The D9N, N291S and S447X variants in the lipoprotein lipase (LPL) gene are not associated with Type III Hyperlipidemia

<p>Abstract</p> <p>Background</p> <p>Type III hyperlipidemia (Type III HLP) is associated with homozygosity for the ε2 allele of the APOE gene. However only about 10% of ε2 homozygotes develop Type III HLP and it is assumed that additional genetic and/or environmental factors are required for its development. Common variants in the LPL gene have been proposed as likely genetic co-factors.</p> <p>Methods</p> <p>The frequency of the LPL SNPs D9N, N291S and S447X in 100 patients with hyperlipidemia and APOE2/2 genotype has been determined and compared to that in healthy blood donors and patients with hyperlipidemia.</p> <p>Results</p> <p>There were no statistically significant difference in the frequencies of the variants between APOE2/2 patients and controls.</p> <p>Conclusion</p> <p>It is unlikely that the D9N, N291S or S447X variants in the LPL gene play an important role in the development of Type III HLP.</p

FXR agonism protects against liver injury in a rat model of intestinal failure-associated liver disease

Background: Intestinal failure-associated liver disease (IFALD) is a clinical challenge. The pathophysiology is multifactorial and remains poorly understood. Disturbed recirculation of bile salts, e.g. due to loss of bile via an enterocutaneous fistula, is considered a major contributing factor. We hypothesize that impaired signaling via the bile salt receptor FXR underlies the development of IFALD. The aim of this study was to investigate whether activation of FXR improves liver homeostasis during chronic loss of bile in rats. Methods: To study consequences of chronic loss of bile, rats underwent external biliary drainage (EBD) or sham surgery for seven days, and the prophylactic potential of the FXR agonist INT-747 was assessed. Results: EBD for 7 days resulted in liver test abnormalities and histological liver damage. Expression of the intestinal FXR target gene Fgf15 was undetectable after EBD, and this was accompanied by an anticipated increase in hepatic Cyp7a1 expression, indicating increased bile salt synthesis. Treatment with INT-747 improved serum biochemistry, reduced loss of bile fluid in drained rats and prevented development of drainage-associated histological liver injury. Conclusions: EBD results in extensive hepatobiliary injury and cholestasis. These data suggest that FXR activation might be a novel therapy in preventing liver dysfunction in patients with intestinal failure. Relevance for patients: This study demonstrates that chronic loss of bile causes liver injury in rats. Abrogated recycling of bile salts impairing of enterohepatic bile salt/FXR signaling underlies these pathological changes, as administration of FXR agonist INT747 prevents biliary drainage-induced liver damage. Pharmacological activation of FXR might be a therapeutic strategy to treat disorders accompanied by a perturbed enterohepatic circulation such as intestinal failure-associated liver diseas

Profiling Circulating and Urinary Bile Acids in Patients with Biliary Obstruction before and after Biliary Stenting

Bile acids are considered as extremely toxic at the high concentrations reached during bile duct obstruction, but each acid displays variable cytotoxic properties. This study investigates how biliary obstruction and restoration of bile flow interferes with urinary and circulating levels of 17 common bile acids. Bile acids (conjugated and unconjugated) were quantified by liquid chromatography coupled with tandem mass spectrometry in serum and urine samples from 17 patients (8 men and 9 women) with biliary obstruction, before and after biliary stenting. Results were compared with serum concentrations measured in 40 age- and sex-paired control donors (20 men and 20 women). The total circulating bile acid concentration increases from 2.7 µM in control donors to 156.9 µM in untreated patients with biliary stenosis. Serum taurocholic and glycocholic acids exhibit 304- and 241-fold accumulations in patients with biliary obstruction compared to controls. The enrichment in chenodeoxycholic acid species reached a maximum of only 39-fold, while all secondary and 6α-hydroxylated species –except taurolithocholic acids – were either unchanged or significantly reduced. Stenting was efficient in restoring an almost normal circulating profile and in reducing urinary bile acids

High sensitive troponin T and heart fatty acid binding protein: Novel biomarker in heart failure with normal ejection fraction?: A cross-sectional study

Background: High sensitive troponin T (hsTnT) and heart fatty acid binding protein (hFABP) are both markers of myocardial injury and predict adverse outcome in patients with systolic heart failure (SHF). We tested whether hsTnT and hFABP plasma levels are elevated in patients with heart failure with normal ejection fraction (HFnEF). Methods: We analyzed hsTnT, hFABP and N-terminal brain natriuretic peptide in 130 patients comprising 49 HFnEF patients, 51 patients with asymptomatic left ventricular diastolic dysfunction (LVDD), and 30 controls with normal diastolic function. Patients were classified to have HFnEF when the diagnostic criteria as recommended by the European Society of Cardiology were met. Results: Levels of hs TnT and hFABP were significantly higher in patients with asymptomatic LVDD and HFnEF (both p < 0.001) compared to controls. The hsTnT levels were 5.6 [0.0-9.8] pg/ml in LVDD vs. 8.5 [3.9-17.5] pg/ml in HFnEF vs. < 0.03 [< 0.03-6.4] pg/ml in controls; hFABP levels were 3029 [2533-3761] pg/ml in LVDD vs. 3669 [2918-4839] pg/ml in HFnEF vs. 2361 [1860-3081] pg/ml in controls. Furthermore, hsTnT and hFABP levels were higher in subjects with HFnEF compared to LVDD (p = 0.015 and p = 0.022). Conclusion: In HFnEF patients, hsTnT and hFABP are elevated independent of coronary artery disease, suggesting that ongoing myocardial damage plays a critical role in the pathophysiology. A combination of biomarkers and echocardiographic parameters might improve diagnostic accuracy and risk stratification of patients with HFnEF

The APOA5 Trp19 allele is associated with metabolic syndrome via its association with plasma triglycerides

<p>Abstract</p> <p>Background</p> <p>The goal of the present study was to assess the effect of genetic variability at the APOA5/A4/C3/A1 cluster locus on the risk of metabolic syndrome.</p> <p>Methods</p> <p>The <it>APOA5 </it>Ser19Trp, <it>APOA5 </it>-12,238T>C, <it>APOA4 </it>Thr347Ser, <it>APOC3 </it>-482C>T and <it>APOC3 </it>3238C>G (<it>Sst</it>I) polymorphisms were analyzed in a representative population sample of 3138 men and women from France, including 932 individuals with metabolic syndrome and 2206 without metabolic syndrome, as defined by the NCEP criteria.</p> <p>Results</p> <p>Compared with homozygotes for the common allele, the odds ratio (OR) [95% CI] for metabolic syndrome was 1.30 [1.03–1.66] (<it>p </it>= 0.03) for <it>APOA5 </it>Trp19 carriers, 0.81 [0.69–0.95] (<it>p </it>= 0.01) for <it>APOA5 </it>-12,238C carriers and 0.84 [0.70–0.99] (<it>p </it>= 0.04) for <it>APOA4 </it>Ser347 carriers. Adjustment for plasma triglycerides, (but not for waist girth, HDL, blood pressure or glycemia – the other components of metabolic syndrome) abolished these associations and suggests that triglyceride levels explain the association with metabolic syndrome. There was no association between the <it>APOC3 </it>-482C>T or <it>APOC3 </it>3238C>G polymorphisms and metabolic syndrome. The decreased risk of metabolic syndrome observed in <it>APOA5 </it>-12,238C and <it>APOA4 </it>Ser347 carriers merely reflected the fact that the <it>APOA5 </it>Trp19 allele was in negative linkage disequilibrium with the common alleles of <it>APOA5 </it>-12,238T>C and <it>APOA4 </it>Thr347Ser polymorphisms.</p> <p>Conclusion</p> <p>The <it>APOA5 </it>Trp19 allele increased susceptibility to metabolic syndrome via its impact on plasma triglyceride levels.</p

Fibroblast growth factor 21 reflects liver fat accumulation and dysregulation of signalling pathways in the liver of C57BL/6J mice

Fibroblast growth factor 21 (Fgf21) has emerged as a potential plasma marker to diagnose non-alcoholic fatty liver disease (NAFLD). To study the molecular processes underlying the association of plasma Fgf21 with NAFLD, we explored the liver transcriptome data of a mild NAFLD model of aging C57BL/6J mice at 12, 24, and 28 months of age. The plasma Fgf21 level significantly correlated with intrahepatic triglyceride content. At the molecular level, elevated plasma Fgf21 levels were associated with dysregulated metabolic and cancerrelated pathways. The up-regulated Fgf21 levels in NAFLD were implied to be a protective response against the NAFLD-induced adverse effects, e.g. lipotoxicity, oxidative stress and endoplasmic reticulum stress. An in vivo PPARα challenge demonstrated the dysregulation of PPARα signalling in the presence of NAFLD, which resulted in a stochastically increasing hepatic expression of Fgf21. Notably, elevated plasma Fgf21 was associated with declining expression of Klb, Fgf21’s crucial co-receptor, which suggests a resistance to Fgf21. Therefore, although liver fat accumulation is a benign stage of NAFLD, the elevated plasma Fgf21 likely indicated vulnerability to metabolic stressors that may contribute towards progression to end-stage NAFLD. In conclusion, plasma levels of Fgf21 reflect liver fat accumulation and dysregulation of metabolic pathways in the liver

Znf202 Affects High Density Lipoprotein Cholesterol Levels and Promotes Hepatosteatosis in Hyperlipidemic Mice

Background: The zinc finger protein Znf202 is a transcriptional suppressor of lipid related genes and has been linked to hypoalphalipoproteinemia. A functional role of Znf202 in lipid metabolism in vivo still remains to be established. Methodology and Principal Findings: We generated mouse Znf202 expression vectors, the functionality of which was established in several in vitro systems. Next, effects of adenoviral znf202 overexpression in vivo were determined in normo- as well as hyperlipidemic mouse models. Znf202 overexpression in mouse hepatoma cells mhAT3F2 resulted in downregulation of members of the Apoe/c1/c2 and Apoa1/c3/a4 gene cluster. The repressive activity of Znf202 was firmly confirmed in an apoE reporter assay and Znf202 responsive elements within the ApoE promoter were identified. Adenoviral Znf202 transfer to Ldlr-/- mice resulted in downregulation of apoe, apoc1, apoa1, and apoc3 within 24 h after gene transfer. Interestingly, key genes in bile flux (abcg5/8 and bsep) and in bile acid synthesis (cyp7a1) were also downregulated. At 5 days post-infection, the expression of the aforementioned genes was normalized, but mice had developed severe hepatosteatosis accompanied by hypercholesterolemia and hypoalphalipoproteinemia. A much milder phenotype was observed in wildtype mice after 5 days of hepatic Znf202 overexpression. Interestingly and similar to Ldl-/- mice, HDL-cholesterol levels in wildtype mice were lowered after hepatic Znf202 overexpression. Conclusion/Significance: Znf202 overexpression in vivo reveals an important role of this transcriptional regulator in liver lipid homeostasis, while firmly establishing the proposed key role in the control of HDL levels

Effects of supplemented isoenergetic diets varying in cereal fiber and protein content on the bile acid metabolic signature and relation to insulin resistance

Bile acids (BA) are potent metabolic regulators influenced by diet. We studied effects of isoenergetic increases in the dietary protein and cereal-fiber contents on circulating BA and insulin resistance (IR) in overweight and obese adults. Randomized controlled nutritional intervention (18 weeks) in 72 non-diabetic participants (overweight/obese: 29/43) with at least one further metabolic risk factor. Participants were group-matched and allocated to four isoenergetic supplemented diets: control; high cereal fiber (HCF); high-protein (HP); or moderately increased cereal fiber and protein (MIX). Whole-body IR and insulin-mediated suppression of hepatic endogenous glucose production were measured using euglycaemic–hyperinsulinemic clamps with [6-62H2] glucose infusion. Circulating BA, metabolic biomarkers, and IR were measured at 0, 6, and 18 weeks. Under isoenergetic conditions, HP-intake worsened IR in obese participants after 6 weeks (M-value: 3.77 ± 0.58 vs. 3.07 ± 0.44 mg/kg/min, p = 0.038), with partial improvement back to baseline levels after 18 weeks (3.25 ± 0.45 mg/kg/min, p = 0.089). No deleterious effects of HP-intake on IR were observed in overweight participants. HCF-diet improved IR in overweight participants after 6 weeks (M-value 4.25 ± 0.35 vs. 4.81 ± 0.31 mg/kg/min, p = 0.016), but did not influence IR in obese participants. Control and MIX diets did not influence IR. HP-induced, but not HCF-induced changes in IR strongly correlated with changes of BA profiles. MIX-diet significantly increased most BA at 18 weeks in obese, but not in overweight participants. BA remained unchanged in controls. Pooled BA concentrations correlated with fasting fibroblast growth factor-19 (FGF-19) plasma levels (r = 0.37; p = 0.003). Higher milk protein intake was the only significant dietary predictor for raised total and primary BA in regression analyses (total BA, p = 0.017; primary BA, p = 0.011). Combined increased intake of dietary protein and cereal fibers markedly increased serum BA concentrations in obese, but not in overweight participants. Possible mechanisms explaining this effect may include compensatory increases of the BA pool in the insulin resistant, obese state; or defective BA transport

Hormone-like (endocrine) Fgfs: their evolutionary history and roles in development, metabolism, and disease

Fibroblast growth factors (Fgfs) are proteins with diverse functions in development, repair, and metabolism. The human Fgf gene family with 22 members can be classified into three groups, canonical, intracellular, and hormone-like Fgf genes. In contrast to canonical and intracellular Fgfs identified in invertebrates and vertebrates, hormone-like Fgfs, Fgf15/19, Fgf21, and Fgf23, are vertebrate-specific. The ancestral gene of hormone-like Fgfs was generated from the ancestral gene of canonical Fgfs by gene duplication early in vertebrate evolution. Later, Fgf15/19, Fgf21, and Fgf23 were generated from the ancestral gene by genome duplication events. Canonical Fgfs act as autocrine/paracrine factors in an Fgf receptor (Fgfr)-dependent manner. In contrast, hormone-like Fgfs act as endocrine factors in an Fgfr-dependent manner. Canonical Fgfs have a heparin-binding site necessary for the stable binding of Fgfrs and local signaling. In contrast, hormone-like Fgfs acquired endocrine functions by reducing their heparin-binding affinity during their evolution. Fgf15/19 and Fgf23 require βKlotho and αKlotho as cofactors, respectively. However, Fgf21 might physiologically require neither. Hormone-like Fgfs play roles in metabolism at postnatal stages, although they also play roles in development at embryonic stages. Fgf15/19 regulates bile acid metabolism in the liver. Fgf21 regulates lipid metabolism in the white adipose tissue. Fgf23 regulates serum phosphate and active vitamin D levels. Fgf23 signaling disorders caused by hereditary diseases or tumors result in metabolic disorders. In addition, serum Fgf19 or Fgf21 levels are significantly increased by metabolic disorders. Hormone-like Fgfs are newly emerging and quite unique in their evolution and function