Timo Kuusi

Evidence for the role of hepatic endothelial lipase in the metabolism of plasma high density lipoprotein2 in man.

Previous animal studies have shown that the heparin-releasable hepatic lipase (HL) is located on the luminal surface of the liver endothelial cells and may have a function in the removal of high density lipoprotein lipids from plasma. We therefore examined the relationship between plasma HDL levels and the HL activity of postheparin plasma in a group of young, very fit men who were living under strictly controlled comparable conditions (military academy studients). HDL2 cholesterol, HDL2 phospholipid and HDL2 protein concentrations each showed a highly significant negative correlation with postheparin HL activity. A similar but slightly lower inverse relationship was also present between total HDL lipids and HL activity, whereas no correlation could be observed between any of the HDL3 lipids and HL activity. The cholesterol/protein ratio of HDL2 correlated negatively with the HL activity. These results support the hypothesis that the hepatic endothelial lipase has a physiological role in the degradation and removal of circulating HDL2.

Hepatic endothelial lipase antiserum influences rat plasma low and high density lipoproteins in vivo

Postheparin plasma contains two separate lipolytic enzymes, lipoprotein lipase and hepatic lipase, which are released from vascular endothelial cells. The former is located in extrahepatic capillary beds and has a well-defined role in the catabolism of plasma triglycerides. The hepatic lipase has been recently shown to be located on the surface of hepatic endothelial cells [l] but the physiological function of this enzyme is still far from clear. Hepatic endothelial lipase can hydrolyze chylomicron and VLDL triglycerides in vitro [2] but its activity in postheparin plasma has no correlation to plasma triglyceride levels [3]. It has been suggested that hepatic lipase could be involved in the uptake of chylomicron remnants [4], intermediate density lipoprotein [5] or LDL [6] by the liver but there is little experimental evidence for any of these possibilities. We have recently purified the heparin-releasable lipase from rat liver perfusates [7] and used the enzyme preparation for production of antiserum. The availability of this anti-hepatic lipase serum offered a good opportunity to study the function of the enzyme by searching whether plasma lipoproteins are influenced by specific inhibition of the hepatic endothehal lipase in vivo.

Insulin therapy induces antiatherogenic changes of serum lipoproteins in noninsulin-dependent diabetes.

To study the effect of rigorous inslulin on serum llpoproteins in patients with noninsulin-dependent diabetes not controlled with oral only, we measured serum llpoproteins, apoproteins, lipolytic enzymes, and glucose disposal using anf insulin clamp technique before and after 4 weeks of insulin therapy. Lipoproteins were isolated by ultracentrifugation and high density llpoprotein (HDL) subfractions, by rate-zonal density graddient ultracetrifugation. The group included 11 subfractions, by rate-zonal density gradient ultracentrifugation. The group included 11 women and eight men (age 58 ± 1 years adn RBW 125 ± 4%). Body weight, glycosylated hemoglobin, mean dlurnal glucose, plasma free insulin, and glucose uptake (M-value) were 75 vs. 76 kg; 11.9 vs. 8.9%; 234 vs. 124 mg/di; 123 vs. 27 μU/ml; and 5.0 ± 0.4 vs. 7.1 ± 0.6 mg/kg/min before and after insulin therapy, respectively. After Insulin therapy there was decrease of very low density lipoprotein (VLDL) triglyceride (−60%, p < 0.001) but an increase of HDL2 cholesterol (+21%, p < 0.001); HDL2 phosphollpids (+38%, p < 0.001); HDL2 proteins (+23% p < 0.01); and HDL2 mass (127 ± 11 vs. 158 ± 12 mg/dl, p < 0.001). There was a decrease of HDL3 cholesterol (−13%, p < 0.05); HDL3 phosphollpids (+38%, p < 0.001); HDL2 proteins (+23%, p < 0.01); and HDL2 mass (127 ± 11 vs. 158 ± 12 mg/dl, p < 0.001). There was a decrease of HDL3 cholesterol (−13%, p < 0.025<; HDL3 phospholipids (−16%, p < 0.05); HDL3 proteins (−18%, p < 0.001); and HDL3 mass (179 ± 6 vs. 146 ± 6, p < 0.01). Zonel profiles showed a redisttribution of particles from HDL3 to HDL2. Serum apo A-l increased (p < 0.05), apo A-ll remained constant, but apo B decreased (−29%, p < 0.001). The most marked change during insulin therapy was a 2.3-fold increase in adlpose tissue fllploprotein llpase (LPL) activity (p < 0.001). The changes of VLDL and HDL subfractions were not explained by respective changes of the blood glucose, free insulin, or M-value. The data indicate that intensive insulin therapy induces antiatherogenic changes in serum lipids and lipoproteins and suggest that the induction of LPL by insulin is the major factor responsible for redistribution of HDL particles from HDL3 to HDL2

Effects of Statin Therapy According to Plasma High-Sensitivity C-Reactive Protein Concentration in the Controlled Rosuvastatin Multinational Trial in Heart Failure (CORONA) A Retrospective Analysis

Background— We examined whether the antiinflammatory action of statins may be of benefit in heart failure, a state characterized by inflammation in which low cholesterol is associated with worse outcomes. Methods and Results— We compared 10 mg rosuvastatin daily with placebo in patients with ischemic systolic heart failure according to baseline high sensitivity-C reactive protein (hs-CRP) <2.0 mg/L (placebo, n=779; rosuvastatin, n=777) or ≥2.0 mg/L (placebo, n=1694; rosuvastatin, n=1711). The primary outcome was cardiovascular death, myocardial infarction, or stroke. Baseline low-density lipoprotein was the same, and rosuvastatin reduced low-density lipoprotein by 47% in both hs-CRP groups. Median hs-CRP was 1.10 mg/L in the lower and 5.60 mg/L in the higher hs-CRP group, with higher hs-CRP associated with worse outcomes. The change in hs-CRP with rosuvastatin from baseline to 3 months was −6% in the low hs-CRP group (27% with placebo) and −33.3% in the high hs-CRP group (−11.1% with placebo). In the high hs-CRP group, 548 placebo-treated (14.0 per 100 patient-years of follow-up) and 498 rosuvastatin-treated (12.2 per 100 patient-years of follow-up) patients had a primary end point (hazard ratio of placebo to rosuvastatin, 0.87; 95% confidence interval, 0.77 to 0.98; P=0.024). In the low hs-CRP group, 175 placebo-treated (8.9 per 100 patient-years of follow-up) and 188 rosuvastatin-treated (9.8 per 100 patient-years of follow-up) patients experienced this outcome (hazard ratio, 1.09; 95% confidence interval, 0.89 to 1.34; P>0.2; P for interaction=0.062). The numbers of deaths were as follows: 581 placebo-treated (14.1 per 100 patient-years of follow-up) and 532 rosuvastatin-treated (12.6 per 100 patient-years) patients in the high hs-CRP group (hazard ratio, 0.89; 95% confidence interval, 0.79 to 1.00; P=0.050) and 170 placebo-treated (8.3 per 100 patient-years) and 192 rosuvastatin-treated (9.7 per 100 patient-years) patients in the low hs-CRP group (hazard ratio, 1.17; 95% confidence interval, 0.95 to 1.43; P=0.14; P for interaction=0.026). Conclusion— In this retrospective hypothesis-generating study, we found a significant interaction between hs-CRP and the effect of rosuvastatin for most end points whereby rosuvastatin treatment was associated with better outcomes in patients with hs-CRP ≥2.0 mg/L. Clinical Trial Registration Information— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00206310.

High density lipoprotein subfractions and postheparin plasma lipases in alcoholic men before and after ethanol withdrawal

Abstract Serum lipoproteins (VLDL, LDL, HDL 2 and HDL 3 ) and postheparin plasma lipase activities were measured in 10 male alcoholic subjects at the end of a long drinking period and subsequently after 8 and 15 days of complete abstinence. None of the patients showed any clinical or histological evidence of cirrhosis or other alcoholic liver disease. Reference data were obtained from healthy normolipidemic nonalcoholic men of similar age. In spite of the heavy alcohol intake the serum triglyceride and VLDL triglyceride concentrations of the alcoholics were not different from those of the reference group. On the other hand, the LDL cholesterol of the alcoholics was remarkably low and did not rise significantly during the 2 wk of abstinence. The mean HDL cholesterol concentration of the alcoholic men was 54% higher than that of the controls. This was mainly due to elevation of HDL 2 (+63%) but also the HDL 3 cholesterol was higher than that of the control subjects (+20%). The phospholipid and protein concentrations of HDL 2 and the phospholipid of HDL 3 were also significantly increased in the alcoholic men in comparison with the controls. The composition of HDL subfractions of the alcoholics was only slightly abnormal with an increase of phospholipid and decrease of protein content of HDL 3 . The concentration and composition of the HDLs returned to normal 1 wk after alcohol withdrawal. The postheparin plasma lipoprotein lipase and hepatic lipase activities of the alcoholic men were significantly higher than the respective values of the reference group. During eight off-alcohol days both enzyme activities decreased and reached the normal range. At the end of the drinking period no correlation was present between the levels of total HDL or its subfractions on the hand and any of the two lipase activities on the other. On the 8th off-alcohol day the HDL 2 phospholipid showed a highly significant positive correlation with lipoprotein lipase activity. It is concluded that the elevation of HDL during chronic use of alcohol in mainly due to increased concentration of HDL 2 and that this may be partly explained by an increase of lipoprotein lipase activity but that other mechanisms may also be involved. The low LDL concentration in alcoholic men without manifest liver disease is an interesting finding which should be studied further.

Passive Smoking Induces Atherogenic Changes in Low-Density Lipoprotein

BACKGROUND According to the American Heart Association, passive smoking is an important risk factor for coronary heart disease (CHD), but the mechanisms underlying this association are not fully understood. We studied the acute effect of passive smoking on the factors that influence the development of CHD: the antioxidant defense of human serum, the extent of lipid peroxidation, and the accumulation of LDL cholesterol in cultured human macrophages, the precursors of foam cells in atherosclerotic lesions. METHODS AND RESULTS Blood samples were collected during 2 ordinary working days from healthy, nonsmoking subjects (n=10) before and after (up to 5.5 hours) spending half an hour in a smoke-free area (day 1) or in a room for smokers (day 2). Passive smoking caused an acute decrease (1.5 hours after exposure) in serum ascorbic acid (P<.001) and in serum antioxidant defense (P<.001), a decreased capacity of LDL to resist oxidation (P<.01), and the appearance of increased amounts of lipid peroxidation end products in serum (P<.01). Finally, LDL isolated from subjects after passive smoking was taken up by cultured macrophages at an increased rate (P<.05). CONCLUSIONS Exposure of nonsmoking subjects to secondhand smoke breaks down the serum antioxidant defense, leading to accelerated lipid peroxidation, LDL modification, and accumulation of LDL cholesterol in human macrophages. These data provide the pathophysiological background for the recent epidemiological evidence about the increased CHD risk among passive smokers.

Predictors of fatal and non-fatal outcomes in the Controlled Rosuvastatin Multinational Trial in Heart Failure (CORONA) : incremental value of apolipoprotein A-1, high-sensitivity C-reactive peptide and N-terminal pro B-type natriuretic peptide

Few prognostic models in heart failure have been developed in typically elderly patients treated with modern pharmacological therapy and even fewer included simple biochemical tests (such as creatinine), new biomarkers (such as natriuretic peptides), or, especially, both. In addition, most models have been developed for the single outcome of all‐cause mortality.

Preparation, characterization, and measurement of hepatic lipase

Publisher Summary This chapter discusses the preparation, characterization and measurement of the hepatic lipase (HI). The complete role of Hepatic Lipase (HL) in lipoprotein metabolism is still controversial. Although originally purified as a triacylglycerol lipase, this enzyme can also hydrolyze several other lipid substrates and the question which is the physiological substrate for HL is far from solved. Many of the molecular characteristics of HL have not yet been clarified; one of the main reasons for the lack of this information involves the problems of purifying and assaying HL. The chapter provides a better understanding on the issue. Studies on the lipolytic activity in postheparin plasma indicated that this activity resembled more hepatic than extrahepatic triglyceride lipase activity. Affinity chromatography of postheparin plasma on heparin-Sepharose columns enabled the separation of two different lipases from human postheparin plasma.

Alcohol-induced changes in serum lipoproteins and in their metabolism

The effects of alcohol intake on serum lipids and lipoproteins depend on the dose and mode of alcohol intake, individual susceptibility, genetic variables, and dietary factors. Therefore the changes of lipoprotein pattern are different among moderate and heavy drinkers. Moderate intake of alcohol increases the concentrations of apolipoproteins (apo) AI, apo AII, and high-density lipoprotein subfraction (HDL3) in plasma without any effects on other lipoproteins. If alcohol intake exceeds 60 to 80 gm per day, the synthesis of very low-density lipoprotein (VLDL) particles is stimulated. Even short-term use of alcohol stimulates lipoprotein lipase (LPL) activity in adipose tissue, and consequently the concentration of VLDL in plasma stays normal or is even subnormal. If alcohol intake continues in excessive amounts, the increased transport rate of VLDL particles as a result of high LPL activity results in the up regulation of HDL2. This is clearly evident in chronic alcoholics. Low or subnormal low-density lipoprotein (LDL) levels are another characteristic of the lipoprotein pattern in chronic alcoholics. The increase of HDL (HDL2) and reduction of LDL levels could well explain the reduced risk of coronary heart disease in chronic alcoholics, whereas the causal factors remain open among moderate drinkers.

Lipoproteins and their genetic variation in subjects with and without angiographically verified coronary artery disease.

To examine the concentration of serum lipoproteins and the association of their genetic variation with the occurrence of coronary artery disease (CAD), composite serum lipoprotein profiles including lipoprotein(a) (Lp[a]), apolipoprotein (apo) E phenotypes, and apo B Xba I genotypes were determined in patients with angiographically verified CAD (CAD+ group, n = 111) and in subjects with no angiographic evidence of CAD (CAD- group, n = 46). In addition, we determined the concentrations of serum lipids, lipoproteins, and apolipoproteins in 96 healthy controls. Both CAD- and CAD+ groups had lower concentrations of apos A-I and A-II but higher concentrations of serum total and very low density lipoprotein triglyceride and very low density lipoprotein cholesterol than did healthy controls. The mean concentrations of serum total and low density lipoprotein cholesterol and the median values of Lp(a) were similar in the CAD+ and CAD- groups, both having higher concentrations of low density lipoprotein cholesterol and apo B than the healthy controls. Irrespective of gender, patients with CAD had significantly lower serum high density lipoprotein cholesterol than did those without CAD (1.48 +/- 0.40 versus 1.16 +/- 0.29 mmol/l, p less than 0.001). In women, the mean serum total and very low density lipoprotein triglyceride concentration was also higher in the CAD+ than in the CAD- group. The frequency of the apo E4 allele (epsilon 4) was significantly higher in the CAD+ group (0.293) than in the CAD- group (0.174; p less than 0.001). The frequencies of the two apo B alleles, X1 (Xba I restriction site absent) and X2 (Xba I restriction site present), were similar in the two groups. Stepwise discriminant analysis revealed that in men, serum high density lipoprotein cholesterol had the highest power to discriminate for CAD. In addition, the concentration of plasma apo B levels and the occurrence of apo E phenotypes were independently associated with CAD in men. In women, the only independent factor associated with CAD after adjustment for beta-blocker and diuretics usage was the concentration of serum triglycerides.