Apolipoprotein-B subclasses as acceptors of cholesteryl esters transferred by CETP.

BACKGROUND: Five apolipoprotein (apo)-defined apoB-containing lipoprotein (Lp) subclasses designated LpB, LpB:C, LpB:E, LpB:C:E and LpA-II:B:C:D:E are present in human plasma. This study was to determine whether these subclasses functioned equally as acceptors of cholesteryl esters (CE) transferred from high-density lipoproteins (HDL) by CE transfer protein in healthy subjects with normal and mildly increased plasma triglyceride (TG) levels. MATERIALS AND METHODS: After 4 h incubation of plasma from 14 subjects at 37 degrees C, apoB-containing lipoproteins were separated from HDL by heparin-Mn++ precipitation and fractionated by immunochemical methods into these five subclasses. The neutral lipid (NL) composition for each subclass was measured by gas chromatography (GC) and compared between 0 h and 4 h. A subclass was considered to be a CE acceptor if its CE content increased more than 5% at 4 h and a non-acceptor if no change was observed. RESULTS: Employing the above definition, TG-rich LpB:C and LpB:E + LpB:C:E functioned as CE acceptors and TG-poor LpB and LpA-II:B:C:D:E as non-acceptors. Both LpB:C and LpB:E + LpB:C:E could only actively accept CE as long as they retained their TG-rich character and displayed neutral lipid profiles similar to those of very low-density lipoproteins (VLDL) and intermediate density lipoproteins (IDL). When, as a result of lipolysis their TG content dropped below 25%, they ceased to function as CE acceptors. In subjects with elevated plasma TG, LpB:C was the dominant CE acceptor, a condition that may have pro-atherogenic consequences. CONCLUSIONS: Among the apoB-containing particles, LpB:C and LpB:C:E + LpB:E functioned as CE acceptors while LpB and LpA-II:B:C:D:E did not.

Characterization of a monoclonal antibody that binds equally to all apolipoprotein and lipoprotein forms of human plasma apolipoprotein B. II. Isolation of apolipoprotein B-containing lipoproteins from human plasma.

Monoclonal antibody ('Pan B' antibody) that binds equally to all major forms of human plasma apolipoprotein B was used in an immunoaffinity chromatography procedure to isolate apolipoprotein B-containing lipoproteins from hyperlipidemic human plasma. These lipoproteins were compared with lipoproteins in native plasma, with lipoproteins isolated by polyclonal antibodies and with lipoproteins isolated by the conventional ultracentrifugational method. Judged by the apolipoprotein and lipid composition, lipoproteins isolated with 'Pan B' antibody were virtually identical to those isolated by ultracentrifugation or polyclonal antibodies. Lipoproteins isolated by 'Pan B' antibody were comparable in size and shape to the lipoproteins in native plasma and to the lipoproteins isolated by polyclonal antibodies or ultracentrifugation. The immunoaffinity column with monoclonal 'Pan B' antibody retained all apolipoprotein B-containing lipoproteins and showed significantly higher capacity than polyclonal immunoaffinity column. The column with the highest capacity allowed the isolation from whole plasma of 0.144 mg of apolipoprotein B per ml of gel in less than 2 h.

Isolation and partial characterization of lipoprotein A-II (LP-A-II) particles of human plasma.

High density lipoproteins (HDL) consist of a mixture of chemically and functionally distinct families of particles defined by their characteristic apolipoprotein (Apo) composition. The two major lipoprotein families are lipoprotein A-I (LP-A-I) and lipoprotein A-I:A-II (LP-A-I:A-II). This study describes the isolation of a third minor HDL family of particles referred to as lipoprotein A-II (LP-A-II) because it lacks ApoA-I and contains ApoA-II as its main or sole apolipoprotein constituent. Because ApoA-II is an integral protein constituent of three distinct lipoprotein families (LP-A-I:A-II, LP-A-II: B:C:D:E and LP-A-II), LP-A-II particles were isolated from whole plasma by sequential immunoaffinity chromatography on immunosorbers with antisera to ApoA-II, ApoB and ApoA-I, respectively. In normolipidemic subjects, the concentration of LP-A-II particles, based on ApoA-II content, is 4-18 mg/dl accounting for 5-20% of the total ApoA-II not associated with ApoB-containing lipoproteins. The lipid composition of LP-A-II particles is characterized by low percentage of triglycerides and cholesterol esters and a high percentage of phospholipids in comparison with lipid composition of LP-A-I and LP-A-II: A-II. The major part of LP-A-II particles contain ApoA-II as the sole apolipoprotein constituent; however, small subsets of LP-A-II particles may also contain ApoD and other minor apolipoproteins. The lipid/protein ratio of LP-A-II is higher than those of LP-A-I and LP-A-I:A-II. In homozygous ApoA-I and ApoA-I/ApoC-III deficiencies, LP-A-II particles are the only ApoA-containing high density lipoprotein with levels found to be within the same range (7-13 mg/dl) as those of normolipidemic subjects. However, in contrast to normal LP-A-II, their lipid composition is characterized by higher percentages of triglycerides and cholesterol esters and a lower percentage of phospholipids and their apolipoprotein composition by the presence of ApoC-peptides and ApoE in addition to ApoA-II and ApoD. These results show that LP-A-II particles are a minor HDL family and suggest that, in the absence of ApoA-I-containing lipoproteins, they become an efficient acceptor/donor of ApoC-peptides and ApoE required for a normal metabolism of triglyceride-rich lipoproteins. Their other possible functional roles in lipid transport remain to be established in future experiments.

Changes in plasma lipid and apolipoprotein levels between heparin-induced extracorporeal low-density lipoprotein precipitation (HELP) treatments.

Heparin-induced extracorporeal low-density lipoprotein (LDL) precipitation (HELP) treatments selectively remove LDL with minimal effects on high-density lipoproteins (HDL), but limited data are available on effects between treatments. The levels of factors associated with increased coronary artery disease risk (atherogenic) among treatments may have therapeutic significance, especially for combined HELP and lipid-lowering drug therapy. Hypercholesterolemic and combined hyperlipidemic patients resistant to diet/drug therapy were treated with biweekly HELP therapy. Hypercholesterolemic patients received either lovastatin or no drug, whereas combined hyperlipidemic patients received gemfibrozil. Plasma lipid (total cholesterol, triglycerides, LDL cholesterol, and HDL cholesterol) and apolipoprotein A-I, A-II, B, C-III, and E levels were measured before treatment, then immediately, and 2, 4, 7, and 14 days after treatments (n = 28). Atherogenic factor (LDL cholesterol, total cholesterol, apolipoprotein B) levels decreased > 50% with treatment, gradually increasing over 14 days to pretreatment levels. Factors associated with reduced coronary artery disease risk (HDL cholesterol and apolipoproteins A-I and A-II) decreased 8% to 16% but recovered by 2 days. Components of triglyceride-rich lipoproteins (triglycerides and apolipoproteins C-III and E) decreased 38% to 55% with variable post-treatment recoveries. Lovastatin reduced pretreatment levels of atherogenic and triglyceride-rich lipoprotein components and slowed post-treatment increases compared with no drug therapy. Gemfibrozil produced changes similar to lovastatin. Drug therapy had little effect on factors associated with reduced coronary artery disease risk. HELP apheresis produced large reductions in plasma atherogenic factor levels with gradual return to pretreatment levels over 14 days, whereas antiatherogenic factors were minimally reduced and recovered rapidly.(ABSTRACT TRUNCATED AT 250 WORDS)

Dyslipidemia in peritoneal dialysis--relation to dialytic variables.

OBJECTIVE: To investigate whether the specific lipoprotein (LP) abnormalities of peritoneal dialysis (PD) are associated with functional variables of this mode of dialysis. DESIGN: A survey of the LP profile in relation to peritoneal dialysis capacity (PDC) variables. The LP profile was compared to that of a group of age- and sex-matched controls. SETTING: The Peritoneal Dialysis Unit at Sahlgrenska University Hospital in Gothenburg, Sweden. PATIENTS: Twenty-two nondiabetic PD patients (5 women, 17 men) who had been on PD for at least 6 months. MAIN OUTCOME MEASURES: The LP profile included plasma lipids, apolipoproteins (Apo), and individual ApoA- and ApoB-containing LP. The PDC measurement determined peritoneal glucose uptake, protein losses, effective peritoneal surface area, and total weekly creatinine clearance. RESULTS: The patients had been on PD for 6 to 48 months (mean 15.3 months) and had a total weekly creatinine clearance of 69.7+/-13.3 L/1.73 m2 body surface area, an average peritoneal glucose uptake corresponding to 446+/-162 kcal/24 hour, and a protein loss of 8.1+/-2.5 g/24 hr. The patients had significantly higher total cholesterol (7.1 mmol/L),VLDL-cholesterol (1.0 mmol/L), LDL-cholesterol (4.7 mmol/L), and triglyceride levels (2.5 mmol/L); whereas the HDL-cholesterol level (1.2 mmol/L) was significantly lower than in controls. The PD patients had increased levels of ApoB-containing LPs, both of the cholesterol-rich LP-B and of the triglyceride-rich LP-B complex, reflected in higher plasma concentrations of ApoB, ApoC-III, and ApoE. Furthermore, they had significantly lower levels of LP-A-I:A-II, as well as of ApoA-I and ApoA-II. The LP-A-I:A-II and ApoA-II levels correlated inversely with the duration of PD treatment (r = 0.54, p < 0.01 and r = 0.52, p < 0.05, respectively). The ApoA-II level was inversely correlated with the peritoneal surface area (r = 0.53, p < 0.05). There were no other correlations between LP variables and PDC variables, nor did any of the LP variables correlate with peritoneal glucose uptake or protein losses. CONCLUSION: The proatherogenic lipoprotein profile of patients on PD is characterized by increased concentrations of cholesterol-rich and triglyceride-rich ApoB-containing LPs. While the duration of treatment appears to have some influence on the development of this type of dyslipidemia, the pathophysiological links to the dialysis mode must be further explored.

Effect of fluvastatin on apolipoprotein-defined lipoprotein subclasses in patients with chronic renal insufficiency.

According to the concept of apolipoprotein (apo)-defined lipoproteins, apoA-I-containing lipoproteins consist of two subclasses referred to as lipoprotein A-I (LpA-I) and lipoprotein A-I:A-II (LpA-I:A-II), and apoB-containing lipoproteins of five subclasses, namely lipoprotein B (LpB), lipoprotein B:C (LpB:C), lipoprotein B:E (LpB:E), lipoprotein B:C:E (LpB:C:E), and lipoprotein A-II:B:C:D:E (LpA-II:B:C:D:E). The purpose of this study was to determine the levels of apoA-I- and apoB-containing lipoprotein subclasses before and after fluvastatin treatment of patients with chronic renal insufficiency. ApoA-I- and apoB-containing lipoprotein subclasses were measured in 15 patients with chronic renal failure and 15 asymptomatic subjects. The effect of fluvastatin on lipoprotein subclasses was determined in a randomized, double-blind, placebo-controlled, two-way, treatment period crossover study. Patients were administered fluvastatin 40 mg/day or placebo during 8 weeks in a randomized order. Patients were characterized by significantly higher levels of LpB (P < 0.001), LpB:C (P < 0.001), and LpB:E (P < 0.05), and slightly higher levels of LpB:C:E and LpA-II:B:C:D:E than controls. The levels of LpA-I:A-II were significantly lower (P < 0.01) in patients than controls. Fluvastatin treatment reduced all apoB-containing subclasses, but only the reduced level of LpB subclass was statistically significant (P < 0.02). The levels of LpA-I and LpA-I:A-II were not affected. Fluvastatin treatment reduced and normalized LpB and LpB:E subclasses. Although slightly reduced, the levels of markedly atherogenic LpB:C subclass were not normalized. The potential role of LpB:C on the progression of coronary artery disease in chronic renal insufficiency remains to be determined in future studies.

Identification and partial characterization of discrete apolipoprotein B containing lipoprotein particles produced by human hepatoma cell line HepG2.

The purpose of this study was to test the use of human hepatocarcinoma HepG2 cells as a model for studying the formation and secretion of human hepatic lipoproteins. To this end, we determined the rate of accumulation and percent composition of neutral lipids and apolipoproteins in the culture medium of HepG2 cells and isolated and partially characterized the apolipoprotein B (ApoB) containing lipoprotein particles. The rates of accumulation in the medium of HepG2 cells, grown in minimum essential medium during a 24-h incubation, of triglycerides, cholesterol, and cholesterol esters expressed as microgram/(g of cell protein X h) were 373 +/- 55, 167 +/- 14, and 79 +/- 10, respectively; the secretion rates for apolipoproteins B, A-I, E, A-II, and C-III were 372 +/- 36, 149 +/- 14, 104 +/- 13, 48 +/- 4, and 13 +/- 1 microgram/(g of cell protein X h), respectively. The major portion of ApoB was present in very low density lipoproteins (VLDL) and low-density lipoproteins (LDL) (84%), with the remainder occurring in high-density lipoproteins (HDL) (16%). Approximately 10-13% of ApoA-I and ApoA-II were present in VLDL and LDL, while 60% of ApoE occurred in HDL and 40% in VLDL and LDL. To separate ApoB-containing lipoproteins, secreted lipoproteins were fractionated by either sequential immunoprecipitation or immunoaffinity chromatography with antibodies to ApoB and ApoE. Results showed that 60-70% of ApoB occurred in the culture medium as lipoprotein B (LP-B) and 30-40% as lipoprotein B:E (LP-B:E). Both ApoB-containing lipoproteins represent polydisperse systems of spherical particles ranging in size from 100 to 350 A for LP-B and from 200 to 500 A for LP-B:E. LP-B particles were identified in VLDL, LDL, and HDL, while LP-B:E particles were only present in VLDL and LDL. The major neutral lipid of both ApoB-containing lipoproteins was triglyceride (50-70% of the total neutral lipid content); cholesterol and cholesterol esters were present in equal amounts. The LP-B:E particles contained 70-90% ApoB and 10-30% ApoE. The ApoB was identified in both types of particles as B-100. A time study on the accumulation of ApoB-containing lipoproteins showed that LP-B particles were secreted independently of LP-B:E particles.

Apolipoprotein A-I Milano: sex-related differences in the concentration and composition of apoA-I- and apoB-containing lipoprotein particles.

The presence of apolipoprotein (apo) A-IMilano (A-IM) mutant of apoA-I has a marked effect on plasma lipoproteins of A-IM carriers including variable hypertriglyceridemia, increased levels of very low density lipoproteins (VLDL), slightly elevated levels of triglyceride-enriched low density lipoproteins (LDL) and greatly reduced levels of high density lipoproteins (HDL). To gain further insight into this dyslipoproteinemic syndrome characterized clinically by the absence of coronary artery disease, we have determined the concentration and composition of apoA- and apoB-containing lipoprotein families in four male and four female carriers and corresponding normal controls. Results have shown that A-IM carriers have significantly reduced levels of lipoprotein (LP) A-I (45%), LP-A-I:A-II (60%), and LP-A-II (70%) and significantly increased levels of cholesterol-rich LP-B (67%) and triglyceride-rich LP-B:C, LP-B:C:E, and LP-A-II:B:C:D:E (65%) particles compared to controls. However, there were significant sex-related differences in the levels of apoA-and apoB-containing lipoproteins. Female carriers had significantly higher concentrations of LP-A-I (39 +/- 10 vs. 12 +/- 6 mg/dl) and LP-A-I:A-II (48 +/- 11 vs. 30 +/- 6 mg/dl) than male carriers. Furthermore, female carriers had higher levels of LP-B:C (23 +/- 18 vs. 6 +/- 5 mg/dl) and LP-A-II:B:C:D:E (13 +/- 6 vs. 2.3 +/- 0.8 mg/dl) but lower concentrations of LP-B (103 +/- 52 vs. 152 +/- 54 mg/dl) and LP-B:C:E (5 +/- 2.5 vs. 13 +/- 8 mg/dl) than male carriers. In general, the levels of LP-A-I and LP-A-I:A-II particles correlated positively with the levels of all three types of triglyceride-rich lipoproteins (LP-Bc) and negatively with the levels of LP-B particles. A comparative study of lipoprotein families in several dyslipoproteinemic states characterized by low levels of HDL has indicated that the characteristic lipoprotein particle profile of A-IM carriers results most probably from the selective effect of apoA-IM mutant rather than a general reduction in HDL levels. It appears that increased levels of LP-A-II:B:C:D:E particles, an inefficient substrate for lipoprotein lipase, and structurally defective LP-A-I:A-II particles, the normal acceptors of minor apolipoproteins released during lipolysis of triglyceride-rich lipoproteins, may be the main contributing factors to moderate hypertriglyceridemia characteristic of A-IM carriers.

Apolipoprotein-B-containing lipoproteins and the progression of renal insufficiency.

Hyperlipidemia is associated with accelerated glomerular sclerosis in experimental renal insufficiency. To investigate whether the dyslipoproteinemia seen in human renal failure also influences the future course of renal insufficiency, we have correlated plasma levels of lipids and apolipoproteins at start of follow-up with the subsequent change in renal function in 34 adult patients with chronic renal disease. Nineteen patients had primary renal disease, and 15 patients had diabetic nephropathy. Except for antihypertensive therapy no specific treatment to modify the progression of the disease was given during the follow-up. The rate of progression was determined by repeated measurements of the glomerular filtration rate (GFR). The time of follow-up ranged from 12 to 91 months with an average of 39.7 +/- 16.7 months. The mean initial GFR was 34.7 +/- 13.9 ml/min x 1.73 m2 body surface area and the average decline in renal function was -0.27 +/- 0.26 ml/min/month. The entry levels of triglycerides (TG; p = 0.04), very-low-density lipoprotein cholesterol (p = 0.03), apolipoprotein-B (ApoB; p = 0.008) and systolic blood pressure (SBP; p = 0.04) were significantly correlated with the rate of progression. Among lipoprotein variables, ApoB showed the strongest correlation with the decline in GFR. Patients with a progressive course of their disease also tended to have initially higher levels of total cholesterol (TC) and low-density lipoprotein cholesterol (NS), whereas the initial plasma concentration of high-density lipoprotein cholesterol did not show an association with the progression of renal insufficiency.(ABSTRACT TRUNCATED AT 250 WORDS)

Composition of plasma ApoA-I-containing lipoprotein particles in children and adults.

The purpose of this study was to examine sex- and age-related differences in the concentration and composition of lipoprotein particles containing apoA-I (LP-A-I) and those containing apoA-I and apoA-II (LP-I:A-II), the main HDL as defined by their apolipoprotein composition. Lipoproteins were isolated by immunoaffinity chromatography of whole plasma from 16 normal prepubertal children and 15 normal male and female adults using "pan"-MAb to apoA-I and apoA-II. Although there was no difference between children and adults in the concentration of LP-A-I:A-II, adult females had significantly higher levels of LP-A-I than either children or adult males. Main differences between children and adults as well as between adult males and females were in the apolipoprotein composition of the lipoprotein particles; children had the highest content of minor apolipoproteins (apoC and apoE) in LP-A-I but the lowest in LP-A-I:A-II. The lipid/apolipoprotein ratios of LP-A-I and LP-A-I:A-II were significantly higher in children and women than in men. The LP-A-I and LP-A-I:A-II contained 75% of the total plasma apoC and apoE in women and children but only 50% in men. However, in all three groups, 70-90% of the minor HDL apolipoproteins were associated with LP-A-I:A-II. The nonmolar ratios of minor apolipoproteins in LP-A-I and LP-A-I:A-II and the sex- and age-related differences in apoA-I/apoA-II ratios of LP-A-I:A-II suggest that both lipoproteins may consist of a spectrum of lipoprotein subfamilies differing in their apolipoprotein composition.(ABSTRACT TRUNCATED AT 250 WORDS)

The compositional abnormalities of lipoproteins in diabetic renal failure.

BACKGROUND: Diabetic nephropathy (DN) is a common cause of chronic renal failure (CRF). Patients with DN have abnormal lipoprotein metabolism that can be influenced by both the impairment of renal function and the metabolic control of diabetes. The aim of the study was to explore the specific compositional lipoprotein abnormalities in patients with insulin-dependent DN in comparison with diabetic patients without nephropathy and non-diabetic CRF patients. METHODS: The lipid and apolipoprotein (apo) composition of major lipoprotein density classes was determined in 20 patients with insulin-dependent diabetes mellitus and nephropathy and compared with that in seven diabetic patients without nephropathy, 20 patients with non-diabetic CRF, and nine healthy control subjects. Lipoproteins isolated by preparative ultracentrifugation were very-low-density lipoproteins (VLDL), intermediate-density lipoproteins (IDL), low-density lipoproteins (LDL), and high-density lipoproteins (HDL). RESULTS: Patients with DN had a plasma lipid and apolipoprotein profile characteristic of renal dyslipoproteinaemia with increased concentrations of triglycerides and cholesterol, reduced levels of apoA-I and apoA-II and increased levels of apoB, apoC-II, apoC-III and apoE. These changes were more pronounced in diabetic than in non-diabetic patients with comparable degrees of renal failure. All density classes were characterized by abnormal concentration and composition of some lipid and apolipoprotein constituents. DN patients had a more than four-fold increase of VLDL mass, a three-fold increase of IDL mass, and a significant reduction of HDL mass compared to control subjects. They also had significantly higher concentrations of apoB, apoC-peptides and apoE particularly in VLDL and IDL, and to some extent in LDL. In HDL, DN patients had lower cholesterol, apoA-I, apoA-II and apoC-II levels than controls. The major compositional change in DN patients was a significant increase in the relative content of apoC-peptides in IDL and LDL. The lipoprotein abnormalities were more pronounced in patients with high HbA1c values. In addition, lower GFR and increased proteinuria were associated with higher concentrations of triglycerides and apoC peptides in VLDL, IDL, and LDL in DN patients. CONCLUSIONS: The results indicate that patients with DN share the characteristic features of dyslipidaemia of CRF with accumulation of intact or partially delipidized apoB-containing lipoproteins enriched in apoC-peptides and apoE, which are present not only in VLDL and IDL but also in LDL density range. The alterations are more marked in DN than in nondiabetic CRF patients reflecting the additional impact of metabolic control. Increased levels of these lipoproteins may represent risk factors for the accelerated development of atherosclerotic vascular disease in these patients.

Abnormal lipid and apolipoprotein composition of major lipoprotein density classes in patients with chronic renal failure.

BACKGROUND AND METHODS: To characterize the abnormalities of lipoprotein composition in patients with chronic renal failure (CRF), the lipid and apolipoprotein (apo) concentrations and compositions of major lipoprotein density classes were determined in 20 subjects with moderate to advanced renal failure (GFR 5-59 ml/min) and nine controls. Patients were divided in 14 normotriglyceridaemic (NTG) subjects with triglyceride (TG) levels < or = 1.7 mmol/l (150 mg/dl) and six hypertriglyceridaemic (HTG) subjects with TG > or = 1.7 mmol/l. Lipoproteins were isolated by preparative ultracentrifugation: very low density (VLDL), intermediate density (IDL), low density (LDL) and high density (HDL) lipoproteins. RESULTS: Although all density classes were characterized by abnormal concentration and composition of some lipid and apo constituents, the most profound changes occurred in IDL and HDL. Cholesterol levels were elevated in VLDL and IDL with little change in LDL and reduced in HDL. TG levels were increased in all density classes. ApoB levels were increased in VLDL, IDL and LDL of all CRF patients reaching the significance levels in VLDL and IDL of HTG (P < 0.01). In IDL, the levels of apoC-peptides and apoE were increased (P < 0.01). ApoC-peptides and apo E were also elevated in VLDL of NTG and HTG, but their increase was only significant in HTG (P < 0.01). In LDL, the concentration of apoC-II and apoC-III was significantly increased (P < 0.05). However, in HDL there was significant (P < 0.01) reduction of apoA-I, apoA-II and apoC-peptides in both patient groups. The major compositional change was a significant increase in the relative contents of apoC-II and apoC-III in VLDL, IDL and LDL (P < 0.01). CONCLUSIONS: Results indicate that the characteristic feature of dyslipoproteinemia in CRF is the accumulation of partially delipidized TG-rich apoB-containing lipoproteins enriched in apoC-peptides and distributed characteristically in the IDL density-range irrespective of fasting TG concentrations. Increased levels of these ¿remnant lipoproteins' and reduced levels of HDL may represent risk factors for atherogenesis and progressive renal disease.

Increased concentrations of Apo B-containing triglyceride-rich lipoprotein particles in patients with chronic renal failure.

The dyslipoproteinemia of chronic renal failure (CRF) was characterized by discrete Apo B-containing lipoprotein particles separated by sequential immunoprecipitation of VLDL, IDL and LDL with antisera to Apo E and Apo C-III. CRF patients before and during dialysis had increased concentrations of Apo B-containing lipoproteins (LP) due to increased levels of triglyceride-rich LP-B:C and LP-B:C:E particles with no significant change in the levels of cholesterol-rich LP-B. Patients on hemodialysis had lower concentrations of LP-B:C and higher concentrations of LP-B:C:E than predialytic patients. The increase of Apo B-containing lipoprotein particles in CRF may contribute to atherosclerotic vascular disease and to glomerulosclerosis and progression of renal insufficiency.

The role of triglyceride-rich lipoprotein families in the progression of atherosclerotic lesions as determined by sequential coronary angiography from a controlled clinical trial.

We have demonstrated previously in a subset of Monitored Atherosclerosis Regression Study (MARS) subjects with hypercholesterolemia (190 to 295 mg/dL) and documented coronary artery disease that lovastatin significantly reduces cholesterol-rich lipoprotein B (LpB) but has little effect on complex, triglyceride-rich apolipoprotein (apo) B-containing LpBc (the sum of LpB:C, LpB:C:E and LpA-II:B:C:D:E) particles defined by their apolipoprotein composition. This differential effect of lovastatin on apoB-containing lipoprotein families offered the opportunity to determine in the same subset of MARS subjects the independent relationship of LpB and LpBc with the progression of coronary artery disease. Subjects randomized to either lovastatin (40 mg twice daily) or matching placebo were evaluated by coronary angiography before randomization and after 2 years of treatment, and the overall coronary status was judged by a coronary global change score. In the lovastatin-treated group, there were 22 nonprogressors (69%) and 10 progressors (31%), while in the placebo group 13 subjects (42%) were nonprogressors and 18 (58%) were progressors (P < .03). In the lovastatin-treated group, lipid and lipoprotein parameters did not differ between progressors and nonprogressors except for LpBc and LpA-II:B:C:D:E particle levels, which were statistically higher in progressors (P = .02). In the placebo-treated group, progressors differed from nonprogressors by having significantly higher levels of triglycerides (P = .03) and apoC-III in VLDL + LDL (P = .05), the characteristic constituents of triglyceride-rich lipoproteins. In the placebo- and lovastatin-treated groups combined, progressors had significantly higher on-trial levels of triglycerides (P = .003), VLDL cholesterol (P = .005), apoC-III in VLDL + LDL (P = .008), apoC-III (P = .01), apoB (P = .03), and total cholesterol (P = .04) than nonprogressors. Even after adjustment for treatment group, progressors in the combined placebo- and lovastatin-treated groups had significantly higher levels of LpBc, LpA-II:B:C:D:E, triglycerides, and apoC-III in VLDL + LDL than nonprogressors. Progressors in the placebo-treated, lovastatin-treated, and combined treatment groups had lower levels of LpA-1 but not LpA-I:A-II than non-progressors, and this difference reached statistical significance (P = .047) in the combined sample adjusted for treatment group. Results of this study show that elevated levels of triglyceride-rich LpBc in general and LpA-II:B:C:D:E in particular contribute significantly to the progression of coronary artery disease. Furthermore, they provide additional evidence for the potentially protective role of LpA-I particles in the atherogenic process and suggest that apolipoprotein-defined lipoprotein families may be more specific prognosticators of coronary artery atherosclerosis progression than lipids and apolipoproteins.

Dyslipoproteinemia in diabetic renal failure.

Plasma concentrations of lipids and apolipoproteins (Apo) were determined in 34 patients with long-standing type I (insulin-dependent) diabetes mellitus. Twenty-four patients had renal insufficiency (GFR 4 to 55 ml/min) due to diabetic nephropathy, while 10 patients had no clinical signs of nephropathy. Results were compared with those in 42 non-diabetic patients with comparable degree of renal insufficiency and with asymptomatic control subjects. Diabetic patients without nephropathy had plasma lipid and apolipoprotein concentrations similar to those of the control subjects. Diabetic patients with renal insufficiency had a significant increase in triglycerides (TG) and, to a lesser extent, in total cholesterol (TC). The patients also had reduced levels of ApoA-I and ApoA-II, increased levels of ApoC-II and ApoC-III, while increases in levels of ApoB and ApoE were statistically significant in patients with GFR < 20 ml/min. These lipids and apolipoprotein abnormalities were accentuated with decreasing renal function. The reduction in the ApoA-I/ApoC-III ratio characteristic of renal insufficiency was found in normo- and hyper-TG diabetic patients with nephropathy; this ratio was correlated with the GFR levels. Patients with higher HbA1C values had higher levels of ApoC-II and ApoC-III. The findings in the diabetic patients corresponded with those in non-diabetic patients with renal insufficiency. However, diabetic patients had higher ApoC-III and ApoE levels. The abnormalities of lipid metabolism in diabetic renal insufficiency seem to reflect primarily metabolic impairments characteristic of renal insufficiency, but may be further accentuated by the diabetic state and the metabolic control.

Lipoprotein abnormalities without hyperlipidaemia in moderate renal insufficiency.

To characterize lipoprotein metabolism during early renal insufficiency, plasma lipid and apolipoprotein profiles were determined in normotriglyceridaemic (NTG, n = 31) and hypertriglyceridaemic (HTG, n = 30) middle-aged patients with primary renal disease and with moderately impaired renal function (GFR 20-55 ml/min, mean: 37.2). Mean GFR was similar in the two patient groups. They were compared with 102 normolipidaemic control subjects. In comparison with controls the NTG patients (plasma triglycerides TG < or = 1.7 mmol/l, mean TG: 1.16 mmol/l) had significantly increased plasma concentrations of apo C-III and apoB. The apoA-I levels tended to be lower and as a consequence the apoA-I/apoC-III ratio, considered to represent the hallmark of the altered apolipoprotein profile in renal dyslipoproteinaemia, was markedly lower in NTG patients (8.7 versus 16.8, P < 0.001). There was also a reduction of the antiatherogenic ratio apoA-I/apoB and an increase of the apoC-III/apoE ratio. The HTG patients (mean TG: 3.22 mmol/l) showed the same, but even more accentuated, qualitative changes as the NTG patients. There was a fourfold increase of apoC-III in VLDL-LDL lipoprotein fractions with little change in HDL in the HTG patients. In NTG patients the increase of apoC-III was found in VLDL-LDL and in HDL. Plasma insulin and PTH levels both correlated with the apoA-I/apoC-III ratio independently of GFR and BMI. This suggests a pathogenetic relationship between PTH-mediated alterations of insulin metabolism and the lipoprotein abnormalities.(ABSTRACT TRUNCATED AT 250 WORDS)