BBA - Molecular Basis of Disease (v.1637, #3)

Elevated anticardiolipin antibodies in acute liver failure by K.R. Rozee; P. Acott; S.H.S Lee; J.F.S. Crocker; D. Gough; J. MacDonald; J. Evans; M.G. Murphy (183-186).
Antibodies to cardiolipin (aCLA), a phospholipid primarily localized in inner mitochondrial membranes, were transiently elevated (P<0.01) when mice were exposed to an industrial surfactant and then infected with influenza B virus, a model of acute liver failure (ALF). Children with ALF also had elevated levels of aCLA.
Keywords: Anticardiolipin antibody; Acute liver failure; Reye's syndrome; Surfactant/influenza B mouse model;

Impairment of energy metabolism in hippocampus of rats subjected to chemically-induced hyperhomocysteinemia by Emilio L Streck; Cristiane Matté; Paula S Vieira; Thiago Calcagnotto; Clóvis M.D Wannmacher; Moacir Wajner; Angela T.S Wyse (187-192).
Homocystinuria is an inherited metabolic disease biochemically characterized by tissue accumulation of homocysteine (Hcy). Mental retardation, ischemia and other neurological features, whose mechanisms are still obscure are common symptoms in homocystinuric patients. In this work, we investigated the effect of Hcy administration in Wistar rats on some parameters of energy metabolism in the hippocampus, a cerebral structure directly involved with cognition. The parameters utilized were 14CO2 production, glucose uptake, lactate release and the activities of succinate dehydrogenase and cytochrome c oxidase (COX). Chronic hyperhomocysteinemia was induced by subcutaneous administration of Hcy twice a day from the 6th to the 28th day of life in doses previously determined in our laboratory. Control rats received saline in the same volumes. Rats were killed 12 h after the last injection. Results showed that Hcy administration significantly diminished 14CO2 production and glucose uptake, as well as succinate dehydrogenase and COX activities. It is suggested that impairment of brain energy metabolism may be related to the neurological symptoms present in homocystinuric patients.
Keywords: Homocysteine; Homocystinuria; Brain energy metabolism; Experimental model;

We examined the influence of diets supplemented with fish and vegetable oils on fatty acid and prostaglandin E2 (PGE2) contents in livers of non-7,12-dimethylbenz[a]anthracene (DMBA)- and DMBA-treated rats, and in DMBA-induced tumours. Decreased concentrations of saturated fatty acids and increased unsaturated fatty acid levels were observed in liver phospholipids of rats fed these oils. There was a marked difference in the concentrations of fatty acids found in the tumours and those present in liver lipids. Oleic acid was the main unsaturated fatty acid found in the tumour tissue. Both liver and tumour PGE2 contents were clearly correlated to the diet. The PGE2 concentrations were decreased in livers and tumours of rats fed fish (FO) and linseed oils (LO).
Keywords: Fatty acid; Prostaglandin E2; Carcinogenesis; Fish and vegetable oils; 7,12-Dimethylbenz[a]anthracene;

Variants in the APOC3 promoter insulin responsive element modulate insulin secretion and lipids in middle-aged men by D.M. Waterworth; P.J. Talmud; J. Luan; D.M. Flavell; C.D. Byrne; S.E. Humphries; N.J. Wareham (200-206).
Variation in the insulin responsive element (IRE) of the APOC3 promoter has been shown to be associated with insulin and glucose concentrations after an oral glucose tolerance test (OGTT) in young healthy men. We evaluated two variants in the IRE (−455T>C and −482C>T) in the Ely study, a prospective cohort study of middle-aged men (n=223) and women (n=279), to determine if the effect of these variants on glucose homeostasis could be explained by altered nonesterified fatty acid (NEFA) levels and if these effects are modulated by age and gender. Both variants had significant effects on the 30-min insulin incremental response in men alone (−482C>T, P=0.007; −455T>C, P=0.0155), with rare allele homozygotes having a 33.3% and 23.3% lower insulin increment as compared to common allele homozygotes, respectively. Thirty-minute NEFA concentrations were also significantly associated with genotype in men and levels were approximately 10% higher in carriers homozygous for the rare alleles as compared to subjects homozygous for the common alleles (−482C>T, P=0.04; −455T>C, P=0.006). In addition, there was a strong interaction between both variants and cigarette smoking affecting fasting triglyceride levels in both men (interaction: −455T>C, P=0.02; −482C>T, P=0.008) and women (interaction: −455T>C, P=0.007; −482C>T, P=0.013). Taken together, the data shows that men who carry the rare alleles of the IRE variants have disturbed glucose homeostasis and an unfavourable lipid phenotype. The finding of an elevated 30-min NEFA may be an important mechanistic link between triglyceride-rich lipoprotein (TRL) metabolism and glucose homeostasis.
Keywords: Glucose homeostasis; Nonesterified fatty acid; Triglyceride metabolism; Atherosclerosis; Type 2 diabetes;

URP1: a member of a novel family of PH and FERM domain-containing membrane-associated proteins is significantly over-expressed in lung and colon carcinomas by Edward J. Weinstein; Maureen Bourner; Richard Head; Hamideh Zakeri; Christopher Bauer; Richard Mazzarella (207-216).
In a concerted effort to identify biomarkers for lung and colon carcinomas by genome-wide transcriptional profiling, we describe the identification and cloning of one such gene as well as two additional closely related genes. Due to the strong sequence homology to the C. elegans UNC-112 we call this gene URP1, for UNC-112 related protein. We have also isolated the full-length clones for another novel related gene, URP2 and the previously discovered MIG-2 gene. Collectively, these proteins, together with two from Drosophila, appear to form a novel membrane-associated FERM and PH domain-containing protein family. Transcriptional analysis shows that only URP1 is significantly differentially regulated, being over-expressed in 70% of the colon carcinomas and 60% of the lung carcinomas tested. Quantification of URP1 expression by qRT-PCR showed up-regulation of the gene by 60-fold in lung tumors and up to nearly 6-fold in colon tumors. Northern blot analysis of URP1 indicates that normal expression is restricted to neuromuscular tissues. In contrast, the expression of URP2 appears to be confined primarily to tissues of the immune system. SNP analysis of URP1 reveals that it is highly polymorphic, containing seven sites, four of which are in the coding region and one position that results in the interchangeable substitution of glutamic acid and lysine. Finally, we have shown that the genomic structure for all three genes is nearly identical with all encoded by 15 exons although URP1 gene localized to chromosome 20p13, URP2 to 11q12 and MIG-2 to 14q22. This conserved exon structure suggests that all three members probably arose by gene duplication from one ancestral gene. The presence of multiple FERM domains characteristic of cytoplasmic plasma membrane to cytoskeleton linkers and a PH domain typical of membrane-anchored proteins involved in signal transduction suggest an important role for URP1 in tumorigenesis.
Keywords: Cancer; UNC-112; cDNA microarray; DNA chip; Transcript expression analysis; Cytoskeletal protein; PH domain; FERM domain; URP1; URP2; MIG-2;

The aim of this study was to investigate the influence of APOA5 variants on fasting lipids and to the response to both an oral fat tolerance test (OFTT) and an oral glucose tolerance test (OGTT). The association of two APOA5 SNPs [S19W (SNP5), −1131T>C (SNP3)] and an APOA4/A5 intergenic SNP [−12238T>C (SNP4)] were examined in healthy young men (n=774) who had undergone both an OFTT and an OGTT. Both −1131T>C and S19W rare alleles were associated with triglyceride (TG)-raising effects (11%, P=0.008; 21% (in cases), P<0.026, respectively) and showed additive effects on TG. None of the variants influenced the responsiveness to the OFTT after correcting for baseline TG. Homozygosity for the −12238T>C rare allele was associated with higher waist to hip ratio (P<0.0006), systolic blood pressure (P=0.012) and AUC and peak of insulin after OGTT (P=0.003 and P=0.027, respectively), traits that define the metabolic syndrome. Our results strongly support the role of APOA5 in determining plasma TG levels in an age-independent manner and highlight the importance of the APOC3/A4/A5 gene cluster in both TG and metabolic homeostasis.
Keywords: APOC3/A4/A5; Plasma triglyceride; Oral fat tolerance test; Oral glucose tolerance test; Offspring study;