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

Miettinen, Tatu A.

doi:10.1172/jci109607

Cited by 74 publications

(24 citation statements)

References 30 publications

(31 reference statements)

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“…3). Measurements of absorption of exogenous cholesterol in three patients confirmed the findings of Sedaghat et al 3 and Miettinen et al 4 In our view, therefore, the fundamental action of neomycin on cholesterol metabolism is to block cholesterol absorption. It should also be emphasized that the reduction in the absorption of cholesterol included not only the small amount in the diet but also the much larger amount excreted in the bile.…”

Section: Effects Of Neomycin On Cholesterol Metabolismsupporting

confidence: 87%

“…Some of the increment in fecal steroids may reflect a mobilization of cholesterol from tissue pools, 3 but for reasons discussed previously, 4 the magnitude and duration of the increase indicate that most of it was the result of heightened cholesterol synthesis. In most patients given neomycin, however, absorption is blocked to a such degree that losses cannot be replaced exactly by new synthesis.…”

Section: Effects Of Neomycin On Cholesterol Metabolismmentioning

confidence: 98%

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Turnover of low density lipoproteins during inhibition of cholesterol absorption by neomycin.

Kesäniemi¹,

Grundy²

1984

Arteriosclerosis

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The mechanisms for the hypocholesterolemic action of neomycin were examined in six patients with various levels of plasma total cholesterol and triglycerides. All patients were studied on a metabolic ward. The first period of 6 weeks was for control. Thereafter, neomycin (1.5 g/day) was started, and the patients were readmitted for another 6-week period after 2 to 3 months of treatment with the drug. Cholesterol balance studies showed that neomycin increased fecal excretion of neutral steroids by an average of 45%; the drug also inhibited absorption of exogenous cholesterol by an average of 44%. During treatment with neomycin, the plasma total cholesterol fell by an average of 20%, low density lipoproteins (LDL) fell by 25%, and high density lipoproteins, by 16%. Neomycin did not change plasma triglyceride levels. Turnover of the apoprotein of LDL (apoLDL) was measured following injection of 12S l-apoLDL. Neomycin decreased synthesis of apoLDL by 28%. The decrease in plasma apoLDL level was correlated positively with the decrease in apoLDL synthetic rate. The effect of the drug on clearance of LDL was less constant; four of six patients had an increase in fractional clearance rates of apoLDL, but the change for the whole group was not statistically significant. These data suggest that a decrease in production of LDL is a major factor in the lowering of LDL following inhibition of cholesterol absorption; however, an increase in clearance rates may occur in some patients. (Arteriosclerosis 4:41-48, January/February 1984) N eomycin is an almost nonabsorbable aminogly-coside antibiotic with a broad spectrum of activity. It also reduces plasma cholesterol in relatively low doses. 1-2 Most of the cholesterol lowering occurs in low density lipoproteins (LDL). The mechanism by which neomycin lowers LDL has been attributed mainly to a decrease in intestinal absorption of cholesterol. 34 A reduction in cholesterol absorption presumably decreases the quantity of cholesterol transported to the liver with chylomicrons. One response to a decrease in hepatic cholesterol is an increase in cholesterol synthesis. 5 This response, however, is not sufficient to prevent a fall in plasma LDL. The reason for the decrease in LDL levels has not been explained. One possibility is that a fall in hepatic cholesterol concentrations causes an increase in hepatic receptors for LDL which should promote LDL clearance. If this mechanism pertains, a fall in plasma LDL should be reflected by an increase in the fractional catabolic rate (FCR) of LDL. To test this hypothesis, turnover rates of LDL were estimated in six patients before and during treatment with neomycin.

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Section: Effects Of Neomycin On Cholesterol Metabolismsupporting

confidence: 87%

Section: Effects Of Neomycin On Cholesterol Metabolismmentioning

confidence: 98%

Turnover of low density lipoproteins during inhibition of cholesterol absorption by neomycin.

Kesäniemi¹,

Grundy²

1984

Arteriosclerosis

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“…Previous studies showed that under these experimental conditions, a reasonably steady state of sterol metabolism was obtained both with and without cholestyramine. 24 Thus, body weight was stable, plasma lipid values leveled off, and in successive fecal samples fecal steroids showed no constant increase or decrease. In growing children the sterol balance value (i.e., the difference between dietary cholesterol and fecal elimination of cholesterol as neutral sterols and bile acids) may underestimate cholesterol synthesis because growing tissues retain some cholesterol.…”

Section: Family Studiesmentioning

confidence: 94%

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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“…Bile acid sequestrants such as cholestyramine bind bile acids in the intestinal lumen, thereby preventing their reabsorption. Loss of bile acids from the enterohepatic circulation results in derepression of 7a-hydroxylase expression (6)(7)(8)(9)(10) and an increase in the rate of bile acid synthesis (9,11). The liver compensates for the accelerated loss of cholesterol by increasing the rate of de novo cholesterol synthesis and, if this is inadequate, by increasing the receptordependent uptake of LDL from plasma (10), thereby lowering circulating LDL levels.…”

Section: Introductionmentioning

confidence: 99%

Adenovirus-mediated transfer of a gene encoding cholesterol 7 alpha-hydroxylase into hamsters increases hepatic enzyme activity and reduces plasma total and low density lipoprotein cholesterol.

Spady¹,

Cuthbert²,

Willard³

et al. 1995

J. Clin. Invest.

109

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

Cited by 74 publications

References 30 publications

Turnover of low density lipoproteins during inhibition of cholesterol absorption by neomycin.

Turnover of low density lipoproteins during inhibition of cholesterol absorption by neomycin.

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

Adenovirus-mediated transfer of a gene encoding cholesterol 7 alpha-hydroxylase into hamsters increases hepatic enzyme activity and reduces plasma total and low density lipoprotein cholesterol.

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