Collagen biosynthesis enzymes in serum and hepatic tissue in liver disease. I. Prolyl hydroxylase.
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Adult↗
Biomedical subjects
T A Miettinen
Publications and source records attributed to T A Miettinen.
Collagen biosynthesis enzymes in serum and hepatic tissue in liver disease. II. Galactosylhydroxylysyl glucosyltransferase.
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Adult↗
Effects of weight reduction on squalene, methyl sterols and cholesterol and on their synthesis in human adipose tissue.
Quantitation of cholesterol and its precursors from human adipose tissue biopsies revealed very high squalene and moderately high methyl sterol concentrations. The squalene and cholesterol values were correlated with each other. Weight reduction in obese subjects following a jejuno-ileal bypass resulted in a significant but transient increase in adipose tissue cholesterol. The squalene concentration was also increased postoperatively, the maximum being reached about 6 months later than that of cholesterol as if the mobilization of squalene from shrunken adipocytes had been slow. Weight reduction with a 2--14 day total fast significantly reduced the adipocyte size but had no consistent effect on adipose tissue squalene, methyl sterol and cholesterol concentrations or on their adipocyte contents. Incubation of adipose tissue with labelled acetate and mevalonate revealed that the bulk of the labels in non-saponifiable lipids stayed in the large intermediate pools of methyl sterols and squalene in particular, fairly little being found in the cholesterol fraction itself. The total fast inhibited the incorporation of both 14C-acetate and 3H-mevalonate to squalene, methyl sterols and cholesterol, suggesting that cholesterol synthesis was inhibited before and after the mevalonate step.
Adipose Tissue↗
Effects of neomycin alone and in combination with cholestyramine on serum cholesterol and fecal steroids in hypercholesterolemic subjects.
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 of that 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 different studies by 10+/-2, 17+/-4, and 12+/-4% per 100 mg/d of the increment in fecal steroids, the respective decrease for cholestyramine being only 2.2+/-0.5%. Thus, neomycin effectively reduced serum cholesterol by a relatively small increase in cholesterol elimination (via cholesterol malabsorption) compared with cholestyramine-induced bile acid malabsorption.
Adult↗
New insights into cholesterol dynamics.
Kinetic aspects of cholesterol dynamics are described, with flux from the gut, to the liver, to the tissues, and back to the liver and gut, with a discussion of modifying mechanisms, synthesis, and transport. Overproduction of cholesterol, and bile acid and cholesterol malabsorption, are related to clinical problems.
Bile Acids and Salts↗
Effects of bran on serum cholesterol, faecal mass, fat, bile acids and neutral sterols, and biliary lipids in patients with diverticular disease of the colon.
Twenty-two patients with symptomatic diverticular disease of the colon were randomly allocated to control and high-fibre groups so that the long-term effect (up to 12 months) of bran on serum, faecal and biliary lipids could be studied. Even in cases of high initial values, faecal mass was increased by bran and the change was positively correlated with the change in dietary fibre. Faecal fat and dry weight were also increased. Faecal bile acids were initially slightly raised and were positively correlated with wet weight both off and on bran. The latter significantly decreased the excretion and concentration of bile acids, in particular the high initial values. The change in bile acids was not correlated with the change in dietary fibre or faecal wet weight. Sterol balance values indicated that the bran-induced decrease in faecal bile acids was associated with a lower cholesterol synthesis. Serum cholesterol decreased significantly in two hypercholesterolaemic individuals only. Correlations between different parameters revealed that the higher the initial level or the greater the drop in cholesterol synthesis, the greater the decrease in serum cholesterol. Bran had no effect on the biliary saturation of cholesterol. The percentage of biliary deoxycholate was negatively correlated with faecal mass (less so with faecal bile acid output) both before and during bran and was significantly decreased by bran. The percentage of cholic acid increased correspondingly and that of chenodeoxycholate remained unchanged. Faecal bile acids also indicated that the synthesis of the two primary bile acids was lowered by bran to the same degree.
Adult↗
Release of newly synthesized squalene, methyl sterols and cholesterol from human adipocytes in the presence of lipoproteins.
Upon incubation of free fat cells for 3 h with labelled mevalonate, more than 90% of the radioactivity of the non-saponifiable material was found in the squalene fraction and less than 10% in the methyl sterol and cholesterol fractions. About 25, 30 and 65% of the cholesterol counts were found respectively in VLDL, LDL, or HDL added to the medium while none of the newly synthesized squalene was released into the lipoproteins. The results indicate that adipose tissue squalene can originate from local synthesis. It is not released from the cells into the medium, but can contribute to local cholesterol synthesis in both rapidly and slowly exchangeable cholesterol pools of adipose tissue.
Adipose Tissue↗
Fecal beta-sitosterol in patients with diverticular disease of the colon and in vegetarians.
Fecal sterol analysis showed that excretion of beta-sitosterol, a major component of poorly absorbable dietary vegetable sterols, is subnormal in patients with diverticular disease of the colon. Thus, the patients had evidently consumed a diet low in plant materials. The finding agrees with the current opinion that diverticular disease of the colon is associated with dietary fibre deficiency and suggests that fecal beta-sitosterol provides a rough measure of the vegetable intake. In vegetarians the beta-sitosterol excretion was actually high.
Adult↗
Effect of pectin on serum cholesterol, fecal bile acids and biliary lipids in normolipidemic and hyperlipidemic individuals.
Pectin, 40-50 g/day for two weeks administered to nine normolipidemic and hyperlipidemic patients, had no effect on serum triglycerides but did cause a significant decrease in the serum total and unesterified cholesterol of hypercholesterolemic subjects in particular. This was associated with increased excretion of fecal bile acids and total steroids and increased concentration of plasma methyl sterols. Thus, the serum cholesterol reduction by pectin appears to be caused by increased cholesterol elimination into stools as bile acids which is then balanced by enhanced cholesterol synthesis. The composition of biliary bile acids and lipids was not changed and secondary bile acids and sterols decreased inconsistently in feces. The measurement of fecal dry weight suggested that the bulk of the pectin was degraded by bacteria during passage through the intestine. Consequently fecal mass and dry weight were not consistently increased, suggesting that pectin may not be an ideal fibre for increasing fecal bulk in functional colonic disorders.
Adult↗
Treatment of hyperlipoproteinemias with neomycin, probucol and tibric acid.
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Cholesterol↗
Cholestyramine and ileal by-pass in the treatment of familial hypercholesterolaemia.
A comparison was made of the therapeutic effectiveness of cholestyramine and an ileal by-pass operation as hypocholesterolaemic measures in thirteen patients with familial xanthomatotic type II hypercholesterolaemia. Serum cholesterol and faecal steroids were measured before and at the end of a 10 day course of cholestyramine (32 g/day), and subsequently after an ileal by-pass operation. The mean decrease in serum cholesterol caused by cholestyramine (-17%) was significantly less than that caused by the surgical procedure (-33%). The increase in faecal steroid excretion, mainly as bile acids, was lower with cholestyramine (1.261 g/day) than after the ileal exclusion (2.176 g/day) and a positive correlation was found between the decrease in serum cholesterol and the increase in the faecal elimination of steroids of cholesterol origin. However, even though the increase in faecal steroids with cholestyramine was positively correlated with that resulting from ileal by-pass, the correlation between the corresponding changes in serum cholesterol level was not significant. The findings indicate that ileal by-pass decreases serum cholesterol and increases faecal elimination of cholesterol more effectively than cholestyramine, and that the decrease in the serum cholesterol level induced by ileal exclusion is not consistently predictable by the serum cholesterol response to the preceding cholestyramine treatment.
Adult↗
Serum immunoreactive prolyl hydroxylase in liver disease.
The concentration of serum immunoreactive prolyl hydroxylase (SIRPH) was measured in thirty patients with chronic active hepatitis, thirteen with primary biliary cirrhosis, four with alcoholic or idiopathic cirrhosis, and four with acute hepatitis; the values were compared with those in twenty-three control subjects. Increases in SIRPH were found in all the groups with liver diseases, individual values being highest in primary biliary cirrhosis in which about two-thirds of patients had values more than two standard deviations above the mean value in the control subjects. No correlation was found between SIRPH and other tests of liver function or some routine laboratory tests. SIRPH may reflect some hitherto unknown of unmeasured process in the diseased hepatic cells.
Adolescent↗
Measurement of cholesterol synthesis in kinetically defined pools using fecal steroid analysis and double labeling technique in man.
The purpose of the study was to develop a kinetic method for measurement of different parameters of cholesterol metabolism in man using labeled cholesterol precursors that could initially be incorporated even into the slowly exchangeable cholesterol pool. For this purpose, tritiated water and [2-14C]mevalonate were given to five normocholesterolemic subjects and the activities for serum cholesterol and body water were measured serially for up to eight weeks. Elimination of cholesterol was measured by fecal analysis of neutral and acidic steroids. For comparison, two subjects received a mixture of [4-14C]cholesterol and [2-3H]mevalonate. The data were subjected to multicompartmental analysis by computer, with the assumption that synthesis occurred in two compartments. The rapidly exchangeable cholesterol (pool 1) and the fractional hydrogon transport constant from body water to cholesterol could not be measured directly; therefore, the influence of two different mass transport values was tested. The best fit was obtained with the smaller mass of cholesterol in pool 1 associated with a hydrogen transport constant of 0.700 (32 out of 46 hydrogens originate from water). Kinetic analysis of the data allows estimates of the exchangeable cholesterol mass, flux rates of cholesterol between pools 1 and 2, and synthesis of cholesterol separately in the two pools. The results of computer analysis suggested that, in contrast to what has been assumed earlier on the basis of studies with radiolabelled cholesterol, 22-53% of endogenous cholesterol synthesis took place in pool 2 from body water and that this synthesis tended to correlate with the total body fat mass. The study with [2-3H]mevalonate and [4-14C]cholesterol indicated synthesis in pool 2 to be 20-22% of the total. Up to 50% of the DL[2-14C]mevalonate dose was incorporated into cholesterol. The fractional incorporation of DL-mevalonate into pool 2 was correlated with that of tritiated water, indicating that both precursors studied yielded essentially the same kinetic result.
Adult↗
Treatment of hypercholesterolemia with Secholex. A long-term clinical trial and comparison with cholestyramine.
The efficacy of an anion-exchange gel, Secholex, as a hypocholesterolemic agent was assessed in 46 patients in 4 different studies and the effects were compared with those of cholestyramine. All patients had severe Type II-a or II-b hyperlipoproteinemia. In short-term metabolic studies Secholex (15 g/day) and cholestyramine (16 g/day) decreased serum cholesterol levels and increased total fecal sterol output and serum methyl sterol concentration to a similar extent, but cholestyramine was more effective than Secholex in increasing fecal bile acid excretion. In crossover studies, the two drugs appeared to be equally effective in lowing serum cholesterol levels but the patients mostly preferred Secholex. Twenty patients were treated with Secholex over a two-year period. The average decrease in serum cholesterol levels from the mean pretreatment value of 406 mg/100 ml was 15% during the first year, and 13% during the second year. In 5 patients the serum cholesterol was permanently lowered by more than 20% (good responders), while in 7 patients the average reduction of serum cholesterol level during Secholex administration was less than 10% (non-responders). The serum triglyceride level was slightly decreased by Secholex in Type II-b patients but was unaltered in Type II-a patients. At the end of the treatment period, serum iron and vitamin B12 levels were normal but the serum folic acid concentration was reduced in eight of 20 patients. A dose--response study indicated that a similar cholesterol-lowering effect was obtained with daily doses of 9 and 15 g of Secholex. It is concluded that Secholex is a relatively safe drug which effectively reduces serum cholesterol levels in two-thirds of patients with severe hypercholesterolemia.
Acacia↗
Deaths in connection with chlormethiazole (heminevrin) therapy.
Six cases are described where death occurred in connection with chlormethiazole (Heminevrin) infusion. The close time relationship and indirect evidence strongly suggest that chlormethiazole had an important role in the fatal outcome of the patients, but definite proof of this way was not possible to obtain. Present or past alcohol abuse and respiratory, liver, cardiac or CNS diseases of different degrees seemed to be features in common for the patients possibly rendering them susceptible to the suggested detrimental effect of chlormethiazole therapy. Respiratory depression is supposed to be the primary pathogenetic mechanism of the death. Considering the relatively limited use of chlormethiazole in the department in which these cases were observed and the recommended dosage applied, the risk of serious complication during chlormethiazole infusions seems to be surprisingly high.
Adult↗
Clinical correlations and significance of orceinpositivity in chronic active hepatitis and primary biliary cirrhosis.
Clinical, biochemical and immunological variables were analyzed in 30 patients with orcein-negative (ON) chronic active hepatitis (CAH), 4 patients with ON primary biliary cirrhosis (PBC), 8 patients with orcein-positive (OP; intracellular copper-binding protein seen histologically in liver biopsy specimens) CAH and 15 patients with OP-PBC. A marked elevation of serum bile acids, alkaline phosphatase, leusine aminopeptidase, gammaglutamyl transpeptidase and cholesterol concentrations, and highly pathological BSP Tm values were characteristic for OP-cases. In addition the faecal fat level was increased and bile acids decreased in OP-cases. Serum levels of IgG or IgM and the occurrence of smooth muscle, mitochondrial or glomerular antibodies were identical in ON- and OP-CAH as well as also in ON- and OP-PBC. 49 patients were treated with a combination of prednisone and azathioprine from 4 to 72 months (mean 22). 26 patients with ON-CAH responded biochemically and morphologically to the treatment. No treatment failures were found in ON-CAH. In contrast treatment failure was confirmed in every treated OP-PBC or OP-CAH. The results suggest that orcein-positivity indicates a poor response to prednisone-azathioprine treatment of CAH.
Adult↗
Effect of oxandrolone treatment on the activity of lipoprotein lipase, hepatic lipase and phospholipase A1 of human postheparin plasma.
The effect of a synthetic steroid, oxandrolone, on total postheparin plasma lipolytic activity, postherpain hepatic lipase activity, lipoprotein lipase and phospholipase A1 was studied in seven patients with hypertriglyceridemia. The mean total postheparin lipolytic activity increased 100 per cent during oxandrolone tratement (p smaller than 0.05). This change was caused mainly by postheparin hepatic lipase, whose activity increased on the average more than 2.5 times (p smaller than 0.001). The change in postheparin plasma-lipoprotein-lipase activity was insignificant. A highly significant correlation (r equals +0.87, p smaller than 0.01) was observed between the activities of postheparin hepatic lipase and phospholipase A1 before and during oxandrolone treatment. No relation was observed between serum triglyceride level and various postheparin lipase activities, or between the changes induced by oxandrolone in the level of serum lipids and the activities of postheparin lipases. We conclude that oxandrolone increases the activities of postheparin plasma hepatic lipase and phospholipase A1 but has little influence on lipoprotein lipase.
Adult↗