S. Ericsson

Influence of age on the metabolism of plasma low density lipoproteins in healthy males.

The plasma concentration of the atherogenic low density lipoproteins (LDL) increases with age. To clarify the mechanism of this change, we studied the kinetics of autologous 125I-LDL apolipoprotein B (apo B) in 41 normolipidemic, nonobese healthy males. For comparison, they were divided into three age groups: young, 21-39 yr (n = 18), middle-aged, 40-59 yr (n = 11), and old, 60-80 yr (n = 12). The levels of plasma LDL cholesterol and LDL apo B increased from respectively 3.4 +/- 0.1 (SEM) mmol/liter and 86 +/- 2 mg/dl in the young to 4.1 +/- 0.1 mmol/liter and 95 +/- 3 mg/dl in the old (P less than 0.01), and this increase was linked to a progressively decreased (r = -0.38, P less than 0.02) fractional catabolic rate of LDL apo B (0.348 +/- 0.010 pools per day in the young vs. 0.296 +/- 0.009 pools per day in the old, P less than 0.01). The production rate of LDL apo B did not differ significantly between the groups. The reduced fractional catabolic rate of LDL apo B in the old was not associated with a decrease in binding affinity of the LDL particle to its receptor, as judged from its ability to compete for 125I-LDL fibroblast binding. When hepatic LDL receptor expression was stimulated by cholestyramine treatment in six old males, their LDL apo B fractional catabolic rate increased to the levels observed in the young subjects. We conclude that the increase in LDL which normally occurs with age is explained by a reduced capacity for its removal, and hypothesize that this is mediated via a reduced hepatic LDL receptor expression.

Bile acid sequestrants: mechanisms of action on bile acid and cholesterol metabolism

SummaryInterruption of the enterohepatic circulation of bile acids by cholestyramine or colestipol influences the hepatic metabolism of cholesterol in many ways. The synthesis of bile acids is increased, as reflected by a several-fold increase in the activity of the cholesterol 7a hydroxylase, the rate-determining enzyme in bile acid synthesis. The increased metabolism of cholesterol to bile acids causes an enhanced demand of cholesterol in the hepatocytes, which respond with both new synthesis of cholesterol, as reflected in a several-fold increase of the HMG-CoA reductase activity, and increased expression of LDL receptors. As a consequence, the plasma level of LDL-cholesterol is lowered. The hepatic secretion rate of VLDL particles is increased. Cholestyramine therapy does not affect the output of biliary lipids or the cholesterol saturation of bile, indicating that treatment with bile acid sequestrants should not be associated with any increased risk of gallstone formation.

HYPOCHOLESTEROLAEMIA AND INCREASED ELIMINATION OF LOW-DENSITY LIPOPROTEINS IN METASTATIC CANCER OF THE PROSTATE

To study the influence of tumour mass on lipid metabolism, the lipoprotein pattern in untreated patients with newly diagnosed cancer of the prostate was examined. Total cholesterol levels were reduced in patients with evidence of metastasis (n = 30) compared with those without metastasis (n = 73). Since the major fraction of serum cholesterol is contained in low-density lipoproteins (LDL), turnover of LDL was studied in detail in 8 patients compared with 12 age-matched healthy men. LDL were cleared faster in the 3 patients with metastatic disease than in the patients without metastasis and in controls, indicating faster catabolism of LDL. Thus in prostatic cancer an increased tumour burden is associated with increased elimination of LDL, which contributes to reduced serum cholesterol levels.

Growth Hormone Induces Low-Density Lipoprotein Clearance but not Bile Acid Synthesis in Humans

Objective—Growth hormone (GH) induces hepatic low-density lipoprotein (LDL) receptors and lowers plasma cholesterol. We characterized the influence of GH treatment on plasma LDL clearance in normal humans and investigated the relative role of LDL receptor (LDLR) activity and stimulation of bile acid synthesis in subjects with different LDLR expression. Methods and Results—Plasma clearance of autologous 125I-LDL was measured before and during 3 weeks of treatment with GH (0.1 IU/kg per day) in 9 healthy young males. Plasma LDL cholesterol was reduced by 13% and the fractional catabolic rate of LDL increased by 27%. More marked changes were seen in a patient with hypopituitarism substituted with GH (0.07 IU/kg per day) for 3 months. In a second study, GH dose-dependently reduced LDL cholesterol and increased Lp(a) levels in 3 groups of males: younger and elderly healthy subjects and heterozygous familial hypercholesterolemia (FH). No effect on bile acid synthesis measured by the plasma marker 7&agr;-hydroxy-4-cholesten-3-one was observed. In an LDLR-deficient FH homozygote, LDL cholesterol was not affected by GH. Conclusions—GH treatment reduces plasma LDL cholesterol by inducing LDL clearance. In humans, LDLR expression is a prerequisite for this effect, whereas it is not related to stimulation of bile acid synthesis.

Metabolism of lipoprotein remnants in humans. Studies during intestinal infusion of fat and cholesterol in subjects with varying expression of the low density lipoprotein receptor.

To study the possible importance of the low density lipoprotein (LDL) receptor in regulating the degree of postprandial lipemia, a cholesterol-rich fat emulsion was infused into the duodenum of subjects who were divided into four groups based on the expected variation in the expression of the LDL receptor: young men (n = 11), elderly men (n = 7), male patients on estrogen therapy (n = 5), and patients with familial hypercholesterolemia (n = 9). In familial hypercholesterolemia, fasting plasma levels of lipoproteins of d less than 1.006 g/ml, intermediate density lipoproteins, and LDLs were increased. During the fat infusion, the cholesterol and triglyceride contents in the d less than 1.006 g/ml fraction increased to a similar extent in all groups, whereas a concomitant reduction of LDL cholesterol levels was observed. The degree of the decrease in LDL cholesterol was positively correlated with the observed increase in triglycerides in the d less than 1.006 g/ml fraction. There were no signs of accumulation of intermediate density lipoproteins during infusion in any of the groups studied. The results indicate that the capacity for clearance of chylomicrons and chylomicron remnants is not affected by variation in LDL receptor expression.

The influence of age on low density lipoprotein metabolism: Effects of cholestyramine treatment in young and old healthy male subjects

Ericsson S, Berglund L, Frostegård J, Einarsson K, Angelin B (Karolinska Institute at Huddinge University Hospital, Huddinge; and Karolinska Hospital, Stockholm; Sweden). The influence of age on low density lipoprotein metabolism: effects of cholestyramine treatment in young and old healthy male subjects. J Intern Med 1997; 242:329–37.

Low-density lipoprotein metabolism and its association to plasma lipoprotein(a) in the nephrotic syndrome

Patients with nephrotic syndrome have multiple abnormalities of lipoprotein metabolism, but the cause and exact nature of these abnormalities have not been established. In the present study we have determined the kinetics of plasma low‐density lipoprotein (LDL) apoB in seven nephrotic patients demonstrating an elevated LDL apoB production rate (25.7 ± 6.4 vs. 13.1 ± 0.3 mg kg–1 day–1; P < 0.001) but a normal LDL apoB fractional catabolic rate (FCR) (0.31 ± 0.04 vs. 0.33 ± 0.008 pools day–1; NS) compared with 41 healthy control subjects. However, two out of the seven patients had a markedly low LDL apoB‐FCR. Serum albumin was inversely correlated with the LDL apoB production rate (R = –0.82; P < 0.05). Plasma lipoprotien (a) [Lp(a)] levels were significantly (P < 0.001) increased in the nephrotic patients compared with control subjects. Significant correlations were observed between log Lp(a) and LDL apoB production rate (R = 0.90; P < 0.01), VLDL‐cholesterol (R = 0.95; P < 0.001) and VLDL‐triglycerides (R = 0.80; P < 0.05) respectively. In summary, the present study suggests that nephrotic hyperlipidaemia may be caused by at least two independent mechanisms. The elevated LDL apoB production rate is highly correlated with the prevailing levels of serum albumin, whereas some nephrotic patients seem to have a decreased LDL apoB clearance, suggesting impaired LDL receptor‐mediated clearance. The present results also suggest that the elevated plasma Lp(a) levels in nephrosis are related to an increased hepatic synthesis rather than a decreased catabolism of lipoproteins.

Effect of cholestyramine treatment on biliary lipid secretion rates in normolipidaemic men

Abstract. This study was designed to clarify the effect of bile acid sequestrant treatment on the total biliary output rates of cholesterol, phospholipids and bile acids in man, and to correlate these changes with the alterations in plasma lipoprotein levels. For this purpose nine healthy, normolipidaemic men were treated with 16 g of cholestyramine daily over a period of 4 weeks, and the biliary secretion rates were measured by a duodenal perfusion technique. Resin therapy, which profoundly increases de novo synthesis of bile acids, resulted in a lowering of total plasma cholesterol levels, mainly due to a 35% reduction in low density lipoprotein (LDL) cholesterol, and in a 33% increase in plasma triglyceride levels, reflecting enhanced very low density lipoprotein (VLDL) triglyceride concentrations; high density lipoprotein (HDL) levels did not change. However, these lipoprotein changes did not correlate with any alterations in biliary lipid output. Total hepatic secretion rates of the biliary lipids remained generally unchanged during treatment, with a tendency towards lower cholesterol output, resulting in a lower molar percentage of cholesterol in hepatic bile, 3.4 ± 0.4 vs. 2.9 ± 0.2 mol %. This is probably due to an increased rate of conversion of cholesterol to bile acids in the hepatocyte. It is concluded that, in man, the liver may adapt well to changes in the enterohepatic circulation of bile acids, thereby maintaining output rates of biliary lipids at a relatively constant level.

Gemfibrozil in familial combined hyperlipidaemia : effect of added low-dose cholestyramine on plasma and biliary lipids

Abstract. Gemfibrozil is frequently used for lipid‐lowering in familial combined hyperlipidaemia (FCHL) and in other forms of combined hyperlipidaemia. This therapy increases biliary cholesterol saturation, enhancing the risk for gallstone formation. Furthermore, in hypertriglyceridaemia, LDL cholesterol levels often tend to rise. We have explored the possibility that addition of a low dose of cholestyramine to gemfibrozil therapy obliterates these phenomena. Eighteen gallstone‐free patients with definite (n= 5) or probable (n= 10) FCHL, or combined hyperlipoproteinaemia (n= 3) were randomized to a 6 week treatment with gemfibrozil, 600 mg b.i.d., or gemfibrozil 600 mg b.i.d.plus 4 g cholestyramine o.d. After 6 weeks the patients were crossed over to the alternative treatment. Plasma lipoproteins and biliary lipids were determined at baseline and at the end of each period.

No influence of age on the ileal absorption of bile acids in humans as determined by the SeHCAT test

Objective: To determine the influence of age on ileal absorption of bile acids. Design: Bile acid absorption was evaluated with the γ-emitting bile acid analogue, selenohomocholic acid taurine (SeHCAT) in 11 healthy young (aged 35 years or less) and 11 healthy elderly subjects (aged 65 years or more). Method: SeHCAT was given orally and its fractional catabolic rate (FCR) and 7-day retention were assessed by repeated external counting for the following 7 days. Fasting serum was also analysed for the lipid profile. Results: No significant difference was found between the two groups despite a significant increase in serum total and low density lipoprotein cholesterol with age. Conclusions: We could not observe any influence of age on bile acid absorption evaluated with the SeHCAT test.