Ultrastructural and physiological evidence for corticosteroid-induced alterations in hepatic production of very low density lipoprotein particles

The cause of corticosteroid-induced hyperlipoproteinemia was studied in rats and mice. An ultrastructural morphometric method was utilized to demonstrate alterations in hepatocyte very low density lipoprotein content, and Triton WR 1339-treated rats were used to identify changes in the removal of very low density lipoproteins from plasma. The results show that corticosteroid treatment results in (1) an increase in both plasma triglyceride and cholesterol levels, (2) an increase in rate of accumulation of triglyceride after inhibition of very low density lipoprotein removal by Triton, and (3) an increase in the number and size of Golgi-associated very low density lipoprotein particles in hepatocytes. These combined results suggest that corticosteroids induce hyperlipoproteinemia through increased hepatic production of very low density lipoproteins.     

Characterization of guinea pig plasma lipoproteins: the appearance of new lipoproteins in response to dietary cholesterol

Dietary cholesterol induces a hemolytic anemia in guinea pigs, accompanied by changes in the lipid composition of red cells and of plasma lipoproteins. This report presents a characterization of the lipoprotein species present in each main density class in both control and cholesterol-fed guinea pigs. Traces of a typical high density lipoprotein (HDL) were detected in control plasma. HDL from cholesterol-fed, anemic guinea pigs differed from control HDL in electron microscopic appearance and lipid and peptide composition. Long stacks of discs were observed in the electron microscope in addition to smaller, spherical particles characteristic of control HDL. Low density lipoproteins (LDL) from cholesterol-fed, anemic guinea pigs had two main populations, which were separated by gel chromatography. One population appeared in the electron microscope as large transparent discs and contained mainly unesterified cholesterol and phospholipids in a 2:1 molar ratio. The other population resembled control LDL in size and composition except for its high unesterified cholesterol content. Dietary cholesterol also altered the composition and decreased the electrophoretic mobility of very low density lipoproteins. Gel electrophoretic and immunochemical evidence indicates that a peptide (mol wt 35,000) appears in lipoproteins from cholesterol-fed, anemic guinea pigs that is undetectable in those of controls. Similarities between the cholesterol-induced lipoprotein abnormalities in guinea pigs and those reported in patients with obstructive jaundice, biliary cirrhosis, type III hyperlipoproteinemia, or familial lecithin:cholesterol acyltransferase deficiency are discussed.     

Apolipoprotein E phenotyping with a single gel method: application to the study of informative matings

Two-dimensional gel electrophoresis or isoelectric focusing before and after treatment with cysteamine are currently used to determine the six apolipoprotein E isomorphic phenotypes from isolated very low density lipoproteins. A technique is described that makes this possible by performing isoelectric focusing on a single polyacrylamide cylindrical gel under standardized conditions. The technique is simple and accurate enough to obtain 99.5% concordance when the gels are interpreted independently by four different skilled and unskilled observers in the absence of any knowledge of the origin of the samples. There was complete agreement between our technique and the bidimensional method carried out independently in another laboratory on 74 aliquots of plasma very low density lipoproteins. Its application to 16 informative matings involving 101 subjects confirmed the recent demonstration that the apolipoprotein E phenotype inheritance is autosomal and compatible with three common alleles acting at a single genetic locus. Analyses of the contribution of apoE polymorphism to lipid and lipoprotein variability demonstrated a recessive allelic effect of epsilon 2 on plasma very low density lipoprotein cholesterol and a dominant epsilon 4 effect on low density lipoprotein cholesterol. As much as 30% of the variability in low density lipoprotein cholesterol was attributable to this polymorphic gene locus. A simplified scheme is proposed for the symbolic representation of the six phenotypes for clinical and genetic applications.     

Unmasking of Type III Hyperlipoproteinemia by Hypothyroidism: A Dramatic Illustration of Altered Lipoprotein Metabolism in a Postpartum Woman

ObjectiveTo illustrate the potential abnormalities in lipoprotein metabolism associated with type III hyperlipoproteinemia and the modulation of their clinical expression by thyroid hormone and estrogenic status.MethodsAn illustrative case, with associated clinical and laboratory data, is presented, and relevant clinical and pathophysiologic studies from the literature are reviewed.ResultsA 35-year-old woman, at 7 months after delivery of her first child, presented to her family physician with a complaint of painful eruptions on the palms of her hands. On evaluation, she was found to have new hypothyroidism and severe hypertriglyceridemia (> 1,569 mg/dL). Thyroxine replacement was initiated, and she was referred to the lipid clinic. When seen in the lipid clinic shortly thereafter, her triglyceride level had normalized, but her low-density lipoprotein (LDL) fraction was strikingly elevated (representing a combination of elevated intermediate-density lipoprotein and LDL cholesterol). On physical examination, palmar xanthomas were noted, suggestive of type III hyperlipoproteinemia. This diagnosis was further supported by homozygosity at the apolipoprotein E (apo E) gene locus for the apo E2 allele implicated in this condition. Ultimately, with attainment of euthyroidism in the subsequent weeks, the lipid profile normalized, with the LDL cholesterol concentration particularly reduced at 55 mg/dL.Conclusion: Clinical expression of type III hyperlipoproteinemia necessitates interaction between an underlying genetic defect of lipoprotein metabolism (apo E2 homozygosity) and a secondary metabolic insult such as, in the current case, hypothyroidism and possibly breast-feeding-mediated hypoestrogenemia. As such, in patients with type III hyperlipoproteinemia, it is essential to search for exacerbating factors, particularly because the amelioration of such factors may rectify the effects of the underlying dyslipidemia. (Endocr Pract. 2005;11:394-398)     

Hyperlipoproteinemia in fasting ponies

Ponies fasted for up to 8 days showed, both by agarose electrophoresis and preparative ultracentrifugation, the appearance of a pre-beta-migrating, very low density lipoprotein fraction in plasma. This lipoprotein differs from the very low density lipoprotein found in humans and rats in that it contains a relatively smaller amount of total cholesterol, 85% of which is present in the unesterified form. By the 8th day of fasting, plasma triglyceride concentrations had increased from a prefasting level of 20 mg/dl to as high as 1000 mg/dl. The increase in plasma lipid concentrations as a result of fasting was highly variable. Accumulation of plasma cholesterol and triglyceride after injection of Triton WR 1339 was not related to the degree of fasting hyperlipidemia. This suggests that the hyperlipoproteinemia of fasting may result from an impaired utilization of very low density lipoproteins.     

Role of the apolipoprotein E polymorphism in determining normal plasma lipid and lipoprotein variation.

The structural gene locus for apolipoprotein E (apo E) is polymorphic. Three common alleles (epsilon 2, epsilon 3, epsilon 4) code for three major isoforms in plasma and determine six apo E phenotypes that may be identified by isoelectric focusing on polyacrylamide. To establish what fraction of the inherited variation in a normal plasma lipid and lipoprotein profile is attributable to the segregation of the common alleles at the apo E gene locus, we have estimated the average apo E allelic effects on plasma cholesterol (C), triglycerides, very low-density lipoprotein (VLDL)-C, VLDL-apo B, low-density lipoprotein (LDL)-C, LDL-apo B, and high-density lipoprotein (HDL)-C in a representative sample of normolipidemic individuals from Ottawa, Canada. Data from published studies were also analyzed by the same statistical procedures. As much as 16% of the genetic variance (8.3% of the total variance) for LDL-C could be accounted for by the apo E gene locus. After correction for differences in age, sex, height, and weight, it was found that the epsilon 2 allele lowered and the epsilon 4 allele raised total cholesterol, LDL-C, and LDL-apo B. No other gene has been identified that contributes as much to normal cholesterol variability. Analysis of these data and those of others also indicates that the apo E locus imparts a differential susceptibility to a variety of factors that promote hyperlipidemia. The hypothesis is proposed that the epsilon 2 allele protects against coronary heart disease (CHD) and, hence, gives a reproductive advantage that is balanced by a predisposition to CHD when the epsilon 2 is combined with a second, independent causative factor to give a reproductive disadvantage. A similar mechanism is proposed for the maintenance of the epsilon 4 allele in the population.     

Identification of a recurrent insertion mutation in the LDLR gene in a Pakistani family with autosomal dominant hypercholesterolemia

Familial Hypercholesterolemia (FH) results in elevated levels of blood lipids including total cholesterol (TC) and low density lipoprotein cholesterol (LDL-C) with normal triglycerides (TG). This disease is one of the major contributors towards an early onset of coronary heart disease (CHD). The aim of the present study was to identify the genes responsible for causing FH in Pakistani population, for this purpose a large consanguineous FH family was selected for genetic analysis. Serum lipid levels, including TC, TG, LDL-C and high density lipoprotein cholesterol (HDL-C), were determined in patients and healthy controls. In order to find the causative mutation in this family, direct sequencing of the low density lipoprotein receptor (LDLR) gene was performed. In addition the part of the Apolipoprotein-B (APOB) gene containing the mutations R3500Q and R3500W was also sequenced. Affected individuals of the family were found to have raised TC and LDL-C levels. Sequencing revealed an insertion mutation (c.2416_2417InsG) in exon 17 of the LDLR gene in all the affected individuals of the family. Common FH causing APOB mutations were not present in this family. Heterozygous individuals had TC levels ranging from ~300–500 mg/dl and the only homozygous individual with typical xanthomas had TC levels exceeding 900 mg/dl. This is the first report of a known LDLR gene mutation causing FH in the Pakistani population. Despite a large heterogeneity of LDLR mutations there are still some common mutations which are responsible for FH throughout the world.     

Role of apolipoproteins E and C in type V hyperlipoproteinemia

Type V hyperlipoproteinemia is characterized by elevations of chylomicron (CM) and very low density lipoprotein (VLDL) triglycerides. The development of this lipid disorder involves a multitude of metabolic derangements including deficient clearance of triglycerides and/or their increased output aggravated by obesity, diabetes, alcohol intake, or use of some hormones. Some studies have suggested that the apolipoprotein E4 phenotype is involved in this dyslipoproteinemia but this concept is still a matter of controversy. Therefore, we determined the apoE phenotype in 21 patients with severe hypertriglyceridemia classified as type V. Their apoE4 gene frequency was 0.595 which is 2.6-fold higher (P less than 0.001) than that in the Finnish population. Correspondingly, their apoE3 gene frequency was lower than that in the normal population. No differences were noted in plasma lipoproteins of the apoE4 phenotypes and the other type V subjects. The apolipoprotein C-II and C-III distribution was similar to that in normolipidemic subjects. The results suggest that apoE4 may be involved in the development of type V hyperlipoproteinemia.     

Chemical characterization of the serum very low density and high density lipoproteins from bullfrog, Rana catesbeiana.

The chemical properties of very low density and high density lipoproteins of adult bullfrog serum were determined. This serum contained extremely low levels of both very low density lipoprotein (10-30 mg/100 ml) and high density lipoprotein (5-10 mg/100 ml). The constituents of very low density lipoprotein, on a weight percentage basis, were found to be 48.1% triglyceride, 17.3% cholesterol ester, 8.8% cholesterol, 11.6% phospholipid, and 12% protein. These constituents were also present in high density lipoprotein with weight percentage values of 3.7%, 19.3%, 11.9%, 25.2%, and 36.8%, respectively. The fatty acid compositions of the triglycerides, cholesterol esters, and phosphatidylcholine were quite similar in the very low density lipoprotein and high density lipoprotein. However, shingomyelin fatty acid composition was appreciably different in the two lipoproteins. Disc gel electrophoresis in sodium dodecyl sulfate-polyacrylamide gels produced patterns with one major (approximate molecular weight, 7,000) and several minor bands for the apoprotein of very low density lipoprotein and one major (approximate molecular weight, 28,000) and several minor bands for that of high density lipoprotein.     

Hypercholesterolemia in five Israeli Christian-Arab kindreds is caused by the “Lebanese” allele at the low density lipoprotein receptor gene locus and by an additional independent major factor

Summary Segregation analyses were performed for plasma low density lipoprotein cholesterol (LDL-C), triglycerides (TG) and high density lipoprotein cholesterol (HDL-C) in five Christian Arab kindreds identified through probands with familial hypercholesterolemia. In this subset of the Christian Arab community, the results were consistent with major gene determination of LDL-C with allele frequency (q) of 0.042 (95% confidence interval 0.008–0.079) in addition to polygenic transmission (h ²= 0.34). The Lebanese allele was identified directly by polymerase chain reaction and HinfI restriction analysis. Analysis of this mutation permits direct diagnosis of familial hypercholesterolemia in most affected individuals although our results indicated the possible existence of an additional independent factor leading to elevated LDL-C levels. The segregation results for TG indicated the presence of a major effect, although the existence of a major gene could not be demonstrated. There was also no evidence of a major locus effect on HDL-C levels.     

A study of the hypolipidemic effect of estrogen in type III hyperlipoproteinemia

Ethinylestradiol (1 microgram/kg/day during 15 days) resulted in a gradual decrease of serum cholesterol, serum triglycerides (TG), very low density lipoprotein (VLDL) cholesterol and VLDL-TG in 2 postmenopausal women and 2 men with type III hyperlipoproteinemia (HLP). The turnover rate of VLDL-TG did not change. These findings contrast with previous observations in normal subjects and patients with type IV HLP. Thus, the catabolism of VLDL and VLDL-remnants increased during treatment with estrogen in type III HLP, probably by direct degradation of VLDL-remnants because in the initial days of treatment no increase of LDL-cholesterol was observed.     

Genetic studies of human apolipoproteins. XI. The effect of the apolipoprotein C-II polymorphism on lipoprotein levels in Nigerian blacks

The human apolipoprotein C-II locus exhibits genetically determined structural polymorphism in United States and African blacks. In the present study, we have investigated the effect of the apoC-II polymorphism on quantitative serum levels of total cholesterol, total high density lipoprotein (HDL) cholesterol, cholesterol in high density lipoprotein subfractions, low density lipoprotein (LDL) cholesterol, and triglycerides (TG) in a sample of 368 unrelated Nigerian blacks. The frequencies of the APOC-II*1 and APOC-II*2 alleles in the samples were 0.947 and 0.053, respectively. In males, the effect of the APOC-II*2 allele was to lower the total serum cholesterol and LDL-cholesterol levels by 13.28 mg/dl and 10.55 mg/dl, respectively, relative to the common allele, APOC-II*1. In females, the effect was to lower total plasma cholesterol by 4.49 mg/dl and LDL-cholesterol by 3.21 mg/dl. The effect of apoC-II on quantitative lipoprotein levels is shown to be independent of variation at the linked apoE locus, but the products of the two loci interact in determining overall quantitative phenotypes.     

Tissue-specific expression, developmental regulation, and chromosomal mapping of the lecithin: cholesterol acyltransferase gene. Evidence for expression in brain and testes as well as liver

Lecithin:cholesterol acyltransferase (LCAT) catalyzes the esterification of cholesterol in high density lipoproteins, thereby facilitating transport of excess cholesterol from peripheral tissues to liver. We report here studies of the developmental, dietary, and genetic control of LCAT gene expression. In adult male Sprague-Dawley rats fed a standard chow diet LCAT mRNA was most abundant in liver, a major source of the plasma enzyme, but appreciable levels were also present in brain and testes. Since both brain and testes are isolated from blood by tight cellular barriers, undoubtedly greatly reducing the level of plasma-derived LCAT in cerebrospinal fluid and testes, the production of LCAT in these tissues may be important for removal of excess cholesterol. Noteworthy changes in the expression of LCAT mRNA were observed during development of both rodents and humans. On the other hand, LCAT mRNA levels were relatively resistant to dietary challenge or to drugs affecting cholesterol metabolism. Since human epidemiological studies have suggested an association between LCAT levels and variations of high density lipoprotein cholesterol, we examined LCAT gene polymorphisms in a mouse animal model. Mapping of the LCAT gene (Lcat) to mouse Chromosome 8 within 2 centimorgans of the Es-2 locus indicates that it does not correspond to any previously mapped loci affecting high density lipoprotein phenotypes in the mouse.     

The effect of oral l-carnitine on lipoprotein composition in the Watanabe Heritable Hyperlipidemic Rabbit (Oryctolagus cuniculus)

1. We have recently reported the ability of orally administered l-carnitine to lower plasma triglyceride in the Watanabe Heritable Hyperlipidemic Rabbit (WHHL), an animal model of familial hyperlipoproteinemia. 2. In the present studies we examined the effect of l-carnitine administration upon individual lipoprotein subfractions in this animal model. 3. Carnitine feeding resulted in a reduction in very low density lipoproteins (VLDL) and high density lipoprotein (HDL). 4. Compositional analysis revealed a reduction in core triglyceride content with a concomitant increase in protein and phospholipid in VLDL and low density lipoproteins (LDL). 5. Conversely, electrophoretic mobility and apolipoprotein composition were unchanged with l-carnitine. 6. These results further demonstrate the ability of l-carnitine to modulate lipoprotein lipid composition in this animal model of familial hyperlipoproteinemia.     

原发性肾病综合征高脂血症发生机制的研究进展*

摘要：原发性肾病综合征高脂血症主要表现为血浆总胆固醇（Ch）和低密度脂蛋白胆固醇（LDL-Ch）明显升高,甘油三酯（TG）和极 低密度脂蛋白胆固醇（VLDL-Ch）升高。高密度脂蛋白胆固醇（HDL-Ch）浓度可降低或不变,但HDL的亚型分布异常,即HDL3 增 加而HDL2 减少。这提示我们HDL3 转变为富含CH的HDL2 成熟障碍。不过,关于高脂血症在肾病综合征的发生机制较为复杂, 还不十分清楚。但是目前有关该机制的观点主要集中在（1）低白蛋白血症刺激肝脏合成胆固醇、甘油三酯、脂蛋白增加,（2）外周 脂蛋白的清除障碍,（3）高密度脂蛋白（HDL）的成熟障碍,本文就此做一综述。     

Swine lipoproteins and atherosclerosis. Changes in the plasma lipoproteins and apoproteins induced by cholesterol feeding.

Cholesterol feeding in miniature swine resulted in a hypercholesterolemia with a distinctive hyperlipoproteinemia and the subsequent development of atherosclerosis. Alterations in the type and distribution of plasma lipoproteins induced by cholesterol feeding were as follows: (a) the occurrence of beta-migrating lipoproteins (B-VLDL) as well as very low density lipoproteins in the d less than 1.006 ultracentrifugal fraction; (b) an increased prominence of the intermediate lipoproteins (d = 1.006-1.02); (c) an increased prominence of low density lipoproteins; and (d) the occurrence of a distinctive lipoprotein with alpha mobility which was referred to as HDLc (cholesterol induced). Characterization of the various plasma lipoproteins included chemical composition, size by electron microscopy, and apoprotein content. The B-VLDL resembled the beta-migrating lipoproteins of human Type III hyperlipoproteinemia and contained a prominent protein equivalent to the arginine-rich apoprotein in addition to the B apoprotein, apo-A-I, and the fast-migrating apoproteins (apo-C). The HDLc were rich in cholesterol, ranged in size from 100 to 240 A in diameter, and contained the arginine-rich apoprotein and apo-A0I but lacked the B apoprotein. The arginine-rich apoproteins isolated from B-VLDL and HDLc by gel chromatography were similar in amino acid analyses, with glutamic acid as their amino-terminal residue. The occurrence of a spectrum of cholesterol-rich lipoproteins which contained the arginine-rich apoprotein with the occurrence of accelerated atherosclerosis suggested an interesting, although speculative, association.     

The beta very low density lipoprotein present in hepatic lipase deficiency competitively inhibits low density lipoprotein binding to fibroblasts and stimulates fibroblast acyl-CoA:cholesterol acyltransferase

Beta very low density lipoprotein (VLDL) was isolated from a patient with hepatic lipase deficiency. The particles were found to contain apolipoprotein B-100 (apoB) and apolipoprotein E (apoE) and were rich in cholesterol and cholesteryl ester relative to VLDL with pre beta electrophoretic mobility. These particles were active in displacing human low density lipoprotein (LDL) from the fibroblast apoB,E receptor and produced a marked stimulation of acyl-CoA:cholesterol acyltransferase. Treatment of intact beta-VLDL with trypsin abolished its ability to displace LDL from fibroblasts. Incubation of trypsin treated beta-VLDL with fibroblasts resulted in a significant stimulation of acyl-CoA:cholesterol acyltransferase activity. beta-VLDL isolated from a patient with Type III hyperlipoproteinemia and an apoE2/E2 phenotype had a higher cholesteryl ester/triglyceride ratio than the beta-VLDL of hepatic lipase deficiency and contained apoB48. It displaced LDL from fibroblasts to a small but significant extent. The Type III beta-VLDL stimulated acyl-CoA:cholesterol acyltransferase to a level similar to that of trypsin-treated beta-VLDL isolated from the hepatic lipase-deficient patient. These results demonstrate that the cholesterol-rich beta-VLDL particles present in patients with hepatic lipase deficiency are capable of interacting with fibroblasts via the apoB,E receptor and that this interaction is completely due to trypsin-sensitive components of the beta-VLDL. These particles were very effective in stimulating fibroblast acyl-CoA:cholesterol acyltransferase. This stimulation was due to both trypsin-sensitive and trypsin-insensitive components.     

Complex segregation analysis of plasma lipid and lipoprotein variables in a Jerusalem sample of nuclear families

Plasma lipid and lipoprotein concentrations from 3,074 nuclear families in the multiethnic Jerusalem Lipid Research Clinic study population were analyzed for possible involvement of major genes in determination of high levels of these traits. Complex segregation analysis under a mixed model including major gene and multifactorial transmissible components was performed on transformed-plasma lipids and lipoproteins after covariance adjustment for age, sex and environmental measures. Likelihood analysis provided evidence for recessive major genes influencing plasma triglyceride, and low-density lipoprotein cholesterol (LDL-C). The estimated gene frequencies for triglyceride and for hyperbetalipoproteinemia in our study population were about 0.1. Our positive results for total cholesterol and high-density lipoprotein cholesterol (HDL-C) were nonconclusive and the major effects could result from causes other than major genes. The mixed-model parameters were homogeneous across origin groups for LDL-C and HDL-C and heterogeneous for total plasma cholesterol and triglyceride. The multifactorial-transmission heritability index was similar in all origin groups for all the traits. The origin heterogeneity in the major gene parameters appeared to be mainly due to the North African group which favored a multifactorial transmission for all traits except for LDL-C.     

Endothelial lipase modulates susceptibility to atherosclerosis in apolipoprotein-E-deficient mice

Endothelial lipase (EL) expression correlates inversely with circulating high density lipoprotein (HDL) cholesterol levels in genetic mouse models, and human genetic variation in this locus has been linked to differences in HDL cholesterol levels. These data suggest a role for EL in the development of atherosclerotic vascular disease. To investigate this possibility, LIPG-null alleles were bred onto the apoE knockout background, and the homozygous double knockout animals were characterized. Both apoE knockout and double knockout mice had low HDL cholesterol levels when compared with wild-type mice, but the HDL cholesterol levels of the double knockout mice were higher than those of apoE knockout mice. Atherogenic very low density lipoprotein and intermediate density lipoprotein/low density lipoprotein cholesterol levels of the double knockout mice were also greater than those of the apoE knockout animals. Despite this lipid profile, there was a significant approximately 70% decrease in atherosclerotic disease area in double knockout mice on a regular diet. Immunohistochemistry and protein blot studies revealed increased EL expression in the atherosclerotic aortas of the apoE knockout animals. An observed decrease in macrophage content in vessels lacking EL correlated with ex vivo vascular monocyte adhesion assays, suggesting that this protein can modulate monocyte adhesion and infiltration into diseased tissues. These data suggest that EL may have indirect atherogenic actions in vivo through its effect on circulating HDL cholesterol and direct atherogenic actions through vascular wall processes such as monocyte recruitment and cholesterol uptake.     

Expression of human apolipoprotein A-II in apolipoprotein E-deficient mice induces features of familial combined hyperlipidemia

Familial combined hyperlipidemia (FCHL) is a common inherited hyperlipidemia and a major risk factor for atherothrombotic cardiovascular disease. The cause(s) leading to FCHL are largely unknown, but the existence of unidentified "major" genes that would increase VLDL production and of "modifier" genes that would influence the phenotype of the disease has been proposed. Expression of apolipoprotein A-II (apoA-II), a high density lipoprotein (HDL) of unknown function, in transgenic mice produced increased concentration of apoB-containing lipoproteins and decreased HDL. Here we show that expression of human apoA-II in apoE-deficient mice induces a dose-dependent increase in VLDL, resulting in plasma triglyceride elevations of up to 24-fold in a mouse line that has 2-fold the concentration of human apoA-II of normolipidemic humans, as well as other well-known characteristics of FCHL: increased concentrations of cholesterol, triglyceride, and apoB in very low density lipoprotein (VLDL), intermediate density lipoprotein (IDL) and low density lipoprotein (LDL), reduced HDL cholesterol, normal lipoprotein lipase and hepatic lipase activities, increased production of VLDL triglycerides, and increased susceptibility to atherosclerosis. However, FCHL patients do not have plasma concentrations of human apoA-II as high as those of apoE-deficient mice overexpressing human apoA-II, and the apoA-II gene has not been linked to FCHL in genome-wide scans. Therefore, the apoA-II gene could be a "modifier" FCHL gene influencing the phenotype of the disease in some individuals through unkown mechanisms including an action on a "major" FCHL gene. We conclude that apoE-deficient mice overexpressing human apoA-II constitute useful animal models with which to study the mechanisms leading to overproduction of VLDL, and that apoA-II may function to regulate VLDL production.