Type II Secretory Phospholipase A2 and Prognosis in Patients with Stable Coronary Heart Disease: Mendelian Randomization Study

Serum type II secretory phospholipase A(2) (sPLA(2)-IIa) has been found to be predictive of adverse outcomes in patients with stable coronary heart disease. Compounds targeting sPLA(2)-IIa are already under development. This study investigated if an association of sPLA(2)-IIa with secondary cardiovascular disease (CVD) events may be of causal nature or mainly a matter of confounding by correlated cardiovascular risk markers.Eight-year follow-up data of a prospective cohort study (KAROLA) of patients who underwent in-patient rehabilitation after an acute cardiovascular event were analysed. Associations of polymorphisms (SNP) in the sPLA(2)-IIa-coding gene PLA2G2A with serum sPLA(2)-IIa and secondary fatal or non-fatal CVD events were examined by multiple regression. Hazard ratios (HR) were compared with those expected if the association between sPLA(2)-IIa and CVD were causal. The strongest determinants of sPLA(2)-IIa (rs4744 and rs10732279) were associated with an increase of serum concentrations by 81% and 73% per variant allele. HRs (95% confidence intervals) estimating the associations of the SNPs with secondary CVD events were increased, but not statistically significant (1.16 [0.89-1.51] and 1.18 [0.91-1.52] per variant allele, respectively). However, these estimates were very similar to those expected when assuming causality (1.18 and 1.17), based on an association of natural log-transformed sPLA(2)-IIa concentration with secondary events with HR = 1.33 per unit.The present findings regarding genetic polymorphisms, determination of serum sPLA(2)-IIa, and prognosis in CVD patients are consistent with a genuine causal relationship and thus might point to a valid drug target for prevention of secondary CVD events

Total and High Molecular Weight Adiponectin and Hepatocellular Carcinoma with HCV Infection

Adiponectin is shown to be inversely associated with development and progression of various cancers. We evaluated whether adiponectin level was associated with the prevalence and histological grade of hepatocellular carcinoma (HCC), and liver fibrosis in patients with hepatitis C virus (HCV) infection.A case-control study was conducted on 97 HCC patients (cases) and 97 patients (controls) matched for sex, Child-Pugh grade and platelet count in patients with HCV infection. The serum total and high molecular weight (HMW) adiponectin levels were measured by enzyme-linked immunosorbent assays and examined in their association with the prevalence of HCC. In addition, the relationship between these adiponectin levels and body mass index (BMI), progression of liver fibrosis, and histological grade of HCC was also evaluated. Liver fibrosis was assessed using the aspartate aminotransferase to platelet ratio index (APRI).There were no significant differences in the serum total and HMW adiponectin levels between cases and controls. Moreover, there were no inverse associations between serum total and HMW adiponectin levels and BMI in both cases and controls. On the other hand, serum total and HMW adiponectin levels are positively correlated with APRI in both cases (r = 0.491, P<0.001 and r = 0.485, P<0.001, respectively) and controls (r = 0.482, P<0.001 and r = 0.476, P<0.001, respectively). Interestingly, lower serum total (OR 11.76, 95% CI: 2.97–46.66 [P<0.001]) and HMW (OR 10.24, CI: 2.80–37.40 [P<0.001] adiponectin levels were independent risk factors of worse histological grade of HCC.Our results suggested that serum total and HMW adiponectin levels were predictors of liver fibrosis, but not prevalence of HCC in patients with HCV infection. Moreover, low these adiponectin levels were significantly associated with worse histological grades

Metabolic pathways promoting intrahepatic fatty acid accumulation in methionine and choline deficiency:implications for the pathogenesis of steatohepatitis

The pathological mechanisms that distinguish simple steatosis from steatohepatitis (or NASH, with consequent risk of cirrhosis and hepatocellular cancer) remain incompletely defined. Whereas both a methionine- and choline-deficient diet (MCDD) and a choline-deficient diet (CDD) lead to hepatic triglyceride accumulation, MCDD alone is associated with hepatic insulin resistance and inflammation (steatohepatitis). We used metabolic tracer techniques, including stable isotope ([13C4]palmitate) dilution and mass isotopomer distribution analysis (MIDA) of [13C2]acetate, to define differences in intrahepatic fatty acid metabolism that could explain the contrasting effect of MCDD and CDD on NASH in C57Bl6 mice. Compared with control-supplemented (CS) diet, liver triglyceride pool sizes were similarly elevated in CDD and MCDD groups (24.37 ± 2.4, 45.94 ± 3.9, and 43.30 ± 3.5 μmol/liver for CS, CDD, and MCDD, respectively), but intrahepatic neutrophil infiltration and plasma alanine aminotransferase (31 ± 3, 48 ± 4, 231 ± 79 U/l, P < 0.05) were elevated only in MCDD mice. However, despite loss of peripheral fat in MCDD mice, neither the rate of appearance of palmitate (27.2 ± 3.5, 26.3 ± 2.3, and 28.3 ± 3.5 μmol·kg−1·min−1) nor the contribution of circulating fatty acids to the liver triglyceride pool differed between groups. Unlike CDD, MCDD had a defect in hepatic triglyceride export that was confirmed using intravenous tyloxapol (142 ± 21, 122 ± 15, and 80 ± 7 mg·kg−1·h−1, P < 0.05). Moreover, hepatic de novo lipogenesis was significantly elevated in the MCDD group only (1.4 ± 0.3, 2.3 ± 0.4, and 3.4 ± 0.4 μmol/day, P < 0.01). These findings suggest that important alterations in hepatic fatty acid metabolism may promote the development of steatohepatitis. Similar mechanisms may predispose to hepatocyte damage in human NASH