Decreased cholesterol biosynthesis in sitosterolemia with xanthomatosis: Diminished mononuclear leukocyte 3-hydroxy-3-methylglutaryl coenzyme a reductase activity and enzyme protein associated with increased low-density lipoprotein receptor function

Nguyen, Lien; Salen, Gerald; Shefer, Sarah; Tint, St Stephen; Shore, Virgie G.; Ness, Gene C.

doi:10.1016/0026-0495(90)90260-j

Cited by 42 publications

(22 citation statements)

References 31 publications

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“…3 - 46 The reduced cholesterol formation has been related to a severe deficiency of HMG-CoA reductase in the liver 30 or mononuclear leukocytes 31 from these subjects. Both HMG-CoA reductase activity and enzyme protein were about 10% of normal, and mRNA for HMG-CoA reductase was almost lacking in the liver of a homozygote.…”

Section: Sitosterol Turnovermentioning

confidence: 99%

Increased sitosterol absorption is offset by rapid elimination to prevent accumulation in heterozygotes with sitosterolemia.

Salen

Tint

Shefer

et al. 1992

Arterioscler Thromb

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Using plasma isotope-kinetic methods, we measured the absorption and turnover rates of cholesterol and sitosterol (24-ethylcholesterol) in two obligate heterozygotes (parents) and their homozygous daughter with sitosterolemia with xanthomatosis. Diets contained approximately 500 mg/day cholesterol and 100 mg/day sitosterol. In the homozygote, plasma cholesterol and apolipoprotein B concentrations were slightly higher, but sitosterol levels were 22 and 58 times higher than in her heterozygous parents. Cholesterol absorption was at the high end of the normal range in both heterozygotes (59% and 84%) and in the homozygote (62%) (value in the control subject 48%). In contrast, cholesterol synthesis was severely depressed in the homozygote (28% and 26% as great as in the heterozygotes and the control, respectively). Sitosterol absorption in the homozygote (34%) was 12 and 2.0 times greater than in the heterozygotes and 6.8 times greater than in the control. The sitosterol turnover rate, calculated independently by mathematical analysis of specific-activity decay curves, amounted to 15 and 24 mg/day in the heterozygotes compared with 27 mg/day in the homozygote and 7.9±2J mg/day in five control subjects. However, the total body sitosterol pool was 15 and 103 times larger in the homozygote (4,080 mg) than in her heterozygous parents because of extremely slow removal. The average sitosterol elimination constant in the heterozygotes (K A =0.11 day" 1 ) was 10 times that in the homozygote (K A =0.01 day" 1 ) but 35% less than that in the controls (K A =0.17 day" 1 ). These results demonstrate that despite enhanced sitosterol absorption, small body pools and low plasma concentrations result from rapid elimination associated with adequate cholesterol synthesis in sitosterolemic heterozygotes. In distinction, sitosterol accumulates and body pools are disproportionately enlarged because increased absorption is combined with decreased removal, which may compensate for reduced cholesterol synthesis in sitosterolemic homozygotes. S itosterolemia with xanthomatosis is a rare lipid storage disease that presents clinically with accelerated atherosclerosis, tendon and tuberous xanthomas, hemotysis, and symmetrical arthritis and arthralgias involving the ankle and knee joints.1 Increased amounts of plant sterols (sitosterol, campesterol, and stigmasterol) and 5a-stanols (cholestanol, 5a-sitostanol, and 5a-campestanol) are present in plasma and all tissues except brain.2 Enhanced absorption of sitosterol and structurally related sterols has been suggested to account for the enlarged pools, 3 -7 while cholestanol and 5o-saturated plant sterol derivatives are produced endogenousry because diets are virtually devoid of these stanols. 8 - 10 The disease isFrom the Veterans Administration Medical Center, East Orange, and the University of Medicine and Dentistry-New Jersey Medical College, Newark, NJ.Supported by Research Service, Veterans Administration, and US Public Health Service grants HL-17818, DK-18707, and DK-26756.Address for c...

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Section: Sitosterol Turnovermentioning

confidence: 99%

Increased sitosterol absorption is offset by rapid elimination to prevent accumulation in heterozygotes with sitosterolemia.

Salen

Tint

Shefer

et al. 1992

Arterioscler Thromb

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“…In sitosterolemic humans ( 32 ) and mice ( 20 ), reduced activities of several hepatic enzymes involved in cholesterol synthesis have been shown. Although sitosterol has been shown to have a direct effect on CYP7 ␣ activity, it does not affect HMG-CoA reductase, and paradoxically, there is an upregulation of LDL-receptors in tissues from sitosterolemic individuals ( 32,(36)(37)(38)(39). To date, direct biological activity for most of these noncholesterol sterols has been diffi cult to demonstrate.…”

Section: Gene Expression Changes In Wat Of Abcg8mentioning

confidence: 99%

Dietary xenosterols lead to infertility and loss of abdominal adipose tissue in sterolin-deficient mice

Solcà

Tint²,

Patel

2013

Journal of Lipid Research

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Journal of Lipid Research Volume 54, 2013397 noncholesterol sterols. These noncholesterol sterols are primarily plant sterols, and the mammalian body prevents the retention of these noncholesterol sterols, only allowing cholesterol to be retained and metabolized by the body. The molecular mechanism(s) by which this occurs was elucidated by studies of the rare genetic disorder sitosterolemia (MIM #210250), which led to the identifi cation of two ABC "half-transporters" that are key to keeping these molecules out of the body ( 4-8 ). The genetic defect in Sitosterolemia results in the increased absorption of dietary sterols, including plant sterols, compounded by a profound inability to excrete biliary or intestinal sterols, thus leading to their retention ( 9-14 ). Mutations in either ABCG5 (sterolin-1) or ABCG8 (sterolin-2) cause the disease ( 5,8,15 ). ABCG5 and ABCG8 are found on the apical surface of enterocytes and hepatocytes ( 16-18 ), function as obligate heterodimers, and are the long-sought-after sterol exporters responsible for biliary and intestinal excretion ( 17,(19)(20)(21)(22)(23)(24). It is becoming increasingly clear that ABCG5/ABCG8 are responsible for preventing accumulation of a host of dietary noncholesterol sterols ( 25 ), and thus, the term "xenosterol" should be used to refer to the class of sterols they prevent from accumulating. Three mouse models for the study of xenosterol/sitosterol traffi cking are now available: a murine model simultaneously defi cient in both Abcg5/Abcg8 ( 22, 24 ), a model lacking only of Abcg8 ( 20 ), and one defi cient in Abcg5 ( 21 ). Despite some differences, all three models recapitulate important sitosterolemic features, such as increased plasma and tissue levels of plant sterols (phytosterols) and massively reduced Abstract The investigation of the human disease sitosterolemia (MIM 210250) has shed light not only on the pathways by which dietary sterols may traffi c but also on how the mammalian body rids itself of cholesterol and defends against xenosterols. Two genes, ABCG5 and ABCG8, located at the sitosterolemia locus, each encodes a membranebound ABC half-transporter and constitutes a functional unit whose activity has now been shown to account for biliary and intestinal sterol excretion. Knockout mice defi cient in Abcg5 or Abcg8 recapitulate many of the phenotypic features of sitosterolemia. During the course of our studies to characterize these knockout mice, we noted that these mice, raised on normal rodent chow, exhibited infertility as well as loss of abdominal fat. We show that, although sitosterolemia does not lead to any structural defects or to any overt endocrine defects, fertility could be restored if xenosterols are specifi cally blocked from entry and that the loss of fat is also reversed by a variety of maneuvers that limit xenosterol accumulation. These studies show that xenosterols may have a signifi cant biological impact on normal mammalian physiology and that the Abcg5 or Abcg8 knockout mouse model may prove useful in investigating...

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“…Previously, we demonstrated that reduced cholesterol synthesis and HMG-CoA reductase activity in sitosterolemic mononuclear leukocytes were due to decreased microsomal HMG-CoA reductase enzyme protein. 9 Therefore, sitosterolemic cells depend on enhanced high affinity LDL degradation to meet cellular sterols needs. When even more sterols are required to serve as precursors for augmented bile acid synthesis, only plasma lipoproteins are available as evidenced by the marked decline in plasma sterols and apolipoprotein B concentrations.…”

Section: Discussionmentioning

confidence: 99%

“…467 Furthermore, freshly isolated mononuclear leukocytes from sitosterolemic subjects show markedly diminished cholesterol synthesis and microsomal hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase activity and enzyme protein 9 that are coupled with increased high affinity LDL receptor function. 10 We have, therefore, postulated that reduced cholesterol synthesis is the primary biochemical abnormality in sitosterolemia and may be compensated for by enhanced intestinal plant sterol absorption, lipoprotein sterol transport (elevated circulating low density lipoprotein [LDL]), and the augmented expression of tissue LDL receptors.…”

mentioning

confidence: 99%

Unexpected failure of bile acid malabsorption to stimulate cholesterol synthesis in sitosterolemia with xanthomatosis. Comparison with lovastatin.

Nguyen¹,

Salen²,

Shefer³

et al. 1990

Arteriosclerosis

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We examined the relationship between cholesterol synthesis and high affinity low density llpoproteln (LDL) catabollsm In freshly Isolated mononuclear leukocytes and plasma sterols and apollpoproteln concentrations In three homozygous and one heterozygous subject with srtosterolemla with xanthomatosis and in 12 control subjects. Observations In untreated subjects were compared during therapy with lovastatin or interruption of the enterohepatic circulation of bile acids. Plasma cholesterol, plant sterol, and apollpoproteln B concentrations declined more than 50% In the two homozygous sHosterolemlc subjects after lleal bypass surgery. In contrast, plasma cholesterol, plant sterol, and apollpoproteln B concentrations remained constant In a homozygous sttosterolemlc subject and declined only 7% In a heterozygous sttosterolemlc subject during 20 weeks of lovastatin (40 mg/day) treatment compared to a 28% decrease In similarly treated control subjects. Lovastatin treatment decreased cholesterol synthesis more than 60% but did not Increase high affinity catabollsm of LDL further In the sitosterolemic cells, compared to a more than 20% rise In control mononuclear leukocytes. Conversely, bile acid malabsorption Increased cholesterol synthesis 59%, total hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase activity 13%, and receptor-mediated LDL degradation 41 % In control cells, but did not stimulate cholesterol synthesis or microsomal HMG-CoA reductase activity In sitosterolemic mononuclear leukocytes although receptor-mediated LDL catabollsm rose an additional 26%. These results demonstrate a greater than expected decrease In plasma sterols and apollpoproteln B concentrations In sitosterolemic subjects after stimulation of bile acid synthesis because of the Inability to up-regulate cholesterol production. We suggest that bile acid-sequestering drugs or lleal exclusion surgery may be more effective treatments to mobilize accumulated sterol deposits and prevent atherosclerosis in this disease. (Arteriosclerosis 10:289-297, March/April 1990)

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Decreased cholesterol biosynthesis in sitosterolemia with xanthomatosis: Diminished mononuclear leukocyte 3-hydroxy-3-methylglutaryl coenzyme a reductase activity and enzyme protein associated with increased low-density lipoprotein receptor function

Cited by 42 publications

References 31 publications

Increased sitosterol absorption is offset by rapid elimination to prevent accumulation in heterozygotes with sitosterolemia.

Increased sitosterol absorption is offset by rapid elimination to prevent accumulation in heterozygotes with sitosterolemia.

Dietary xenosterols lead to infertility and loss of abdominal adipose tissue in sterolin-deficient mice

Unexpected failure of bile acid malabsorption to stimulate cholesterol synthesis in sitosterolemia with xanthomatosis. Comparison with lovastatin.

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