Elevated cholesterol and bile acid synthesis in an adult patient with homozygous familial hypercholesterolemia. Reduction by a high glucose diet.

Stacpoole, Peter W.; Grundy, Scott M.; Swift, Larry L.; Greene, Harry L.; Slonim, Alfred E.; Burr, Ian M.

doi:10.1172/jci110361

Cited by 24 publications

(6 citation statements)

References 27 publications

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“…10 High cholesterol synthesis (34.2 mg/kg/day) in an adult homozygote 20 suggests that the twofold difference between the heterozygous parents and their homozygous children in the present study need not be due to age.…”

Section: Discussionmentioning

confidence: 60%

“…A heterozygote with a markedly high cholesterol production has been recently described. 32 A marked variation in the cholesterol production of the homozygotes (from 6.86 mg/kg/day 19 to 34.2 mg/kg/ day 20 ) could represent different combinations of parents with varying type of familial hypercholesterolemia. Low synthetic rates of cholesterol and bile acids in a large number of heterozygous patients suggest that low production predominates in Finnish familial hypercholesterolemia.…”

Section: Discussionmentioning

confidence: 99%

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Cholesterol and bile acid synthesis in two families with homozygous and heterozygous hypercholesterolemia.

Miettinen¹

1984

Arteriosclerosis

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Measurements of cholesterol and bile acid synthesis and of cholesterol precursors were performed in two hypercholesterolemic families with two homozygous girls under basal conditions and during treatment with cholestyramine. The concentrations of serum methyl sterols, squalene, cholesterol, and triglycerides, and the responses to cholestyramine were not consistently different in the two families. However, in both families stimulation of cholesterol synthesis by cholestyramine markedly increased the methyl sterol content of serum lipoproteins both in heterozygotes (with a lowering of serum cholesterol) and in homozygotes (with virtually no lowering of serum cholesterol concentration). The bile acid and cholesterol synthesis rates were modestly low in one family and markedly high in the other both with and without cholestyramine treatment, the baseline production rates being significantly correlated with the increments in the synthesis caused by cholestyramine. The two families apparently represent low and high producing types of familial hypercholesterolemia. Cholesterol synthesis in the two homozygous girls was about twice that of their respective heterozygous parents with and without cholestyramine treatment, suggesting that the double dose of the mutant gene doubled cholesterol production. A t the cellular level the homozygous state of famili ial xanthomatotic hypercholesterolemia is characterized by either absent, defective, or poorly functioning cell membrane receptors for low density lipoprotein (LDL). 1 " 3 Consequently, catabolism of LDL is impaired and results in a marked increase in the plasma level of LDL, i.e., in hypercholesterolemia. The production rate of LDL also appears to be enhanced, 4 " 7 but the overall cholesterol metabolism is poorly understood. In heterozygous adults cholesterol and especially bile acid synthesis is frequently subnormal 8 probably due to low hepatic cholesterol synthesis, 9 and the response to choiestyramine is low especially in subjects with a low baseline production.10 Hepatic cholesterol synthesis of homozygous hypercholesterolemic rabbits, Watanabe rabbits, also appears to be subnormal.11 Studies on cholesterol and bile acid synthesis in homozygous patients Received September 27,1983; revision accepted February 27, 1984. (mostly children) have revealed high, normal, and low production rates 6 ' 712 " 21 with no apparent relation to the LDL receptor status.7 No family studies have been performed, however. In the present study fecal steroids were measured in two homozygous hypercholesterolemic Finnish children and their parents before and during cholestyramine treatment to learn to what extent the heterozygous state of the parents is related to cholesterol metabolism in their homozygous children. Cholesterol precursors, squalene and unesterified methyl sterols, were also determined in serum because methyl sterols, and less consistently, squaiene relay changes in cholesterol synthesis in many clinical conditions. 2223 Methods Family StudiesThe clinical data about the ...

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Section: Discussionmentioning

confidence: 60%

Section: Discussionmentioning

confidence: 99%

Cholesterol and bile acid synthesis in two families with homozygous and heterozygous hypercholesterolemia.

Miettinen¹

1984

Arteriosclerosis

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“…Interestingly, a patient with homozygous familial hypercholesterolemia (LDL receptor deficiency) was found to have increased synthesis rates of cholesterol and bile acids when fed a normal diet. 122 On a high-glucose diet, this patient showed a decrease in total, HDL, and LDL cholesterol levels, whereas plasma triglyceride levels increased. At the same time, at least one large cutaneous xanthoma disappeared, demonstrating that the decline in plasma cholesterol was not caused by accelerated storage in peripheral organs.…”

Section: Role Of Fxr In Glucose Homeostasismentioning

confidence: 81%

“…Fecal balance studies showed that the high cholesterol and bile acid synthesis rates in this patient decreased on ingestion of the highglucose diet. 122 Because FXR expression is induced by glucose, 121 because FXR activation decreases HDL cholesterol, 22 and because FXR suppresses bile acid synthesis, 37 it is tempting to speculate that the high-glucose diet increased hepatic FXR expression, which, in turn, was followed by repression of apoA-I and CYP7A1 expression. Finally, the fact that not only homozygous familial hypercholesterolemic patients [123][124][125] but also normocholesterolemic men 126,127 on total parenteral nutrition (a diet extremely rich in glucose) display a significant reduction in plasma cholesterol and a decreased excretion of bile acids suggest that glucose interference with FXR signaling is likely to constitute a novel mechanism involved in the control of plasma cholesterol levels.…”

Section: Role Of Fxr In Glucose Homeostasismentioning

confidence: 99%

The Farnesoid X Receptor

Claudel

Staels

Kuipers

2005

ATVB

439

106

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Key Words: bile acid Ⅲ FXR Ⅲ glucose metabolism Ⅲ lipid Ⅲ nuclear receptor A s a direct consequence of the obesity epidemic, 1-3 the prevalence of the metabolic syndrome is increasing at an alarming rate. 4 Almost 25% of the adult US population is currently affected, and the situation is even worse in people older than 60 years. 5 The metabolic syndrome has been defined by the National Cholesterol Education Program as a cluster of at least 3 of 5 criteria: insulin resistance and glucose intolerance, abdominal obesity, hypertension, low high-density lipoprotein (HDL) cholesterol, and hypertriglyceridemia. 6 Given the fact that the metabolic perturbation associated with the metabolic syndrome predisposes to cardiovascular diseases and stroke, 7 novel and more specific therapeutical strategies are urgently needed. Certain ligand-activated nuclear receptors provide promising new targets for this purpose. In this review, we discuss the biology of the Farnesoid X receptor (FXR, NRIH4), recently identified as a modulator of lipid and glucose homeostasis.Nuclear receptors are transcription factors that, on ligand binding by specific molecules and cofactor recruitment, regulate the expression of specific target genes. 8 FXR is highly expressed in liver and intestine 9 and was cloned during a search for new Retinoid X receptor (RXR or NR2B1) heterodimers. 9,10 Originally described as a farnesol-activated receptor interacting with RXR, and accordingly named, FXR was later identified as a Original

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“…Furthermore, noncompetitive inhibitors may also be effective in reducing cholesterol synthesis and circulating cholesterol levels in patients with homozygous FH. This premise is substantiated by the observation that chronic administration of DCA leads to marked and sustained decreases in serum total and LDL cholesterol concentrations in two receptornegative homozygous FH patients (27), one of whom was found subsequently to have an elevated rate of cholesterol synthesis (46). DCA is not without potential toxicity.…”

Section: Discussionmentioning

confidence: 92%

Regulation of rat liver hydroxymethylglutaryl coenzyme A reductase by a new class of noncompetitive inhibitors. Effects of dichloroacetate and related carboxylic acids on enzyme activity.

Stacpoole¹,

Harwood²,

Varnado³

1983

J. Clin. Invest.

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A B S T R A C T Dichloroacetate (DCA) markedly reduces circulating cholesterol levels in animals and in patients with combined hyperlipoproteinemia or homozygous familial hypercholesterolemia (FH). To investigate the mechanism of its cholesterol-lowering action, we studied the effects of DCA and its hepatic metabolites, glyoxylate and oxalate, on the activity of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG CoA reductase) obtained from livers of healthy, reverse light-cycled rats. Oral administration of DCA for 4 d decreased HMG CoA reductase activity 46% at a dose of 50 mg/kg per d, and 82% at a dose of 100 mg/kg per d. A 24% decrease in reductase activity was observed as early as 1 h after a single dose of 50 mg/ kg DCA. The inhibitory effect of the drug was due to a fall in both expressed enzyme activity and the total number of reductase molecules present. DCA also decreased reductase activity when added to suspensions of isolated hepatocytes. With chronic administration, DCA inhibited 3H20 incorporation into cholesterol by 38% and into triglycerides by 52%. When liver microsomes were incubated with DCA, the pattern of inhibition of reductase activity was noncompetitive for both HMG CoA (inhibition constant [Ki] 11.8 mM) and NADPH (K; 11.6 mM). Inhibition by glyoxylate was also noncompetitive for both HMG CoA (K1 1.2 mM) and NADPH (K1 2.7 mM). Oxalate inhibited enzyme activity only at nonsaturating concentrations of NADPH (K, 5.6 mM Department of Medicine, College ylene glycol, all of which can form glyoxylate, also inhibited reductase activity. Using solubilized and 60-fold purified HMG CoA reductase, we found that the inhibitory effect of glyoxylate was reversible. Furthermore, the inhibition by glyoxylate was an effect exerted on the reductase itself, rather than on its regulatory enzymes, reductase kinase and reductase phosphatase. We conclude that the cholesterol-lowering effect of DCA is mediated, at least in part, by inhibition of endogenous cholesterol synthesis. The probable mechanisms are by inhibition of expressed reductase activity by DCA per se and by conversion of DCA to an active metabolite, glyoxylate, which noncompetitively inhibits HMG CoA reductase. These studies thus identify a new class of pharmacological agents that may prove useful in regulating cholesterol synthesis and circulating cholesterol levels in man.

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Elevated cholesterol and bile acid synthesis in an adult patient with homozygous familial hypercholesterolemia. Reduction by a high glucose diet.

Cited by 24 publications

References 27 publications

Cholesterol and bile acid synthesis in two families with homozygous and heterozygous hypercholesterolemia.

Cholesterol and bile acid synthesis in two families with homozygous and heterozygous hypercholesterolemia.

The Farnesoid X Receptor

Regulation of rat liver hydroxymethylglutaryl coenzyme A reductase by a new class of noncompetitive inhibitors. Effects of dichloroacetate and related carboxylic acids on enzyme activity.

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