Lipid Transfer Proteins ABCG5 and ABCG8: more than a defense against xenosterols

The role of genetic testing in dyslipidaemia

Cardiovascular Disease Prevention: The Earlier the Better? A Review of Plant Sterol Metabolism and Implications of Childhood Supplementation

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