Disruption of cholesterol homeostasis by plant sterols

Yang, Chendong; Yu, Liqing; Li, Weiping; Fang, Xu; Cohen, Jonathan C.; Hobbs, Helen H.

doi:10.1172/jci200422186

Cited by 45 publications

(68 citation statements)

References 51 publications

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“…Surprisingly in this context, expression of the gene encoding 3-hydroxy-3-methylglutaryl-CoA reductase was not affected in megakaryocytes from Abcg5 Ϫ/Ϫ mice, suggesting that cellular cholesterol synthesis was unchanged. High plant sterol levels have previously been reported to be associated with increased Abca1 expression in adrenal glands in Abcg5 Ϫ/Ϫ /Abcg8 Ϫ/Ϫ double knock-out mice due to activation of the liver X receptor (45). However, this clearly does not happen in megakaryocytes, indicating that cholesterol homeostasis is differentially affected by plant sterols in different cell types.…”

Section: Discussionmentioning

confidence: 98%

Plant Sterols Cause Macrothrombocytopenia in a Mouse Model of Sitosterolemia

Kruit

Drayer

Bloks

et al. 2008

Journal of Biological Chemistry

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Mutations in either ABCG5 or ABCG8 cause sitosterolemia, an inborn error of metabolism characterized by high plasma plant sterol concentrations. Recently, macrothrombocytopenia was described in a number of sitosterolemia patients, linking hematological dysfunction to disturbed sterol metabolism. Here, we demonstrate that macrothrombocytopenia is an intrinsic feature of murine sitosterolemia. Abcg5-deficient (Abcg5 ؊/؊ ) mice showed a 68% reduction in platelet count, and platelets were enlarged compared with wild-type controls. Macrothrombocytopenia was not due to decreased numbers of megakaryocytes or their progenitors, but defective megakaryocyte development with deterioration of the demarcation membrane system was evident. Lethally irradiated wild-type mice transplanted with bone marrow from Abcg5 ؊/؊ mice displayed normal platelets, whereas Abcg5 ؊/؊ mice transplanted with wild-type bone marrow still showed macrothrombocytopenia. Treatment with the sterol absorption inhibitor ezetimibe rapidly reversed macrothrombocytopenia in Abcg5 ؊/؊ mice concomitant with a strong decrease in plasma plant sterols. Thus, accumulation of plant sterols is responsible for development of macrothrombocytopenia in sitosterolemia, and blocking intestinal plant sterol absorption provides an effective means of treatment.Plant sterols structurally differ from cholesterol only by the presence of an additional methyl or ethyl group at C-24 (campesterol and sitosterol, respectively), in some cases with an additional double bond at C-22 (brassicasterol and stigmasterol, respectively). These structural differences appear to have a major impact on their handling in the body. Despite the fact that regular Western diets contain similar amounts of cholesterol and plant sterols (intakes of ϳ200 -400 mg/day for both) (1), plasma levels of plant sterols are Ͼ100 times lower than those of cholesterol in healthy individuals (2), indicating the presence of effective systems to prevent plant sterol accumulation in the human body. It has become clear that the ATPbinding cassette half-transporters ABCG5 and ABCG8, most abundantly present in intestine and liver, are critically involved herein. ABCG5 and ABCG8 function as an obligate heterodimer and mediate cholesterol and plant sterol transport out of intestinal and hepatic cells (3, 4). The functional heterodimer is present at the apical membranes of enterocytes and hepatocytes, where it transports (plant) sterols back into the intestinal lumen or bile, respectively (4, 5). Expression of ABCG5 and ABCG8 in other organs and tissues is relatively low (6 -8), and functionality at sites other than intestine and liver has not been reported.Mutations in either the ABCG5 or ABCG8 gene cause sitosterolemia (9, 10). Sitosterolemia is a relatively rare autosomal recessive disorder characterized by the accumulation of plant sterols in blood and tissues. Patients frequently develop tendon and cutaneous xanthomas and, most important, are at risk of developing premature coronary atherosclerosis (11)(12)(13)(14). A ...

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Section: Discussionmentioning

confidence: 98%

Plant Sterols Cause Macrothrombocytopenia in a Mouse Model of Sitosterolemia

Kruit

Drayer

Bloks

et al. 2008

Journal of Biological Chemistry

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“…However, the mechanism by which serum cholesterol levels increase during breastfeeding in sitosterolaemia is still unclear. Stigmasterol, the other plant sterol that accumulates in sitosterolaemia, inhibits the processing of a transcription factor, sterol regulatory element binding protein-2 which stimulates the transcription of hepatic LDLR (Yang et al 2004). Accordingly, the transcription of hepatic LDLR is assumed to be inhibited, resulting in an increase in circulatory cholesterol.…”

Section: Discussionmentioning

confidence: 99%

Infantile Cases of Sitosterolaemia with Novel Mutations in the ABCG5 Gene: Extreme Hypercholesterolaemia is Exacerbated by Breastfeeding

et al. 2015

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Few data exists regarding the clinical impact of breastfeeding in infantile sitosterolaemic cases. We report four Japanese infantile cases of sitosterolaemia, an extremely rare inherited disease characterised by increased serum levels of plant sitosterol, presenting with severe hypercholesterolaemia and systemic xanthomas exacerbated by breastfeeding. In these four cases, genetic analyses were performed for low-density lipoprotein (LDL) receptor, proprotein convertase subtilisin/kexin type 9 (PCSK9), LDL receptor adaptor protein 1 and ATP-binding cassette (ABC) subfamily G member 5 and 8 (ABCG5 and ABCG8) genes. We assessed their clinical manifestations, including responsiveness to a variety of treatments, especially to weaning from breastfeeding and use of ezetimibe. Two pairs of mutations in the ABCG5 gene in each case, including two novel mutations (c.130C>T or p.Ser44Ala and c.1813_1817delCTTTT or p.Pro558GlufsX14) and two known mutations (c.1306G>A or p.Arg389His and c.1336C>T or p.Arg446X), were identified. Significant reductions in cholesterol levels were obtained by means of weaning from breastfeeding alone. Substantial reductions in sitosterol levels, without any apparent side effects, were observed with ezetimibe. In conclusion, we have identified infantile Japanese sitosterolaemic subjects with extreme hypercholesterolaemia exacerbated by breastfeeding. Their unique response to weaning from breastfeeding, as well as to use of ezetimibe, could provide insights into the metabolic basis of sterols in humans.

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“…This observation indicates that sitosterol might possess a cell-proliferating or cell-protecting property which overcomes ER stress and the proposed cytotoxic effect of free sterol accumulation. A previous study which analyzed differential effects among different sterols on cholesterol homeostasis in adrenal cell line Y1-BS1 cells has shown that sitosterol had less potency in the processing of SREBP-2 than cholesterol, leading to less potent suppression of HMG-CoA reductase in these cells 33) ; thus it is probable that a slight but distinct difference in the chemical structure among sterols leads to a difference in the plasticity of cell membranes, causing differential effects on cell proliferation or viability. Future studies are awaited to clarify this mechanism.…”

Section: Discussionmentioning

confidence: 99%

Plant Sterols Increased IL-6 and TNF-α Secretion from Macrophages, but to a Lesser Extent than Cholesterol

Kurano

Iso-O

Hara

et al. 2011

JAT

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Aim:Phytosterolemia is an inherited disorder characterized by hypercholesterolemia and premature atherosclerosis, together with increased inflammatory states in some cases. The underlying mechanisms of atherogenesis in phytosterolemia, however, have not been completely elucidated. In this study, we investigated whether phytosterols would affect inflammatory reactions in macrophages and macrophage cell lines. Methods:We incubated RAW264.7 cells (RAW) and mouse peritoneal macrophages (MPMs) with sitosterol (Sito), campesterol (Camp) or cholesterol (Chol) at low (8 M, 16 M) or high (160 M) concentrations, and investigated their effects on LPS-induced secretion of IL-6 and TNF-. We also analyzed their effects on endoplasmic reticulum (ER) stress in both cells, and on the cell proliferation of RAW.Results: At low sterol concentrations, only Chol resulted in a tendency toward the increased secretion of TNF-from MPMs. At high concentrations, Chol induced a significant increase in TNF-secretions from both cells; however, Sito resulted in a non-significant increase in TNF-secretion. The effects on IL-6 secretions of Sito were also significantly less than those of Chol. Camp increased the secretions of both cytokines from MPMs; however, the extent of these increases was less pronounced than that of Chol. Augmentation of ER stress was greatest with Chol among the sterols, and the proliferation of RAW cells was inhibited only with Chol. Conclusion: The lesser degree of inflammatory reactions and toxicity in macrophages with phytosterols than with cholesterol suggests that plant sterols themselves might not be primarily responsible for atherogenesis in phytosterolemia. , raising controversy regarding the role of plant sterols in atherosclerosis. J AtherosclerPhytosterolemia or sitosterolemia, characterized by elevated plasma levels of plant sterols, is a rare autosomal recessive disease which is caused by mutations in either of the 2 sterolins, sterolin-1 and sterolin-2 4-7). The major clinical manifestations of phytosterolemia are tendon and tuberous xanthomas and premature atherosclerotic diseases [7][8][9][10] , and several lipid-lowering agents have been proven to be effective in amelioration of the lipid profile of phytosterolemia [11][12][13] . In spite of the clear association of phytosterolemia and atherosclerotic diseases, the underlying mechanisms leading to atherogenesis have not been elucidated. One possible mechanism proposed is the increased plasma levels of plant sterols in phytosterolemia, leading to the accumulation of plant sterols in atherosclerotic lesions. The autopsy of patients with phytosterolemia revealed that the proportion of plant sterols and cholesterol in atherosclerotic lesions was almost the same as that found in plasma LDL particles 14,15) , leading to the speculation that plant sterols might be more proatherogenic than cholesterol. Another proposal is elevated cholesterol levels in phytosterolemia 9) ; however, phytosterolemia patients whose plasma cholesterol levels are not elevated have be...

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Disruption of cholesterol homeostasis by plant sterols

Cited by 45 publications

References 51 publications

Plant Sterols Cause Macrothrombocytopenia in a Mouse Model of Sitosterolemia

Plant Sterols Cause Macrothrombocytopenia in a Mouse Model of Sitosterolemia

Infantile Cases of Sitosterolaemia with Novel Mutations in the ABCG5 Gene: Extreme Hypercholesterolaemia is Exacerbated by Breastfeeding

Plant Sterols Increased IL-6 and TNF-α Secretion from Macrophages, but to a Lesser Extent than Cholesterol

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