Direct correlation between in vivo cholesterol synthesis and hepatic secretion of apolipoprotein B-100 in normolipidaemic subjects

266

Abstracts/Atherosclerosis 112 (1995) 261-267

DIRECT CORRELATION BETWEEN IN VW0 CHOLESTEROL SYNTHESIS AND HEPATIC SECRETION OF APOLIPOPROTEIN B-100 IN NORMOLIPIDAEMIC SUBJECTS. Naoumova RP, Cummings MH*, Watts GF‘, Thompson GR. MRC Lipoprotein Team, Hammersmith Hospital, London; ‘Dept. of Endocrinology and Chemical Pathology, St. Thomas’ Hospital, London. To test that the availability of cholesterol substrate controls the hepatic secretion of apoB in vivo, we measured the plasma concentration of mevalonic acid (MVA) which reflects in vivo cholesterol synthesis and hepatic secretion of very-low-density (VLDL) apoB in 8 normolipidaemic subjects. MVA was assayedin fasting samples by GC MS. Hepatic secretion of apoB was measuredusing a primed, constantinfusion of ‘%Z-leucine (1 mglkglhr over 8 hr) and monitoring isotopic enrichment of VLDL apoB by GC MS. The mean plasma MVA was 5.0 rig/ml (SD 2.5) and absolute synthetic rate (ASR) of apoB was 9.7 mglkglday (SD 2.6). There was a significant positive correlation betweenthe ASR of apoB and plasma mevalonate, r = 0.88, p = 0.004. These findings are consistent with the hypothesis that apoB is constitutively expressed and that its hepatic secretion varies directly with the availability of cholesterol substrate. We suggestthe rate of in vivo cholesterol synthesis plays a key role in the regulation of the hepatic secretion of apoB in normolipidaemic subjects.

CHANGES IN REVERSE CHOLESTEROL TRANSPORT (RCT) IN NEPHROTIC SYNDROME G NI Wood. D Bhamagar. MI Mackness, B Haynes, C Short, PN Durrington. University Departmentsof Medicine & Nephrology, ManchesterRoyal Infirmary. Manchester. Ml3 9WL. UK

The mechanismsleading to hyperlipidaemia in patients with proteinuriaare poorly understoodIn order to studyalterationsin RCT we have examined lecithin:cholesterol acyl transferase (SCAT) activity & the transfer of choles1erylestersfrom KDL to LDL& VLDL (CET) in 18 patients with nephrotic syndrome (albuminexcretion 10.8g/day; serumalbumin 32.7 g/l; creatinine clearance 50.6 mUmin)& 27 healthycontrols.Results: 8.2i2.0 2.58 (5.40-12.00) 0.98fl.23

Healthy controls 5.9+0.9 1.16 (0.33-4.40) 1.3W.32

5.3i1.8

3.9il.O

1.97 (0.55-6.50) 75.2h26.5

0.46 (0.11-1.18) 59.3i16.0

25.7k11.7

17.8ti.5

Nephrotic

patients TC (mmov1)

TG (mmol/I)* HDL-c (mmOVI)

LDL-C (mmol/l)* VLDL-C (mmol/I) LCAT (nmoUmYh) CET (nmol/mvh) * median & The higher mcreased lipoproteins

P 0.001

0.001 0.001 0.001 0.002 0.002 0.006

range CET in nephrotic syndrome may be due to an pool of cholesterol-enriched triglyceride-rich and may lead to lower HDLC levels.

RELATIVE CONTRIBUTION OF PLASMA SMALL, DENSE LDL TO CORONARY HEART DISEASE (CHD) RISK.

GLYCOSYLATED LOW DENSITY LIPOPROTEIN MECHANISM OF BINDING TO ENDOTHELIAL CELLS AND MACROPHAGES

B. Griffin, D. Freeman. G. Tait, M. Caslake, C. Packard, .I. Shepherd. Department of Pathological Biochemistry, Universityof Glasgow,Glasgow,G4 OSF,U.K.

College Dublin, The Royal College of Surgeons in Ireland, and The Adehide Hospital, Dublin, Ireland

The purpose of this study was to determine whether

small. denseLDL (LDL-III) fultils certain criteria for a

CHD risk factor. The concentration of LDL-III was measured in four groups consisting of men (total cl~olesterol(TC)<6.4mmol/l, < 60years. (n)) with and without coronary artery disease (CAD+(46). ‘- (24)). post-infarct survivors (PM1 (40)) and normal controls (Con (58)). The frequency distributions of LDL-III showed a bimodal distribution, falling to the right and left of l(K) mg/dl in subjects with and without CHD respectively. Plasma triglyceride (TG) >1.5 mmolll appeared to be a threshold determinant of an LDL-III

level of > l(K). Estimatesof relative risk based on this fieure were CornDared with TG and a more traditional e&mate of CHD’risk : Jtelative Risk (p) LDL-III>lol) TG >1.5 TC HDL C 6 CAD(+) vs (-) 4.5 (0.01) 4.1 (0.01) 4 i” ;0$; PM1 vs Con 6.9~0.001~ 6.1~0.Of~lJ 7. ( II . Despite these relative risks of equal magnitude, LDLIII proved to be the most specific and independent index of coronary risk. This study provides quantitative evidence for the value of a raised LDL-III level in predicting the probability of developing CHD.

0wens.D.. Deogan,P.,Collins,P.,1ohnson.A..Tomkin,G.H. Trinity

Is glycatedlow densitylipoprotein(LDL) atherogenic?We examined therelationshipbetweenLDL gjycosylationin diabeticpatientsandits uptakeby endothelial cell and macrophage receptors. LDL from10 non-insulin-dependentdiabetic (NIDDM) patients was isolated by sequential ultracentrifugadon (d1.019-1.063) and iodinated. LDL @ycosylation was measured by affinity chromatography. Control LDL was oxidised with malondialdehyde. Monocyb-derived mxrophages were cultured from the blood of healthy volunteers. Binding/uptake and degradation were measured following a 16h incubation with [12sI]-

LDL (Si&/ml) at 37OCin the presenceor absenceof excessnative LDL or LDLox. Endothelialcell biding was measuredin cells from humanumbilicalveinsincubated with 112511-LDL (lOpg/ml) at 4V for lh in the presenceor absenceof cold native LDL. LDL-receptor-

mediatedbindinganduptakefor the macrophage was42.1+4.2%

while endothelial cell binding was 71.8+2.3% of total binding (p
binding and LDL glycosylation (r=O.57,p&.05) and betweenLDL degradation and glycosylation (0.56, ~~0.05) in lhe macrophage but there was an inverse correlation between binding and LDL g?vcosylation in the endothelial cell (r=-0.66, FO.05). The, uptake of

diabetic LDL in macrophageswas not inhibited by oxidised LDL. Thus, in the macrophage, glycosylated LDL appears to be avidly taken

up by theLDL receptor,the oppositebeing the casein tie endothelial cell. ‘Ihe scavengerreceptordoesnot appearto play a part in uptake of diabeticLDL.