ApoA-I(R151)Paris is a natural apolipoprotein (apo) A-I variant that is associated with low levels of high-density lipoprotein cholesterol (HDL-cholesterol) and the partial deficiency of lecithin:cholesterol acyl-transferase (LCAT) in the plasma of heterozygous carriers. We compared the abilities of recombinant normal apoA-I and recombinant apoA-I(R151C)Paris to clear an emulsion of dimyristoylphosphatidylcholine (DMPC), to form reconstituted lipoproteins with dipalmitoylphosphatidylcholine (DPPC), to activate LCAT, and to promote efflux of biosynthetic cholesterol from porcine aortic smooth muscle cells (SMCs) or of exogenous cholesterol from lipid-loaded mouse peritoneal macrophages. Recombinant apoA-I(R151C)Paris occurred in monomeric and dimeric forms at a ratio of 60:40. Normal apoA-I and apoA-I(R151C)Paris cleared DMPC emulsions at equal rates. Both isoforms associated completely with DPPC during cholate dialysis. Normal apoA-I formed one single particle with a mean diameter of 9.3 nm, whereas apoA-I(R151)Paris gave rise to three particles with mean diameters of 9.3 nm (containing 74% of apoA-I), 10.6 nm, and 12.1 nm, respectively. Compared to normal apoA-I, apoA-I(R151C)Paris had a reduced LCAT-cofactor activity with a 60% lower Vmax/Km ratio due to a 50% higher affinity constant, Km. During incubations for 10 min and 360 min, normal apoA-I/DPPC complexes and apoA-I(R151C)Paris/DPPC complexes were equally efficient in releasing biosynthetic cholesterol from SMCs. In the lipid-free form, apoA-I(R151C)Paris induced normal hydrolysis of cholesteryl esters and normal cholesterol efflux from lipid-loaded mouse-peritoneal macrophages. In conclusion, in addition to its ability to form homo- and heterodimers, apoA-I(R151C)Paris is characterized by defective LCAT-cofactor activity but by normal lipid binding and cholesterol-efflux-promoting abilities.

BACKGROUND: There is lack of agreement on which dietary regimen is most suitable for treatment of hypertriglyceridemia, especially if high triglyceride concentrations are not due to obesity or alcohol abuse. We compared the effects on blood lipids of a diet high in total and unsaturated fat with a low-fat diet in patients with triglyceride concentrations of b 2.3 mmolal. METHODS: Nineteen non-obese male outpatients with triglycerides ranging from 2.30 to 9.94 mmolal received two consecutive diets for 3 weeks each: ®rst a modi®ed high-fat diet (39% total fat, 8% SFA, 15% monounsaturated fatty acids, 1.6% marine n-3 polyunsaturated fatty acids), and then a low-fat diet (total fat 28%, carbohydrates 54%). RESULTS: The high-fat diet signi®cantly decreased triglycerides (À63%), total cholesterol (À22%), VLDL cholesterol (À54%), LDL cholesterol (À16%), total apoC-III (À27%), apoC-III in apoB containing lipoproteins (apoC-III LpB; À31%) and in HDL (apoC-III nonLpB; À29%), apoE in serum (À33%) and apoB-containing lipoproteins (nonHDL-E; À42%), LpA-I (À16%), insulin (À36%), and leptin (À26%) and signi®cantly increased the means of HDL cholesterol ( 8%), LDL size ( 6%), lipoprotein lipase (LPL, 11%), hepatic lipase ( 13%), and lecithin: cholesterol acyltransferase (LCAT, 2%). The subsequent low-fat diet increased triglycerides ( 63%), VLDL cholesterol ( 19%), apoC-III ( 23%), apoC-III LpB ( 44%) apoC-III nonLpB ( 17%), apoE ( 29%) and nonHDL-E ( 43%), and decreased HDL cholesterol (À12%), LPL (À3%), and LCAT (À3%). Changes in triglycerides correlated with changes in LPL activity and insulin levels. CONCLUSIONS: In hypertriglyceridemic patients, a modi®ed diet rich in mono-and n-3 polyunsaturated fatty acids is more effective than a carbohydrate-rich low-fat diet in correcting the atherogenic lipoprotein phenotype.

In Caucasians, a histidine for glutamine substitution (Gln->His) at residue 360 in apolipoprotein (apo)

We investigated in a pilot study the effect of testosterone suppression on lipoprotein metabolism, insulin, and leptin in 10 men who were treated either with cetrorelix, an antagonist of gonadotropin releasing hormone, or with placebo (P). Group C + C (n = 4) was treated with 10 mg cetrorelix as daily subcutaneous injections for five days and with a subsequent injection of 60 mg cetrorelix depot. Group C + P (n = 3) received 10 mg cetrorelix as daily intramuscular injections for five days and a subsequent injection of placebo depot. Group P + P (n = 3) received placebo both as daily and depot injections. Treatment with cetrorelix reversibly suppressed testosterone to castrate levels for three weeks in group C + C and for one week in group C + P. Compared to baseline, treatment with cetrorelix increased serum levels of apolipoprotein (apo) A-I, HDL subclass LpA-I, insulin, and leptin. In the group P + P, treatment with placebo was not associated with any change of these parameters. Compared to baseline and group P + P, treatment with cetrorelix in groups C + C and C + P did not lead to considerable or consistent changes in the plasma activities of lecithin:cholesterol acyltransferase (LCAT), phospholipid transfer protein (PLTP), cholesteryl ester transfer protein (CETP), lipoprotein lipase, and hepatic lipase (HL). Only the pooled data of groups C + C and C + P unraveled small but statistically significant decreases of HL and CETP activities in response to cetrorelix. In conclusion, the small or absent effects of cetrorelix on LCAT, CETP, PLTP, LPL, and HL indicate that testosterone regulates HDL levels by other metabolic pathways. The increases of insulin and leptin in response to cetrorelix suggest that testosterone influences HDL metabolism also via obesity and insulin resistance. These effects, however, are rather in contrast to the HDL raising effect of suppressed testosterone.