👤 C Ehnholm

In this chapter, we review how HDL is generated, remodeled, and catabolized in plasma. We describe key features of the proteins that participate in these processes, emphasizing how mutations in apolipoprotein A-I (apoA-I) and the other proteins affect HDL metabolism. The biogenesis of HDL initially requires functional interaction of apoA-I with the ATP-binding cassette transporter A1 (ABCA1) and subsequently interactions of the lipidated apoA-I forms with lecithin/cholesterol acyltransferase (LCAT). Mutations in these proteins either prevent or impair the formation and possibly the functionality of HDL. Remodeling and catabolism of HDL is the result of interactions of HDL with cell receptors and other membrane and plasma proteins including hepatic lipase (HL), endothelial lipase (EL), phospholipid transfer protein (PLTP), cholesteryl ester transfer protein (CETP), apolipoprotein M (apoM), scavenger receptor class B type I (SR-BI), ATP-binding cassette transporter G1 (ABCG1), the F1 subunit of ATPase (Ecto F1-ATPase), and the cubulin/megalin receptor. Similarly to apoA-I, apolipoprotein E and apolipoprotein A-IV were shown to form discrete HDL particles containing these apolipoproteins which may have important but still unexplored functions. Furthermore, several plasma proteins were found associated with HDL and may modulate its biological functions. The effect of these proteins on the functionality of HDL is the topic of ongoing research. Show less

USF1 is a ubiquitous transcription factor governing the expression of numerous genes of lipid and glucose metabolism. APOA5 is a well-established candidate gene regulating triglyceride (TG) levels and has been identified as a downstream target of upstream stimulatory factor. No detailed studies about the effect of APOA5 on atherosclerotic lesion formation have been conducted, nor has its potential interaction with USF1 been examined. We analyzed allelic variants of USF1 and APOA5 in families (n=516) ascertained for atherogenic dyslipidemia and in an autopsy series of middle-aged men (n=300) with precise quantitative measurements of atherosclerotic lesions. The impact of previously associated APOA5 variants on TGs was observed in the dyslipidemic families, and variant rs3135506 was associated with size of fibrotic aortic lesions in the autopsy series. The USF1 variant rs2516839, associated previously with atherosclerotic lesions, showed an effect on TGs in members of the dyslipidemic families with documented coronary artery disease. We provide preliminary evidence of gene-gene interaction between these variants in an autopsy series with a fibrotic lesion area in the abdominal aorta (P=0.0028), with TGs in dyslipidemic coronary artery disease subjects (P=0.03), and with high-density lipoprotein cholesterol (P=0.008) in a large population cohort of coronary artery disease patients (n=1065) in which the interaction for TGs was not replicated. Our findings in these unique samples reinforce the roles of APOA5 and USF1 variants on cardiovascular phenotypes and suggest that both genes contribute to lipid levels and aortic atherosclerosis individually and possibly through epistatic effects. Show less

To provide an overview of recent advances that have defined the first putative genes behind familial combined hyperlipidemia, the most common genetic dyslipidemia and a major risk factor for early coronary heart disease. The first locus for familial combined hyperlipidemia on 1q21-23 revealed a gene encoding a transcription factor critical in lipid and glucose metabolism, USF1. All the associated variants represent noncoding single nucleotide polymorphisms, one of which affects the binding site of nuclear proteins with a putative effect on transcript levels of USF1. Transcript analyses of fat biopsies have exposed risk-allele related changes in the downstream genes. Another recent clue to the molecular pathogenesis of familial combined hyperlipidemia is the association of the high triglyceride trait with the APOA5 gene, located on 11q. More familial combined hyperlipidemia genes are expected to be found, since linkage evidence exists for additional loci on 16q24 and 20q12-q13.1. Genetic research of familial combined hyperlipidemia families has revealed several linked loci guiding to susceptibility genes. The USF1 transcription factor is the major gene underlying the 1q21-23 linkage. Modifying genes, especially influencing the high triglyceride trait, include APOC3 and APOA5, the latter representing a downstream target of USF1 and implying a USF1-dependent pathway in the molecular pathogenesis of dyslipidemias. Show less

137 Russians living in Estonia was screened by isoelectric focusing and immunoblotting procedures to determine the distribution of genetic variations in apolipoprotein E (apoE) and apolipoprotein A-IV (apoA-IV) genes. The apoA-IV-2 allele and epsilon4 allele frequency of the Russians tended to be lower than in most other European populations. Show less

Both hepatic lipase (HL) and apolipoprotein C-III (apoC-III) influence lipid metabolism. Common variation in promoters of both genes, LIPC -514C > T and APOC3 -482C > T, respectively, have been shown to affect plasma lipids and lipoproteins and glucose tolerance. We studied the interaction between both variants on parameters of glucose tolerance and lipid metabolism in 714 healthy young males participating in the second European Atherosclerosis Research Study (EARS-II). Approximately 18% of the subjects were carriers of at least one rare LIPC and APOC3 allele. These subjects exhibited, after fasting and oral fat loading, the highest values of triglyceride-rich lipoproteins, but there was no significant interactive effect on any lipid variable. However, interaction occurred on basal diastolic blood pressure (p =0.036) and, during oral glucose tolerance testing, on peak (p = 0.0065) and area under the curve for glucose (p =0.049), and insulin (p = 0.035). This resulted in the highest diastolic blood pressure and lowest glucose tolerance in carriers of at least one rare allele of both genes. Thus gene:gene interaction between LIPC and APOC3, even in these healthy young males, leads to changes in parameters that are typically characteristic of Syndrome-X. Show less

The aims of the study were to investigate associations of the apolipoprotein (apo) A-IV polymorphisms Thr347Ser and Gln360His with anthropomorphic measurements and fasting and postprandial lipids in subjects participating in the European Atherosclerosis Research Study II (EARS II). The allelic frequencies of Ser347 and His360 were 0.185 and 0.067, respectively, in the sample as a whole. There were no significant differences in rare allele frequency between cases (offspring of fathers who suffered a myocardial infarction before the age of 55 years) and controls. Control subjects who were carriers of Ser347 had significantly higher body mass indices (BMIs), waist:hip ratios, total and low density lipoprotein cholesterol and triacylglycerol (TG) concentrations (all P < or = 0.02) than control subjects who were non-carriers, but these effects were not seen in the cases. Control subjects who were carriers of His360 had lower BMIs (P = 0.04), cholesterol and TG concentrations (both P < or = 0.07) compared to non-carriers, but these effects were not seen in the cases. After consumption of an oral fat load, carriers of His360 who were most obese (subjects in the third tertile of BMI) had significantly reduced postprandial lipemia (P < 0.03, as assessed by area under the curve).-Fisher, R. M., H. Burke, V. Nicaud, C. Ehnholm, and S. E. Humphries. Effect of variation in the apoA-IV gene on body mass index and fasting and postprandial lipids in the European Atherosclerosis Research Study II. Show less

Familial combined hyperlipidemia (FCHL) is the most frequent familial lipoprotein disorder associated with premature coronary heart disease. However, no genetic defect(s) underlying FCHL has been identified. A linkage between FCHL and the apoA-I/C-III/A-IV gene cluster has been reported but not verified in other populations. A recent study identified FCHL susceptibility haplotypes at this gene cluster. To study whether such haplotypes are also associated with FCHL susceptibility in Finns, we studied 600 well-defined Finnish FCHL patients and their relatives belonging to 28 extended FCHL families by using haplotype, linkage, sib-pair, and linkage disequilibrium analyses. The genotypes of the MspI polymorphisms were associated with total serum cholesterol (P<0.01) and apoB (P<0.05) levels in spouses, which represent the general Finnish population. However, no evidence of direct involvement of any of these loci or their specific haplotypes in the expression of FCHL in the Finnish FCHL families was found. Show less

Apolipoprotein A-IV (apoA-IV) is a glycoprotein constituent of triglyceride-rich and high-density lipoproteins (HDL) and may thus play an important role in lipid metabolism. In Finland two common isoforms (A-IV-1 and A-IV-2) of apoA-IV have been found. The isoforms are the result of the G to T substitution in the third base of the codon 360 in the apoA-IV-2 allele of the apoA-IV gene. The purpose of the study was to determine the apoA-IV allele frequencies in the Saami and the Finns, and to relate the apoA-IV phenotypes to serum lipids. The sample was drawn in connection with a Reindeer Herders' Health Survey performed in northern Finland in 1989. The study group included 248 men with known ethnic origin, Saami and Finns, who lived in the area of the nine northernmost municipalities of Finland. ApoA-IV phenotypes from 71 Saami (both parents Saami) and 177 Finns (both parents Finns) were determined by isoelectric focusing and Western blotting. Serum lipids were determined enzymatically. ApoA-IV allele frequencies in the Saami and the Finns were for A-IV-1 0.894 vs 0.944 and for A-IV-2 0.106 vs 0.056, respectively (chi2-test, P < 0.05). The effect of the apoA-IV phenotype on serum HDL-cholesterol levels differed significantly between the Saami and the Finns (two-way ANCOVA, interaction between ethnicity and apoA-IV phenotype, P < 0.02). In the Saami, HDL-cholesterol levels were significantly higher in the apoA-IV-2/1 than in the apoA-IV-1/1 phenotypes (ANCOVA, P < 0.05). Mean total cholesterol, low-density lipoprotein (LDL)-cholesterol, apolipoprotein B, HDL-cholesterol and triglyceride levels did not differ statistically significantly between the Saami and the Finns. Yet, there was a trend in the Saami of having higher mean total cholesterol, LDL-cholesterol and apolipoprotein B levels than the Finns among the apoA-IV-2/1 phenotypes, while there was only a small difference in these parameters between the Saami and the Finns among the apoA-IV-1/1 phenotypes. In conclusion, the Saami have a higher frequency of the apoA-IV-2 allele than the Finns and most of the other studied populations. Show less