Human macrophages incubated for prolonged periods with mildly oxidized LDL (oxLDL) or cholesteryl ester-rich lipid dispersions (DISP) accumulate free and esterified cholesterol within large, swollen lysosomes similar to those in foam cells of atherosclerosis. The cholesteryl ester (CE) accumulation is, in part, the result of inhibition of lysosomal hydrolysis due to increased lysosomal pH mediated by excessive lysosomal free cholesterol (FC). To determine if the inhibition of hydrolysis was long lived and further define the extent of the lysosomal defect, we incubated THP-1 macrophages with oxLDL or DISP to produce lysosome sterol engorgement and then chased with acetylated LDL (acLDL). Unlike oxLDL or DISP, CE from acLDL normally is hydrolyzed rapidly. Three days of incubation with oxLDL or DISP produced an excess of CE in lipid-engorged lysosomes, indicative of inhibition. After prolonged oxLDL or DISP pretreatment, subsequent hydrolysis of acLDL CE was inhibited. Coincident with the inhibition, the lipid-engorged lysosomes failed to maintain an acidic pH during both the initial pretreatment and subsequent acLDL incubation. This indicates that the alterations in lysosomes were general, long lived, and affected subsequent lipoprotein metabolism. This same phenomenon, occurring within atherosclerotic foam cells, could significantly affect lesion progression.

Hypercholesterolaemia is a common finding in patients with anorexia nervosa (AN). To investigate the type, frequency and pathophysiological mechanisms of changes in lipoprotein metabolism in AN we performed a cross-sectional study in fifty-eight female patients (mean age 24·2 years, BMI 15·3 (SD 1·5) kg/m2) and fifty-eight healthy age-matched controls (CO; BMI 22·2 (SD 1·7) kg/m2). Total cholesterol and LDL-cholesterol were higher in AN (5·5 (SD 1·3) v. 5·0 (SD 0·8) mmol/l, P=0·023; 3·6 (SD 1·1) v. 3·2 (SD 0·7) mmol/l, P=0·025 respectively). LDL particles were significantly more enriched in cholesterol and triacylglycerol in AN. In multiple regression analysis with LDL-cholesterol as the dependent and BMI, total body fat ( %), lathosterol:cholesterol ratio (endogenous cholesterol synthesis), 7α-hydroxy-4-cholesten-3-one (bile acid synthesis), non-esterified glycerol, free triiodothyronine and free thyroxine as independent variables, BMI was the only significant predictor in CO (R2 0·36, overall P=0·001). In AN the variability of LDL-cholesterol was significantly predicted by total body fat, free thyroxine, BMI, free triiodothyronine and non-esterified glycerol (R2 0·55, overall P<0·001). Subgroup analysis between restricting (AN-R) and binge-eating–purging patients (AN-B) indicated that in AN-R changes in lipoproteins, BMI and total body fat were more pronounced. AN-R patients had lower bile acid synthesis than AN-B (P=0·02). We conclude that elevated cholesterol concentrations in AN are generally due to an increase in LDL-cholesterol, which is mostly determined by the severe loss of body fat and the resulting changes in thyroid hormones, increased lipolysis and decreased endogenous cholesterol synthesis with resulting decrease in LDL removal. The clinical subtype of AN plays a major role in the mechanisms leading to hypercholesterolaemia.

The present study examines the interactive effects of three fatty acids: myristic, palmitic and stearic acids, with dietary cholesterol, on lipoprotein metabolism in the hamster. Each saturated fatty acid was fed at a concentration of 100 g pure synthetic triacylglycerol/kg in the presence of 100 g triolein/kg and was fed in the presence of 0·05, 1·2 or 2·4 g dietary cholesterol/kg. Dietary cholesterol increased the concentration of cholesterol in each of the major plasma lipoprotein fractions. The largest effects on VLDL and LDL were seen in the presence of tripalmitin where the increase between the lowest and highest dietary cholesterol groups were 129 % and 38 % respectively. In contrast, HDL showed the greatest change in the tristearin group when the equivalent increase was 59 %. No interactive effects of dietary cholesterol and fat were seen on hepatic mRNA concentrations for the LDL receptor, hydroxymethylglutaryl-CoA reductase or the microsomal triacylglycerol transfer protein. As the amount of cholesterol in the diet increased, large differences were seen in the storage of hepatic cholesterol ester. At the highest dietary cholesterol intake the amount of hepatic cholesterol ester was 1·7-fold higher in the animals fed trimyristin compared with those fed tripalmitin. These results suggest that, as the amount of cholesterol in the diet is increased, palmitic acid becomes more hypercholesterolaemic. This is associated with a reduced ability to store cholesterol ester in the liver.

Concern about the cholesterol content of the human diet has led to many attempts to reduce the cholesterol content of eggs. Although this has involved a number of different approaches, including genetic selection and nutritional or pharmacological manipulation, the overwhelming evidence is that egg yolk cholesterol level is very resistant to change. The present review argues that this is because of the particular mechanisms involved in yolk formation. Yolk precursors are synthesized in the liver of the laying hen and transported in the plasma to the ovary where they are taken up into the developing follicles by receptor-mediated endocytosis. As a consequence, the cholesterol content of the yolk is primarily dependent on the cholesterol content of triglyceride-rich lipoproteins. Studies in mammals have shown that inhibition of cholesterol synthesis can reduce the rate of synthesis and secretion of lipoproteins by the liver, but has little effect on the composition of the lipoproteins that are secreted. This response, and the key role of cholesterol in the synthesis of steroid hormones, would seem to preclude the possibility of any substantial reductions in egg yolk cholesterol levels through manipulation of cholesterol metabolism. Possible alternative approaches are briefly discussed.