Lipoprotein Metabolism during Acute Inhibition of Hepatic Triglyceride Lipase in the Cynomolgus Monkey

Goldberg, Ira J.; Le, Ngoc‐Anh; Paterniti, James R.; Ginsberg, Henry N.; Lindgren, Frank T.; Brown, W. Virgil

doi:10.1172/jci110717

Cited by 250 publications

(90 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Most of the factors that regulate HDL heterogeneity have yet to be identified, but we are aware of dietary effects and species differences in apo A-l production and catabolism 91516 that could influence HDL distribution. In the context of HTGL effects on plasma HDL, it is also interesting to note that no effects on HDL concentrations were found by Goldberg et al 13 after acute inhibition of HTGL activity in cynomolgus monkeys with an antisera to HTGL…”

Section: Discussionmentioning

confidence: 94%

“…In studies in which triglyceride distribution has been measured, the distribution of triglycerides among plasma lipoproteins in fasting plasma of nonhuman primates is similar to the distribution of cholesterol. 6 Goldberg et al 13 have studied the effects of acute inhibition of HTGL activity in cynomolgus monkeys with an antiserum developed to the enzyme isolated from human plasma. Their findings also support a role for HTGL in plasma triglyceride clearance.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Species, diet, and gender differences in plasma postheparin lipolytic activities in nonhuman primates. Relationships with plasma lipids and high density lipoproteins.

Rudel

Star

1990

Arteriosclerosis

View full text Add to dashboard Cite

Studies were done in selected groups of nonhuman primates in which the diet (low fat and high fat as either polyunsaturated or saturated fat), gender, and species (African green monkeys and cynomolgus monkeys) were varied. Large differences In plasma lipld and llpoprotein concentrations were found among these groups, providing the opportunity to examine their relationships to postheparin lipolytic activities (PHLA) including lipoproteln llpase (LPL) and hepatic trlglycerlde lipase (HTGL). PHLA was measured in plasma drawn 20 minutes after injection of heparin (100 units/kg). The assay was done with a radioactive trlglyceride emulsion, and LPL and HTGL activities were estimated after 1 M NaCI Inhibition of the former. LPL activity was high in both species of monkeys, and HTGL activity was low; the ratio of HTGL/LPL was consistently less than 0.5. The mean values for LPL activity did not vary significantly among experimental groups, but significant negative correlations between LPL activity and plasma trlglycerlde concentration were found. Statistically significant diet, species, and gender differences In HTGL activities were found. In hlgh-fat-fed compared to low-fat-fed animals, HTGL activities were higher, and high density llpoprotein (HDL) cholesterol concentrations and the percentages of HDLa, were also higher. African green monkeys had consistently higher HTGL activities than cynomolgus monkeys and had higher concentrations of HDL cholesterol and a greater proportion of HDL as the larger HDL 2b subtraction. Significantly lower HTGL activities were found in females compared to males fed the low-fat diets, and females had a significantly greater proportion of total HDL in the HDL 2b subtraction. In conclusion, these studies have shown that postheparin lipolytic activity in nonhuman primates Is responsive to species, diet, and gender differences and that this response is primarily in HTGL In most cases, total HDL cholesterol concentration and the proportion of HDL as the HDLa, subtraction were higher In groups with higher HTGL activity. If plasma HDL concentration and subtraction distribution are affected by HTGL to decrease HDL and the amounts of larger HDU subtractions, as has been often suggested by others, then our data show that other factors can override this relationship. LPL activity was consistently twofold greater than HTGL activity among the various groups, a finding that may partially explain the low plasma triglycerlde concentrations common in nonhuman primates.

show abstract

Section: Discussionmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 99%

Species, diet, and gender differences in plasma postheparin lipolytic activities in nonhuman primates. Relationships with plasma lipids and high density lipoproteins.

Rudel

Star

1990

Arteriosclerosis

View full text Add to dashboard Cite

show abstract

“…In contrast, HL has greater affinity in vitro for smallersize IDL, LDL, and HDL particles than for TG-rich lipoproteins. 8,27,28 HL in vitro can convert larger, TG-rich LDL into smaller LDL. 27,28 Thus, the relative lack of affinity of HL for TG-rich lipoproteins, compared with LPL, might explain how a genetic mutation affecting HL activity, namely HL S267F, might affect LDL TGs but not total plasma TGs.…”

Section: Discussionmentioning

confidence: 97%

“…[1][2][3] In vitro and in vivo experiments have implicated a complex role for HL in the metabolism of several lipoprotein classes. 4 -12 For example, HL affects conversion of HDL 2 to HDL 3 , 4-6 conversion of VLDL remnants to LDL, [7][8][9] and catabolism of chylomicrons and their remnants. 10 -12 Studies in transgenic rabbits suggest that HL overexpression can result in reduced plasma HDL and IDL and in reduced atherosclerosis.…”

mentioning

confidence: 99%

Elevated LDL Triglyceride Concentrations in Subjects Heterozygous for the Hepatic Lipase S267F Variant

Hegele

Breckenridge

Cox

et al. 1998

ATVB

View full text Add to dashboard Cite

Abstract-Although naturally occurring loss-of-function mutations in human hepatic lipase (HL) have been described, the biochemical phenotype of heterozygous HL deficiency remains ill defined. This may be due to the relatively small numbers of heterozygous adult carriers of HL mutations in index kindreds. We have identified several new heterozygotes for the catalytically inactive, nonsecreted HL variant S267F in the kindred that was originally ascertained because of hypertriglyceridemia due to the mutant, secreted, circulating apolipoprotein (apo) CII variant apo CII-T. Pairwise comparisons with family controls showed that only the plasma low density lipoprotein triglycerides (LDL TGs) were higher in 11 simple heterozygotes for HL S267F (Pϭ0.002). In contrast, both plasma total TGs and LDL TGs were significantly higher in 12 simple heterozygotes for apo CII-T than in family-matched control subjects (Pϭ0.005 and 0.009, respectively). These findings suggest that the TG content of LDL is increased by heterozygosity for 2 different mutations that affect different proteins involved in lipolysis. However, the mechanisms underlying this compositional change in LDL appear to be different for the 2 mutations, because the total TGs are also elevated in subjects heterozygous for apo CII-T but not in subjects heterozygous for HL S267F. 10 -12 Studies in transgenic rabbits suggest that HL overexpression can result in reduced plasma HDL and IDL and in reduced atherosclerosis. 4 In contrast, disruption of HL in mice can result in increased HDL and, on an APOE-deficient background, increased ␤-migrating VLDL but reduced atherosclerosis. 13 The relevance of such results to human lipoprotein metabolism is unclear.Most patients with HL deficiency due to HL mutations have been ascertained on the basis of dyslipidemia. However, among carriers of HL mutations associated with loss of function, such as R186H, S267F, L334F, and T383M, there are disparities in both the biochemical phenotype and the association with atherosclerosis susceptibility.14 -17 For example, in a Canadian family, compound heterozygotes for HL S267F and T383M had (1) combined hyperlipidemia, (2) TG enrichment of LDL and HDL, (3) ␤-migrating VLDL, (4) impaired chylomicron remnant metabolism, and (5) early coronary heart disease.14 However, the limited number of subjects in this family made it difficult to conclude whether simple heterozygotes had a discrete phenotype. In a Finnish family, compound heterozygotes for L334F and T383M did not have ␤-migrating VLDL but did have TG enrichment of LDL and HDL.15 Also, Finnish heterozygotes for an HL allele that carried R186H and L334F appeared to have TG enrichment of LDL and HDL.16 Homozygosity for a splice-site mutation in HL intron I was associated with hypertriglyceridemia and coronary heart disease; however, there was no obvious biochemical phenotype among heterozygotes. 17The disparity among the results of studies of phenotype in heterozygotes for loss-of-function mutations in HL has many possible explanations. First, ...

show abstract

“…Lipoprotein lipase originates from extra-hepatic tissues and is involved in the metabolism of triacylglycerol-rich lipoproteins. Hepatic lipase is present in the liver and is believed to play a role in the metabolism of highdensity lipoproteins, intermediate-density lipoproteins and chylo-micron remnants [5][6][7][8][9]. Both lipoprotein lipase and hepatic lipase are synthesized and secreted by parenchymal cells and are bound specifically to the endothelial-cell lining [10][11][12][13][14][15].…”

Section: Introductionmentioning

confidence: 99%

Rat liver contains a limited number of binding sites for hepatic lipase

Schoonderwoerd

Verhoeven

Jansen

1994

Biochemical Journal

View full text Add to dashboard Cite

The binding of hepatic lipase to rat liver was studied in an ex vivo perfusion model. The livers were perfused with media containing partially purified rat hepatic lipase or bovine milk lipoprotein lipase. The activity of the enzymes was determined in the perfusion media before and after passage through the liver. During perfusion with a hepatic-lipase-containing medium the lipase activity in the medium did not change, indicating that there was no net binding of lipase by the liver. In contrast, more than 80% of the lipoprotein .lipase was removed from the medium. This lipoprotein lipase activity could be recovered into the perfusion medium completely by heparin perfusion of the liver. If livers, first depleted of hepatic lipase by heparin, were subsequent perfused with a hepatic-lipase-containing medium, 90 + 24 m-units of the lipase activity was bound per g of liver (up to 1000 m-units/total liver). However, heparin treatment of the liver decreases the ability of the liver to re-bind hepatic lipase by 80 %. Perfusion of rat livers with 0.3 M NaCl released 60 % of the lipase activity into the medium. Upon subsequent perfusion of these livers with hepatic-lipase-containing media, 541 + 164 munits of hepatic lipase could be bound per g of liver (up to 5000 m-units/total liver). The binding of hepatic lipase was also studied in livers of corticotropin (ACTH)-pre-treated rats. In these rats also, hepatic lipase bound only to livers which had been pre-perfused with heparin or 0.3 M NaCl. After heparin pre-perfusion, 88 + 12 m-units of hepatic lipase could be bound per g of liver, similar to that with livers of control rats not treated with ACTH. After prior salt perfusion, however, the capacity of the livers of ACTH-pre-treated rats to bind hepatic lipase was 212 + 60 m-units/g of liver. This is less than in livers of control rats (541 + 164 m-units/g of liver). These results indicate that in rat liver the binding ofhepatic lipase is heterogeneous in character and consists of heparin-resistant and heparin-sensitive components. The hepatic-lipase binding capacity of the liver is saturable and fully utilized under various conditions. The heparin-sensitive binding capacity is lowered in ACTH-treated rats, whereas the heparin-resistant binding is unaffected. We postulate that the functional hepatic lipase activity can be regulated by changes in the binding capacity of the liver.

show abstract

Lipoprotein Metabolism during Acute Inhibition of Hepatic Triglyceride Lipase in the Cynomolgus Monkey

Cited by 250 publications

References 36 publications

Species, diet, and gender differences in plasma postheparin lipolytic activities in nonhuman primates. Relationships with plasma lipids and high density lipoproteins.

Species, diet, and gender differences in plasma postheparin lipolytic activities in nonhuman primates. Relationships with plasma lipids and high density lipoproteins.

Elevated LDL Triglyceride Concentrations in Subjects Heterozygous for the Hepatic Lipase S267F Variant

Rat liver contains a limited number of binding sites for hepatic lipase

Contact Info

Product

Resources

About