Regulation of Angiopoietin-Like Proteins (ANGPTLs) 3 and 8 by Insulin

Objective: Circulating ANGPTL8 has recently been used as a marker of insulin action. We studied expression and insulin regulation of ANGPTL8 and ANGPTL3 in vivo and in vitro. Design and Methods: Expression of ANGPTL8 and ANGPTL3 was studied in 34 paired samples of human liver and adipose tissue. Effects of insulin on 1) plasma concentrations and adipose tissue expression of ANGPTL8 and ANGPTL3 (in vivo 6-h euglycemic hyperinsulinemia; n = 18), and 2) ANGPTL8 and ANGPTL3 gene and protein expression in immortalized human hepatocytes (IHH) and adipocytes were measured. Effect of ANGPTL3 on secretion of ANGPTL8 in cells stably over-expressing ANGPTL3, -8, or both was determined. Results: ANGPTL3 was only expressed in the liver, whereas ANGPTL8 was expressed in both tissues. In vivo hyperinsulinemia significantly decreased both plasma ANGPTL8 and ANGPTL3 at 3 and 6 hours. Insulin increased ANGPTL8 expression in human adipose tissue 14- and 18-fold at 3 and 6 hours and ANGPTL8 was the most insulin-responsive transcript on microarray. Insulin also increased ANPGTL8 in cultured adipocytes and IHH but the protein mainly remained intracellular. In vitro in IHH, insulin decreased ANGPTL3 gene expression and secretion of ANGPTL3 into growth medium. Overexpression of ANGPTL8 in CHO cells did not result in its release into culture medium while abundant secretion occurred in cells co-expressing ANGPTL3 and -8. Conclusions: Insulin decreases plasma ANGPTL3 by decreasing ANGPTL3 expression in the liver. Insulin markedly increases ANGPTL8 in adipose tissue and the liver but not in plasma. These data show that measurement of plasma ANGPTL3 but not -8 reflects insulin action in target tissues.Peer reviewe

Severe coronary and extracoronary atherosclerosis in autosomal recessive hypercholesterolemia detected by whole-body computed tomography angiography

[No abstract available

Genetic variants in adipose triglyceride lipase influence lipid levels in familial combined hyperlipidemia

OBJECTIVE: Familial combined hyperlipidemia (FCHL) has been associated with abnormalities in fatty acid metabolism. The adipose triglyceride lipase (PNPLA2) plays a pivotal role in the turnover of fatty acids in adipose tissue and liver. This study was designed to evaluate whether selected PNPLA2 variants may influence the susceptibility to FCHL or its lipid-related traits. METHODS: Four SNPs within the PNPLA2 gene (rs7925131, rs7942159, rs66460720 and the nonsynonymous P481L) were selected based on previous association with decreased plasma levels of free fatty acids (FFA) and total triglycerides (TG) and their high frequency (MAF>0.25). These SNPs were genotyped in 214 FCHL individuals from 83 families and in 103 controls and the corresponding haplotypes were reconstructed. RESULTS: No association between individual SNPs and the FCHL trait was observed. However, two PNPLA2 haplotypes were associated with lower risk of FCHL (P<0.004 after Bonferroni's correction). Compared to the others, these haplotypes were related to lower TG (118.9 ± 66.8 vs. 197.1 ± 114.7 mg/dl; P=0.001) and higher HDL-C (62.3 ± 15.8 vs. 51.0 ± 15.0 mg/dl; P<0.005). In a subgroup of studied subjects (n=63) protective haplotypes were also associated with lower FFA levels (0.33 ± 0.11 vs. 0.46 ± 0.18 mEq/L; P<0.05). These effects were independent from age, BMI and HOMA(IR). CONCLUSION: These data demonstrate that variants within PNPLA2 may modulate the TG component of FCHL trait, thus implicating PNPLA2 as modifier gene in this lipid disorder. They also suggest a potential role of PNPLA2 in the metabolism of TG-rich lipoprotein

Novel mutations in the adipose triglyceride lipase gene causing neutral lipid storage disease with myopathy

A subgroup of neutral lipid storage disease has been recently associated with myopathy (NLSDM) and attributed to mutations in the gene (PNPLA2) encoding an adipose triglyceride lipase involved in the degradation of intracellular triglycerides. Five NLSDM patients have been described thus far and we reported three additional patients. A 44-year old Iranian woman and two Italian brothers, aged 40 and 35, presented with exercise intolerance and proximal limb weakness, elevated CK levels, and Jordan's anomaly. Muscle biopsies showed marked neutral lipid accumulation in all patients. The 10 exons and the intron-exon junctions of the PNPLA2 gene were sequenced. Two novel homozygous mutations in exon 5 of PNPLA2 gene were found (c.695delT and c.542delAC). Both mutations resulted in frameshifts leading to premature stop codons (p.L255X and p.1212X, respectively). These Mutations predict a truncated PNPLA2 protein lacking the C-terminal hydrophobic domain. These findings indicate that NLSDM is rare, but genetically heterogeneous. (C) 2008 Elsevier Inc. All rights reserved

Autosomal recessive hypercholesterolemia in Spanish kindred due to a large deletion in the ARH gene

Autosomal recessive hypercholesterolemia (ARH) is a rare genetic defect that causes marked elevation of plasma low-density lipoprotein cholesterol (LDL-C) and premature atherosclerosis. It is due to mutations in the ARH gene that plays a critical role in the internalization of LDL receptor (LDLR) in liver cells. We describe a Spanish family where a 24-year-old proband and his 13-year-old sister showed the typical characteristics of ARK The proband's LDLR activity in peripheral lymphocytes was 14% of normal and his in vivo LDL catabolism was reduced by 64% compared to normal. Notably, the sister showed normal lipid levels when her umbilical cord blood was tested. In this family, ARH was due to homozygosity for a large similar to 1.6 kb deletion that eliminates exon 4 of ARH gene. Analysis of ARH mRNA demonstrated that the fusion of exon 3 to exon 5 during the splicing of the primary transcript changes the reading frame leading to stop codon 7 amino acids downstream in exon 5. No protein product was detected in affected individuals by immunoblot analysis. This novel mutation adds new support to the molecular heterogeneity of ARH in the Mediterranean basin. (C) 2007 Elsevier Inc. All rights reserved

Prevalence and clinical features of heterozygous carriers of autosomal recessive hypercholesterolemia in Sardinia

Objective: Autosomal recessive hypercholesterolemia (ARH) is a lipid disorder caused by mutations in a specific adaptor protein for the LDL receptor. ARH is rare except in Sardinia where three alleles (ARH1, ARH2 and ARH3) explain most of cases. The prevalence of ARH heterozygotes in Sardinia is not well determined as well as inconclusive data are available on the effect of the ARH carrier status on LDL cholesterol (LDL-C) and coronary risk. Methods: 3410 Sardinians (986 blood donors, 1709 with hypertension and 715 with myocardial infarction (MI)) were screened for ARH alleles. For comparison purposes, lipid data of 60 ARH heterozygous carriers and 60 non-carriers identified within 24 ARH families were also considered. Results: In the whole study cohort, no ARH homozygotes were found, but 15 ARH1 (0.44%) and 9 ARH2 (0.26%) heterozygous carriers were identified. The frequency of ARH alleles in blood donors was 0.0030, not different from that in hypertensive subjects (0.0032). ARH alleles tended to be more common in MI patients (0.0049), but no association between ARH carrier status and MI risk was detected after controlling for conventional risk factors. ARH carriers and non-carriers showed similar LDL-C levels. This result was confirmed when ARH carriers and non-carriers identified throughout family-based and population-based screenings were combined and compared (141.0 +/- 41 mg/dl vs. 137.0 +/- 41 mg/dl, respectively; p = 0.19). Conclusions: These data indicate that the frequency of ARH heterozygotes in Sardinia is similar to 1:143 individuals, thus making this condition one of the most common in the Sardinian population. However, ARH carrier status does not influence LDL-C concentration and coronary risk, thus suggesting that ARH can be regarded as a truly recessive disorder. (C) 2009 Elsevier Ireland Ltd. All rights reserved

Serum adiponectin is decreased in patients with familial combined hyperlipidemia and normolipaemic relatives and is influenced by lipid-lowering treatment

Background and aims: Hypoadiponectinemia has been reported in patients with familial combined hyperlipidemia (FCHL) presenting increased waist circumference and insulin resistance. However, no studies have evaluated this association in non-obese FCHL patients. Moreover, it is unclear whether correction of lipoprotein abnormalities may influence adiponectin levels in FCHL. Methods and Results: We have compared serum levels of adiponectin in 199 non-obese FCHL patients (BMI 25.96 ± 3.7), 116 normolipaemic (NL) non-affected relatives (BMI 24.4 ± 4.0) and 192 controls (BMI 28.0 ± 7.4). In a subgroup of FCHL patients, changes in adiponectin levels after treatment with atorvastatin (n = 22) or fenofibrate (n = 26) were also evaluated. FCHL patients as well as their NL relatives showed lower serum adiponectin levels compared to controls (9.7 ± 5.4 μg/mL, 10.7 ± 5.3 μg/mL and 17.3 ± 13.7 μg/mL, respectively; p < 0.0001 for all comparisons). After controlling for confounders, the strongest association with hypoadiponectinemia was observed with family history of FCHL, followed by HDL-C (negatively) and age (positively). These variables jointly explained 15% of the total variance of serum adiponectin levels. After 24-week of treatment, adiponectin was increased by 12.5% (p < 0.05) by atorvastatin and was reduced by 10% by fenofibrate, resulting in a treatment difference of 22.5% in favor of atorvastatin (p < 0.017). Conclusions: FCHL patients showed lower serum adiponectin levels compared to controls. Also normolipaemic relatives of FCHL patients presented decreased levels of adiponectin, suggesting a possible common background in the determination of this abnormality. Overall, these observations indicate that hypoadiponectinemia may be an inherent characteristic of the FCHL phenotype. In FCHL patients hypoadiponectinemia may be partially corrected by atorvastatin but not by fenofibrate treatment. © 2008 Elsevier B.V. All rights reserved

An Essential Role for Liver ERα in Coupling Hepatic Metabolism to the Reproductive Cycle

Lipoprotein synthesis is controlled by estrogens, but the exact mechanisms underpinning this regulation and the role of the hepatic estrogen receptor α (ERα) in cholesterol physiology are unclear. Utilizing a mouse model involving selective ablation of ERα in the liver, we demonstrate that hepatic ERα couples lipid metabolism to the reproductive cycle. We show that this receptor regulates the synthesis of cholesterol transport proteins, enzymes for lipoprotein remodeling, and receptors for cholesterol uptake. Additionally, ERα is indispensable during proestrus for the generation of high-density lipoproteins efficient in eliciting cholesterol efflux from macrophages. We propose that a specific interaction with liver X receptor α (LXRα) mediates the broad effects of ERα on the hepatic lipid metabolism