Elevated cholesterol and bile acid synthesis in an adult patient with homozygous familial hypercholesterolemia. Reduction by a high glucose diet.
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Elevated levels of cholesterol synthesis are reported for several young children with homozygous familial hypercholesterolemia (HFH) and are considered to contribute directly to their hypercholesterolemia. In contrast, increased cholesterol production has not previously been found in adult patients with HFH. Using the fecal steroid balance technique, we studied rates of cholesterol and bile acid synthesis in a 24-yr-old man who had severe hypercholesterolemia typical of HFH and who lacked skin fibroblast low density lipoprotein (LDL) receptor activity. On an average diet (45% carbohydrate, 40% fat, 15% protein) mean +/- SEM cholesterol (24.8 +/- 1.4 mg/kg per d) and bile acid (11.1 +/- 1.6 mg/kg per d) excretion were approximately threefold higher than normal. When an isocaloric high carbohydrate, low fat diet (90.5% glucose oligosaccharides, 1.3% safflower oil, 8.2% crystalline amino acids was substituted, mean cholesterol (13.0 +/- 0.5 mg/kg per d) and bile acid (8.6 +/- 0.4 mg/kg per d) fell markedly. The decline in fecal steroid excretion was accompanied by modest reductions in plasma total and LDL cholesterol concentrations and by a softening of cutaneous xanthomata. Although the patient phenotypically and biochemically resembled the HFH state, his family pedigree was not noteable for hypercholesterolemia. While the patient's father had premature cardiovascular disease, his mother had no evidence of heart disease, had normal plasma total and LDL cholesterol levels, and had normal fibroblast LDL receptor activity. Likewise, the plasma cholesterol levels of three other members of the patient's family were normal. Despite the unusual genotypic background of this individual, however, the fecal balance data shows that elevated cholesterol and bile acid synthesis may occur in adult, as well as juvenile, patients with HFH and may be responsive to dietary control.MATSUSHIRO, T, CHO, H., NAGASHIMA, H., OMOKAWA, S, YAMAMOTO, K., HARIU, T. and TATEYAMA, T. Factors Affecting the Cholesterol Dissolution Ability of Human Bile. Tohoku J. exp. Med., 1981, 135 (1), 51-61 - Bile samples were obtained from 13 patients with cholesterol gallstones at laparotomy. Control bile samples were obtained from 15 patients with gastric cancer or gastric ulcer. One mixed stone was cut in half and serial thin sections, 10μm in thickness, were prepared from the cut surface. The solubility of cholesterol in these gallstone sections after immersion in the bile samples was observed microscopically after 1, 3, 5 and 24hr. Of 15 control bile samples, 9 showed a marked cholesterol dissolution after 1hr, and 6 showed it after 3 and 5hr. Three out of 13 bile samples from the patients with cholesterol stones dissolved the gallstone section after 1hr, and 7 after 3 and 5hr. The dissolution was not observed in the remaining 3 bile samples. Cholesterol and total bile acid concentrations of the control bile were significantly higher than those of the bile from the cholesterol gallstone patients (p<0.05 and p<0.02, respectively). Correlative studies of the composition of bile and its ability to dissolve cholesterol revealed that bile samples with a high total bile acid concentration possessed a higher dissolution ability, even when the ratios of total bile acid to cholesterol were almost the same in control and cholesterol gallstone bile. On the basis of these findings, it may be concluded that the solubility of cholesterol in bile cannot simply be explained in terms of relative concentrations of cholesterol, phospholipids and total bile acid, because the absolute concentration of total bile acid also plays a significant role for the dissolution ability.
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Reverse cholesterol transport
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We investigated the effect of increasing dietary cholesterol on bile acid pool sizes and the regulation of the two bile acid synthetic pathways (classic, via cholesterol 7α-hydroxylase, and alternative, via sterol 27-hydroxylase) in New Zealand white rabbits fed 3 g cholesterol/per day for up to 15 days. Feeding cholesterol for one day increased hepatic cholesterol 75% and cholesterol 7α-hydroxylase activity 1.6 times without significant change of bile acid pool size or sterol 27-hydroxylase activity. After three days of cholesterol feeding, the bile acid pool size increased 83% (P < 0.01), and further feeding produced 10%–20% increments, whereas cholesterol 7α-hydroxylase activity declined progressively to 60% below baseline. In contrast, sterol 27-hydroxylase activity rose 58% after three days of cholesterol feeding and remained elevated with continued intake. Bile drainage depleted the bile acid pool and stimulated downregulated cholesterol 7α-hydroxylase activity but did not affect sterol 27-hydroxylase activity. Thus, increasing hepatic cholesterol does not directly inhibit cholesterol 7α-hydroxylase and initially favors enzyme induction, whereas increased bile acid pool is the most powerful inhibitor of cholesterol 7α-hydroxylase. Sterol 27-hydroxylase is insensitive to the bile acid flux but is upregulated by increasing hepatic cholesterol.
Reverse cholesterol transport
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Purpose of review To provide an overview about the molecular basis of familial hypercholesterolemia. Recent findings Familial hypercholesterolemia is a common hereditary cause of premature coronary heart disease. It has been estimated that 1 in every 250 individuals has heterozygous familial hypercholesterolemia and that fewer than 1% of patients with familial hypercholesterolemia have been identified across the globe. If heterozygous familial hypercholesterolemia is left untreated, it is likely that coronary heart disease will manifest clinically prior to the age of 55 years and that half of all patients will prematurely die from the consequences of myocardial infarction. It is crucial to understand the molecular basis of familial hypercholesterolemia to diagnose familial hypercholesterolemia properly. Summary The phenotype of familial hypercholesterolemia is caused by more than 1700 mutations the LDLR, apoB and PCSK9 genes, which explains approximately 85% of familial hypercholesterolemia cases. By means of next-generation sequencing, an increasing number of mutations in established and putative novel genes associated with this phenotype have been identified.
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Patient registry
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Choline
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