New Insights Into Cholesterol Dynamics

199

A B S T R A C T To investigate the gene-dosage effect in familial hypercholesterolemia (FH), metabolic studies were conducted in a group of well-characterized patients with either heterozygous (n = 7) or homozygous (n = 7) FH and the results were compared to those obtained in normal subjects (n = 6). 524 these seven patients is caused by variation in the plasma apoLDL synthetic rates. Consistent with this conclusion was the finding that the correlation between the plasma LDL level and the apoLDL synthetic rates in the seven FH homozygotes was 0.943.The rate of total body cholesterol synthesis determined by chemical cholesterol balance did not appear to clearly differ between normals and patients with either one or two mutant FH genes. Two of the youngest FH homozygotes exhibited cholesterol overproduction but the other five did not. No consistent abnormality of bile acid metabolism was observed in these patients. Because the daily plasma flux of cholesterol on LDL is about threefold greater than the amount of cholesterol produced per day, a significant amount ofthe cholesterol liberated from LDL degradation must be reused.

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Metabolic Studies in Familial Hypercholesterolemia

Bilheimer¹,

Stone²,

Grundy³

1979

199

“…4) DAYS ON DRUGS FIGURE 4 Effects of cholestyramine and neomycin on serum lipids and fecal steroids. Relative changes (mean±SE) calculated from studies in Table III the long term only occasional cases with heterozygous familial hypercholesterolemia became normocholesterolemic even after an ileal bypass operation (23,24). Ofthe suitable hypolipidemic drugs, clofibrate, nicotinic acid, ion exchangers, and probucol frequently fail for one reason or another.…”

Section: Methodsmentioning

confidence: 99%

“…This suggests that stimulation of synthesis is mediated by different mechanism(s). Cholestyramine enhances the removal of cholesterol solely as bile acids and depletes hepatocyte cholesterol in man (24), a change considered to be the major factor in stimulating hepatic cholesterol synthesis (38). In addition, the drug may stimulate intestinal cholesterol synthesis to some extent in man (39).…”

Section: Methodsmentioning

confidence: 99%

Effects of Neomycin Alone and in Combination with Cholestyramine on Serum Cholesterol and Fecal Steroids in Hypercholesterolemic Subjects

Miettinen¹

1979

Self Cite

A B S T R A C T Effects of neomycin were studied on serum cholesterol and fecal steroids in hypercholesterolemic patients during a short treatment period (4 wk) and a long treatment period (16 mo), using small (1.5 g/d) and large (up to 6 g/d) doses alone and in combination with cholestyramine. In the short-term low-dose study the decrease in serum cholesterol by 21% was associated with a proportionate increase in fecal cholesterol elimination as neutral sterols through impaired cholesterol absorption. Serum cholesterol remained low and fecal steroid excretion remained elevated in the long-term neomycin study. Increasing the dosage from 1.5 to 6 g/d at the end of the 16-mo period brought about a further slight decrease in serum cholesterol and a small further increase in fecal neutral and acidic steroids. The increases in fecal bile acids and fat but not in neutral sterols were positively correlated with the increases in the neomycin dosage. Thus, large neomycin doses can also cause bile acid malabsorption. In another series of patients, a decrease (25%) in serum cholesterol by cholestyramine was associated with a proportional increase in the fecal elimination of cholesterol (2.5-fold) as bile acids. The inclusion of neomycin in cholestyramine therapy further increased fecal steroid output (solely as neutral sterols) by only about one-fifth ofthat due to cholestyramine, but further decreased serum cholesterol almost to the same extent (-17%) as cholestyramine alone. The overall decrease was 38%, no side effects occurred, and the patients found combination therapy convenient. Neomycin decreased serum cholesterol in

“…Indeed, an overproduction of cholesterol has been found in several young children with HFH (2)(3)(4). Older homozygous patients (5,6), or those with heterozygous FH (2,(7)(8)(9), however, have not been found previously to have abnormal cholesterol synthesis. These observations led to the hypothesis (4) that excessive production of cholesterol in HFH is manifested only in childhood and is offset later in life by other factors restoring cholesterol production to normal.…”

Section: Introductionmentioning

confidence: 99%

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

Stacpoole¹,

Grundy²,

Swift³

et al. 1981

A B S T R A C T 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