Increase In Hepatic Lipase Activity Research Articles

Effects of diel-cycling hypoxia and salinity on lipid metabolism and fatty acid composition of the oyster Crassostrea hongkongensis

For marine animals living in estuarine, coastal, and intertidal areas, salinity changes and periodic hypoxia are typical stressors; however, how the varying salinity and dissolved oxygen affect the quality and nutrition of marine aquaculture species, such as oysters remains unknown. In this study, we evaluated the diel-cycling hypoxia under different salinities on fatty acid composition and lipid metabolism in oyster Crassostrea hongkongensis digestive glands. After 28 days of exposure, both hypoxia and elevated salinity caused a decrease in the saturated fatty acid (SFA)/polyunsaturated fatty acid (PUFA) ratio of C. hongkongensis, salinity mainly causes changes in C17:0, C17:1, C18:1n9, C20:1n9, C20:4n6, C21:5n3, C22:5n3, with high salinity being more damaging to the fatty acid fractions. Also, Hypoxia accelerates the synthesis of C18:1n9 and C20:4n6. Fatty acid synthase (FAS) synthesis is increased by reduced salinity or hypoxia, but Acetyl CoA carboxylase (ACC) only weakly promotes fatty acid synthesis. Under hypoxic conditions, the activity of both hepatic lipase (HL) and lipoprotein lipase activity (LPL) decreases, which is contrary to the results for dissolved oxygen. The increase in salinity under dissolved oxygen leads to a decrease in LPL activity and an increase in HL activity. Our findings highlighted that exposure to a combination of salinity and hypoxia stressors, can disrupt the protective mechanisms of the oyster and affect the function of its lipid metabolism. Therefore, long-term exposure to periodic hypoxia with salinity changes poses a risk to the nutritional quality of C. hongkongensis, affecting oyster aquaculture and the coastal ecosystem.

Low molecular weight heparin-induced increase in chylomicron-remnants clearance, is associated with decreased plasma TNF-α level and increased hepatic lipase activity

The acute effect of heparin on lipoprotein clearance is well characterized. Yet, the effect of prolonged low-molecular-weight-heparin (LMWH) administration on post-prandial lipemia has remained so far unexplored. Recent reports suggest that LMWH could modify lipid and carbohydrate metabolism by diminishing TNFα-mediated inflammatory response. This, together with the known negative effect of TNF-α on insulin sensitivity, prompted us to hypothesize that LMWH would favorably affect post-prandial lipoprotein disposal. Twenty four patients were given a vitamin A-fat loading meal at the end of 6-week enoxaparin treatment and after 3-month washout period. Post-prandial lipemia was assessed by measuring retinyl-palmitate (RP) during 8hours following the meal. Insulin sensitivity index (ISI), plasma lipolytic activity and plasma TNF-α were measured. Enoxaparin did not impact fasting plasma lipids and lipoproteins levels. Enoxaparin increased RP clearance in the chylomicron remnant (CMR) fraction by 32% (P<0.01). Additionally, enoxaparin decreased plasma TNF-α by 22% (P<0.01), increased hepatic lipase (HL) activity by 81% (P<0.01), along with a 2-fold increase in ISI (P<0.01). The decrease in CMR correlated with the reduction in TNFα and the increase in ISI and HL activity (R=0.48, -0.68, -0.56, respectively, p<0.05). Significant correlations were also found between the reduction in TNFα and both the increase in ISI and increase in HL activity (R=-0.43, -0.54, respectively, P<0.05). The association of the effect on post-prandial metabolism, plasma TNFα level and HL activity during prolonged enoxaparin treatment may support the hypothesis that the beneficial outcome of enoxaparin may possibly be linked to anti-inflammatory and lipase-potentiating impact.

Circulating small dense LDL, endothelial injuring factors and fibronectin in healthy postmenopausal women

Background In postmenopausal women (PMW), an adverse lipoprotein pattern and high risk of coronary artery disease has been described. Studies of the mechanisms promoting the higher atherogenic risk observed in healthy PMW are relevant. We evaluated the interactions among several circulating factors involved in the endothelial injury and inflammation in relation to LDL characteristics, beyond LDL cholesterol. Methods Lipoprotein profile, including apolipoproteins A-I and B, small dense LDL, hepatic lipase, cholesterol transfer protein (CETP), LDL composition and oxidability were assessed in PMW ( n = 30) in comparison to premenopausal (PreMW, n = 28). The following emerging factors were measured: homocysteine, phospholipase A2, ferritin, hs-CRP and fibronectin from extracellular vascular matrix. Insulin-resistance was evaluated by waist circumference, HOMA and TG/HDL cholesterol ratios. Results The risk index apo B/apo A-I was significantly increased in PMW ( p < 0.0001), PMW showed higher proportion of small dense LDL which correlated with the increase in hepatic lipase activity ( p < 0.005) and with insulin-resistance markers ( p < 0.05), but not with CETP. Phospholipase A2 ( p < 0.05), homocysteine ( p < 0.005), hs-CRP ( p < 0.005), fibronectin ( p < 0.05) and ferritin ( p < 0.0001) were increased in PMW. LDL oxidability positively correlated with waist ( p < 0.02), homocysteine ( p < 0.05), fibronectin ( p < 0.05), hs-CRP ( p < 0.04), phospholipase A2 ( p < 0.05), and small dense LDL ( p < 0.01). After adjusting by menopausal condition, age and waist, LDL oxidability remained associated with waist ( β: 0.35, p = 0.047), homocysteine ( β: 0,36 p < 0,038), fibronectin ( β: 0,41 p = 0.05), and small dense LDL ( β: 0.36, p = 0.027). Conclusions Evaluation of classic and non-traditional circulating risk factors in hypoestrogenism reflected endothelial and subendothelial inflammation and subclinical atherogenic processes.

Sources of variability in genetic association studies: insights from the analysis of hepatic lipase (LIPC).

Genetic association studies have been widely used to identify loci that influence plasma lipoprotein concentrations, but few of the associations reported have proved consistently reproducible across different study populations. This lack of consistency is a widely recognized limitation of association studies, and is often ascribed to inadequate statistical power, population substructure, and population-specific linkage disequilibrium. However, few studies have assessed the causes of variability underlying a given genotype-phenotype association. We have examined two possible sources of variability in the association between the -514 polymorphism in hepatic lipase (LIPC) and plasma HDL-C concentrations. First, we compared the association between this polymorphism and hepatic lipase activity in four populations. A single copy of the -514C allele was associated with a 10 mmol.hr(-1).l(-1) increase in hepatic lipase activity in white American and Turkish men but only approximately 5 mmol.hr(-1).l(-1) in Chinese and African-American men. Second, we tested the effects of a stanozolol-induced increase in hepatic lipase activity on plasma HDL-C concentrations in men with normal (< 150mg/dl) or elevated (150-300mg/dl) levels of plasma triglyceride. The increase in hepatic lipase activity was similar in the two groups, but the resulting decline in HDL-C levels was significantly greater in normolipidemic men. These data suggest that the effect of a polymorphism on gene expression can vary among individuals, and that the resulting phenotype may be further modified by interactions with other factors. Three novel LIPC polymorphisms were identified in the study (-1596insC, -2740A>G, and -2880G>C).

The C-514T polymorphism in the human hepatic lipase gene promoter diminishes its activity

Four common polymorphisms in the promoter of the hepatic lipase gene (LIPC) that are in almost complete linkage disequilibrium have been described in different ethnic groups. The T and A alleles at positions −514 and −250, respectively, were observed to be associated with decreased hepatic lipase (HL) activity and increased triglyceride content of HDL and LDL particles. We investigated whether these polymorphisms have any effect on transcriptional activity of the proximal promoter (−639 to +29) in transient transfection assays. We found that the promoter with T at position −514 had approximately 30% lower activity than the one with C at the same position (P < 0.0005) regardless of the genotype at position −250. In conclusion, these data indicate that the −514T allele may contribute significantly to decreased HL activity and the resultant increase in plasma levels of triglyceride-rich HDL2 and large buoyant LDL particles. In addition, this promoter variant may explain the finding that its presence attenuates the increase in HL activity with increasing intra-abdominal fat in women. —Deeb, S. S., and R. Peng. The C-514T polymorphism in the human hepatic lipase gene promoter diminishes its activity.

Hepatic lipase affects both HDL and ApoB-containing lipoprotein levels in the mouse

Transgenic mice were created overproducing a range of human HL (hHL) activities (4–23-fold increase) to further examine the role of hepatic lipase (HL) in lipoprotein metabolism. A 5-fold increase in heparin releasable HL activity was accompanied by moderate (approx. 20%) decreases in plasma total and high density lipoprotein (HDL) cholesterol and phospholipid (PL) but no significant change in triglyceride (TG). A 23-fold increase in HL activity caused a more significant decrease in plasma total and HDL cholesterol, PL and TG (77%, 64%, 60%, and 24% respectively), and a substantial decrease in lipoprotein lipids amongst IDL, LDL and HDL fractions. High levels of HL activity diminished the plasma concentration of apoA-I, A-II and apoE (76%, 48% and 75%, respectively). In contrast, the levels of apoA-IV-containing lipoproteins appear relatively resistant to increased titers of hHL activity. Increased hHL activity was associated with a progressive decrease in the levels and an increase in the density of LpAI and LpB48 particles. The increased rate of disappearance of 125I-labeled human HDL from the plasma of hHL transgenic mice suggests increased clearance of HDL apoproteins in the transgenic mice. The effect of increased HL activity on apoB100-containing lipoproteins was more complex. HL-deficient mice have substantially decreased apoB100-containing low density lipoproteins (LDL) compared to controls. Increased HL activity is associated with a transformation of the lipoprotein density profile from predominantly buoyant (VLDL/IDL) lipoproteins to more dense (LDL) fractions. Increased HL activity from moderate (4-fold) to higher (5-fold) levels decreased the levels of apoB100-containing particles. Thus, at normal to moderately high levels in the mouse, HL promotes the metabolism of both HDL and apoB-containing lipoproteins and thereby acts as a key determinant of plasma levels of both HDL and LDL.

Effects of testosterone replacement on HDL subfractions and apolipoprotein A-I containing lipoproteins

Gonadal steroids are important regulators of lipoprotein metabolism. The aims of this study were to determine the effects of a minimum effective dose of testosterone replacement on high density lipoprotein (HDL) subfractions and apolipoprotein (apo) A-I containing particles (lipoprotein (Lp)A-I) and LpA-I:A-II) in hypogonadal men with primary testicular failure and to investigate the underlying mechanisms of these changes. Eleven Chinese hypogonadal men were started on testosterone enanthate 250 mg intramuscularly at 4-weekly intervals. HDL was subfractionated by density gradient ultracentrifugation and LpA-I was analysed by electro-immunodiffusion after 3, 6 and 12 weeks of treatment. Plasma cholesteryl ester transfer protein (CETP) activity and lipolytic enzymes activities in post-heparin plasma were measured to determine the mechanisms underlying testosterone-induced changes in HDL. The dosage of testosterone enanthate used in the present study resulted in suboptimal trough testosterone levels. No changes were seen in plasma total cholesterol, triglyceride, low density lipoprotein cholesterol (LDL-C,) apo B and apo(a) after 12 weeks. There was a drop in HDL3-C compared to baseline (0.82 +/- 0.17 mmol/l vs. 0.93 +/- 0.13, P < 0.01) whereas a small but significant increase was seen in HDL2-C (0.21 +/- 0.13 mmol/l vs. 0.11 +/- 0.09, P < 0.05). Plasma apo A-I decreased after treatment (1.34 +/- 0.25 g/l vs. 1.50 +/- 0.29, P < 0.01), due to a reduction in LpA-I:A-II particles (0.86 +/- 0.18 g/l vs. 0.99 +/- 0.24, P < 0.01). No changes were observed in the levels of LpA-I particles. No significant changes were seen in plasma CETP and lipoprotein lipase activities after testosterone replacement but there was a transient increase in hepatic lipase (HL) activity at weeks 3 and 6. The decrease in HDL correlated with the increase in HL activity (r = 0.62, P < 0.05). Testosterone replacement in the form of parenteral testosterone ester given 4-weekly, although unphysiological, was not associated with unfavourable changes in lipid profiles. The reduction in HDL was mainly in HDL3-C and in LpA-I:A-II particles and not in the more anti-atherogenic HDL2 and LpA-I particles. The changes in HDL subclasses were mainly mediated through the effect of testosterone on hepatic lipase activity.

Decrease in the expression of hepatic lipase activity following partial hepatectomy.

Variations in hepatic lipase (HL) activity were studied for the first time in liver, plasma and adrenal glands of partially hepatectomized (70%), sham-operated and intact rats. Activity profiles performed during 7 days in liver, plasma and adrenal glands of sham-operated rats were similar to those obtained in intact animals. However, HL activity in intact animals appeared to be slightly higher during the first 24 hours. Following surgery, hepatectomized animals showed a reduction of about 300 U in liver HL activity which persisted for 7 days. Plasma HL activity of hepatectomized rats was undetectable at 6 hours post-surgery but in increased afterwards. A high correlation between liver and adrenal gland HL activity was found in hepatectomized but not in sham-operated animals. HL mRNA levels in hepatectomized rats showed a 40% decrease during the first 24 hours after surgery, but they returned to the normal range later. On the other hand, HL mRNA values increased in sham-operated rats but no increase in HL activity was detected in these animals. To conclude, our results show that HL activity decreases dramatically during hepatic regeneration due to a concomitant decrement in the expression of the gene that encodes the enzyme and to other undetermined factors.

Pharmacodynamic activity of lipoprotein lipase and hepatic lipase, and pharmacokinetic parameters measured in normolipidaemic subjects receiving ciprofibrate (100 or 200 mg/day) or micronised fenofibrate (200 mg/day) therapy for 23 days

The activities of lipoprotein lipase (LPL) and hepatic lipase (HL) were investigated after 23 days of ciprofibrate (100 mg or 200 mg) therapy or fenofibrate (200 mg) therapy. In a double-blind, double-placebo, cross-over study, three groups of six healthy volunteers received either 100 mg ciprofibrate/day followed by 200 mg fenofibrate ‘high bioavailability’ (HB)/day, or vice versa (group A), 200 mg ciprofibrate/day followed by 200 mg fenofibrate HB/day, or vice versa (group B), or 100 mg ciprofibrate/day followed by 200 mg ciprofibrate/day, or vice versa (group C). Fasting plasma lipid levels and safety parameters were evaluated before and after treatment. One hundred milligrams ciprofibrate/day therapy was found to be approximately as effective as 200 mg fenofibrate HB/day therapy in altering the lipid profile. The highest activation of LPL was obtained after treatment with 200 mg ciprofibrate/day. A modest, but statistically significant, increase in HL activity was found after 100 or 200 mg ciprofibrate treatment. Investigation of the pharmacokinetics of ciprofibrate and fenofibric acid revealed a shorter time to reach peak plasma levels, but a longer elimination half life for the ciprofibrate preparations in comparison with fenofibrate. A dose of 200 mg ciprofibrate/day is more effective than 100 mg ciprofibrate/day at increasing LPL and HL activity; however, 200 mg ciprofibrate/day is also associated with a potentially detrimental change in safety parameters. Two hundred milligrams fenofibrate HB/day therapy may represent an alternative therapy to 100 mg ciprofibrate/day for hyperlipidaemic patients.

Abnormalities in hepatic lipase in chronic renal failure: role of excess parathyroid hormone.

Post-heparin hepatic lipase activity is reduced in chronic renal failure (CRF). This could be due to reduced synthesis, decreased activity, and/or impaired secretion of the enzyme. Further, the factor(s) responsible for such derangements are not elucidated. We examined hepatic lipase metabolism in normal, 6-wk-old CRF rats, CRF-PTX (parathyroidectomized) rats, and CRF and normal rats treated with verapamil (CRF-V, normal-V) using liver homogenate, hepatic cell culture for 8 h, and in vitro liver perfusion. The Vmax of hepatic lipase in liver homogenate was significantly (P < 0.01) reduced and the Km was significantly (P < 0.01) increased in CRF rats, but the values were normal in CRF-PTX, CRF-V, and normal-V rats. Culture of hepatic cells for 8 h was associated with an increase in hepatic lipase activity but the increment in CRF rats was significantly (P < 0.01) lower than that of normal, CRF-PTX, CRF-V, and normal-V rats. Both parathyroid hormone (PTH)-(1-84) and 1-34 inhibited the production of hepatic lipase in cultured cells from normal, CRF-PTX, CRF-V, and normal-V rats. The expression of the mRNA of the hepatic lipase was significantly reduced in CRF animals with the ratio between it and that of house keeping gene G3DPH being 15 +/-3% compared to 40 +/- 1.3% in normal, 44+/-2.9% CRF-PTX, 44 +/- 5.4% in CRF-V, and 39 +/- 3.9% in normal-V rats. Infusion of heparin to the in vitro hepatic perfusion system increased the activity of hepatic lipase in the effluent in all groups of rat except in CRF animals. Infusion of PTH-(1-34) in dose of 10(-6) M into the liver perfusion system inhibited the increase in post-heparin hepatic lipase activity. The data show that in CRF (a) the mRNA of hepatic lipase is downregulated, and hepatic lipase production, activity and release are impaired, (b) that this is due to the state of secondary hyperparathyroidism of CRF since both acute and chronic excess of PTH were associated with these abnormalities, (c) and that prevention of excess PTH by PTX of CRF rats or blocking the effect of PTH by treatment with verapamil corrected the derangement in hepatic lipase metabolism.

Fasting and postprandial determinants for the occurrence of small dense LDL species in non-insulin-dependent diabetic patients with and without hypertriglyceridaemia: the involvement of insulin, insulin precursor species and insulin resistance

We have studied low density lipoprotein (LDL) subclass distribution in a group of male patients with non-insulin-dependent diabetes mellitus (NIDDM) and investigated its relationships to fasting and postprandial triglyceride (TG)-rich lipoproteins, insulin resistance, lipoprotein lipase (EC 3.1.1.3; LPL), hepatic lipase (EC 3.1.1.34; HL), lecithin:cholesterol acyl transferase (EC 2.3.1.43; LCAT) and cholesteryl ester transfer protein (CETP) activities. LDL was subfractionated by density gradient ultracentrifugation. Postprandial lipoproteins were measured after an oral fat load using retinyl palmitate as a marker for intestinal TG-rich lipoproteins. Hypertriglyceridaemic NIDDMs (HTG) had a preponderance of small dense LDL particles present in the plasma and reduced amounts of large buoyant species when compared to normotriglyceridaemic patients (NTG) and controls. Both groups of diabetics were more insulin resistant than the controls ( P < 0.05) and had raised concentrations of proinsulin ( P < 0.05), although insulin content did not differ significantly. 32–33 split proinsulin (SPI) was the major insulin-like molecule present in HTG and was present in significantly higher amounts in these patients ( P < 0.05) than either NTG or control subjects and correlated significantly with the presence of small dense LDL particles. After a test meal, the postprandial chylomicron response was greater in HTG than either NTG diabetics or controls ( P < 0.05). Chylomicron remnants were present to a greater extent in HTG than in NTG and controls ( P < 0.05), although in this case NTG also contained more chylomicron remnants than control subjects ( P < 0.05). There was no difference in the LPL activity, CETP and LCAT between diabetics and controls, whereas an increase in hepatic lipase activity was seen in the HTG diabetics ( P < 0.05). Both CETP and LCAT activities increased postprandially. Multivariate analysis showed that TG, HDL content and HL activity were the most important determinants of small dense LDL concentration in the fasting state ( R 2 = 67%). Postprandially, chylomicron remnant clearance, HL and insulin resistance were the major determinants ( R 2 = 61%) of LDL-III.

Thyroid replacement therapy and its influence on postheparin plasma lipases and apolipoprotein-B metabolism in hypothyroidism.

T4 replacement at 150 micrograms/day in a group of six hypothyroid subjects led to the development of a euthyroid state and produced a fall in the cholesterol content of plasma and low and high density lipoproteins (LDL and HDL). The effect of T4 on apolipoprotein-B (apoB) metabolism was followed using radioiodinated very low density lipoprotein1 (VLDL1; 60-400 Svedberg units) and VLDL2 (20-60 Svedberg units). The pretreatment plasma concentration of VLDL1 apoB and its rates of synthesis and catabolism were similar to those in normal subjects. VLDL2 apoB was synthesized at a supranormal rate in hypothyroid subjects, and this led to a doubling of its circulating mass. Treatment did not significantly alter the kinetics of apoB in either VLDL1 or VLDL2. The concentration of intermediate density lipoprotein (IDL) apoB in untreated hypothyroids was 170% of normal and fell during T4 treatment due to stimulation of conversion of LDL (from 0.46 +/- 0.14 to 0.91 +/- 0.30 pools/day; mean +/- SD; P < 0.01). Direct IDL apoB clearance was not altered by treatment, whereas the fractional catabolic rate of LDL increased 76% (from 0.17 +/- 0.06 to 0.27 +/- 0.07 pools/day), leading to a 36% decrement in LDL mass. The stimulation of IDL to LDL conversion during therapy was probably due to a 3-fold increase in hepatic lipase activity (P < 0.02). This change together with the known effects of T4 on LDL receptors largely explained the lipoprotein abnormality in hypothyroidism and the effects of replacement therapy.

Infusion of atherogenic lipoprotein particles increases hepatic lipase activity in the rabbit.

Hepatic lipase plays a key role in the turnover of potentially atherogenic lipoprotein remnants and in determining the relative distribution of high density lipoprotein (HDL) particle size subclasses. Rabbits fed a cholesterol-enriched diet have been found to accumulate potentially atherogenic chylomicron remnants and beta-very low density lipoprotein (beta-VLDL) and show a rapid increase in liver and postheparin plasma hepatic lipase activity. To determine whether the particles that accumulate during cholesterol feeding are a stimulus for this increase in hepatic lipase activity, we infused normal chow-fed rabbits with a chylomicron remnant plus beta-VLDL-enriched plasma fraction isolated from rabbits fed 0.5% cholesterol-supplemented chow. The infusion of this plasma fraction for 4 h increased hepatic lipase activity up to 2.9-fold over control rabbits and resulted in a loss of larger sized HDL particles consistent with the action of hepatic lipase. The increase in activity was significantly correlated with the concentration of infusate phospholipid, unesterified cholesterol, and esterified cholesterol, but not with the infusate triglyceride concentration. The change in the plasma cholesterol concentration of recipient rabbits, which reflects the degree of lipoprotein accumulation in these rabbits, was also significantly correlated with the change in hepatic lipase activity. However, a chylomicron remnant and beta-VLDL-depleted fraction of plasma from cholesterol-fed rabbits did not increase hepatic lipase activity. Furthermore, triglyceride presented as an artificial lipid emulsion (Intralipid) was not able to stimulate hepatic lipase activity, although triglyceride is a substrate for hepatic lipase.(ABSTRACT TRUNCATED AT 250 WORDS)

Secretion-coupled increase in the catalytic activity of rat hepatic lipase

Freshly isolated rat hepatocytes synthesize and secrete hepatic lipase (HL). Comparison of secreted HL with intracellular HL indicates a secretion-linked increase in the specific enzyme activity. (a) Immunotitration with polyclonal anti-HL showed a 3-5-fold lower specific enzyme activity of intracellular HL than of secreted HL. This was confirmed by ELISA using a mixture of monoclonal anti-HL's. (b) After isolation on Sepharose-heparin, a similar difference in specific enzyme activity was observed, whereas the apparent Km for glyceroltrioleate was not different. (c) HL activity secreted in the absence of protein de novo synthesis was 5-fold higher than was accounted for by the fall in intracellular activity, whereas HL protein lost from the cells was near-completely recovered in the extracellular medium. (d) The presence of inactive HL protein was demonstrated in cells treated with castanospermine, which inhibits secretion of newly synthesized HL by interfering with maturation at an early stage of N-linked oligosaccharide processing. Upon removal of castanospermine, secretion of HL activity recovered, even when protein de nove synthesis was inhibited, strongly suggesting that part of the inactive HL was mobilized and became activated. This secretion-coupled increase in HL activity in the absence of protein synthesis suggests the existence of inactive precursor within rat hepatocytes. The catalytic activity of HL becomes apparent upon maturation of the protein after oligosaccharide processing by the rough endoplasmic reticulum glucosidases.

Increased hepatic lipase activity and increased direct removal of very-low-density lipoprotein remnants in Watanabe heritable hyperlipidaemic (WHHL) rabbits treated with ethinyl oestradiol

We studied the effects of ethinyl oestradiol on the serum concentrations and metabolism of very-low- and low-density lipoproteins (VLDL and LDL) in Watanabe heritable hyperlipidaemic (WHHL) homozygous rabbits, an animal model for familial hypercholesterolaemia. The results were compared with those in untreated homozygotes as well as in heterozygotes treated or not with ethinyl oestradiol. The gain in body weight was similar in all groups. Treatment with ethinyl oestradiol resulted in the homozygotes in an approx. 80% decrease in the concentrations of lipids and apoprotein B in the d less than 1.019 lipoprotein fraction; those in the LDL fraction did not change. In the heterozygotes, basal serum lipids and apoprotein B levels in the d less than 1.019 fraction were low; ethinyl oestradiol treatment especially affected the LDL fraction (cholesterol -84%, apoprotein B -64%). Turnover experiments with 125I-labelled VLDL revealed that, on treatment with ethinyl oestradiol, the fractional catabolic rate in homozygous rabbits increased 2-fold. The secretion rates of lipids and protein in the d less than 1.019 fraction as estimated after injection of Triton WR-1339 was not decreased. In homozygotes and heterozygotes increases in post-heparin hepatic lipase activity of 62 and 80% respectively were observed, with no changes in lipoprotein lipase activity. We conclude that ethinyl oestradiol induces in homozygous WHHL rabbits a direct removal of VLDL and VLDL remnants from the plasma, apparently due to an increase in hepatic lipase activity.

Time-course of alterations of high density lipoproteins (HDL) during thyroxine administration to hypothyroid women.

Serum HDL cholesterol, apolipoproteins AI and AII and post heparin lipolytic activities (PHLA) have been measured in a group of fourteen hypothyroid women without ovarian oestrogen secretion before and during a 2-month thyroxine treatment. The more rapid and consistent observed event was a decrease in apo AI levels (164 +/- 5 vs. 149 +/- 5 mg dl-1, mean +/- SEM, P less than 0.05) correlated (r = 0.79, P less than 0.05) to a slight increment of PHLA. A slight decrease in apo AII concentration was seen only after 5 days (25 +/- 2 vs. 22 +/- 2 mg dl-1, P less than 0.05) and in HDL cholesterol only after 60 days (1.3 +/- 0.6 vs. 1.1 +/- 0.5 mmol 1-1, P less than 0.05). Apo AI, HDL2 and HDL3 cholesterol were measured in another group of seven hypothyroid postmenopausal women before and after a 2-month thyroxine treatment. We observed a decrease in HDL2 cholesterol (1.69 +/- 0.20 vs. 1.17 +/- 0.09 mmol 1-1, P less than 0.02) with no changes in HDL3 cholesterol (0.88 +/- 0.09 vs. 0.99 +/- 0.06 mmol 1-1, NS). The decrease in HDL2 cholesterol correlated (r = 0.72, P = 0.05) with that for apo AI. The differential influence of thyroxine (T4) administration on the major HDL components might reflect changes in HDL composition due to the multiple effects of thyroid hormones on lipid metabolism. It can be hypothesized that the decrease in apo AI and HDL2 cholesterol concentrations are due, at least in part, to the increase in hepatic lipase activity.

Increase in hepatic lipase activity after testosterone substitution in men with hypogonadism of pituitary origin.

Ten men with hypogonadism of pituitary origin were studied before and during testosterone substitution therapy with regard to effects on the activities of hepatic lipase (HL) and lipoprotein lipase (LPL) in postheparin plasma, and on plasma lipoprotein concentrations. The mean (+/- SEM) testosterone level increased from 1.8 +/- 0.5 to 16.3 +/- 2.4 nmol/l. The mean activity of HL rose from 327.1 +/- 35.2 to 432.8 +/- 57.2 mU/ml (p less than 0.02), while the activity of LPL did not change significantly, 71.0 +/- 9.1 mU/ml before and 62.2 +/- 3.8 mU/ml after treatment. No significant alterations in lipoprotein concentrations were recorded. These results indicate that a normal testosterone level is of importance for maintaining the activity of HL in men, thereby contributing to the sex difference previously recorded for HL activity.

Hepatic triacylglycerol lipase activities after induction of diabetes and administration of insulin or glucagon.

Triacylglycerol lipase activities of homogenates and subcellular fractions of rat liver were measured under optimal conditions at pH 7.5 using emulsified tri[1-14C]oleoylglycerol as substrate. Twenty-four hr after administration of streptozotocin, hepatic alkaline lipase activity was 39% of normal, and this lower level of activity was observed at 72 hr and 7 days, after streptozotocin injection. After 24 hr of starvation, lipase activity also was significantly lower (35%) than normal. Insulin (35 U regular/kg body weight) had no acute (90 min) effect on the hepatic lipase activity of either normal or diabetic rats. Chronic insulin administration (4 subcutaneous injections of 10 U protamine zinc insulin/kg at 16-hr intervals) to normal rats provoked a 40% increase in hepatic lipase activity. Diabetic rats given the same insulin treatment showed lipase activity that was significantly higher (155%) than normal. Lipase activity fell to 65% of normal when insulin was withheld (32 hr) from diabetic rats given chronic insulin therapy. Intracardial injection of glucagon (1 mg/kg) into normal rats had no acute (30 min) effect on hepatic alkaline lipase activity. Hepatic alkaline lipase activity varied independently from the concentrations of either glucose or triacylglycerol in the plasma. However, there was an apparent negative correlation between this lipase activity and the concentration of fatty acids in the plasma; lipase activity was highest when fatty acid concentrations were lowest, and lowest when fatty acid concentrations were elevated. From these data we conclude: 1) changes in hepatic alkaline lipase activity ware provoked by chronic, but not acute, alteration of the hormonal and metabolic status of the rat, and 2) changes in hepatic alkaline lipase activity may be mediated through changes in the levels of circulating fatty acids presented to the liver, but the effect is not an immediate one.