Context.-Lysophosphatidic acid (LPA) has been shown to stimulate proliferation of ovarian cancer cells and is present in the ascitic fluid of patients with ovarian cancer.Objectives.-To determine whether elevated levels of LPA are present in plasma from patients with ovarian cancer and other gynecologic malignancies compared with healthy controls and to evaluate whether an elevated LPA plasma level may be a biomarker for these diseases.Design.-A research assay was used to measure total LPA levels in plasma from healthy women and women with different diseases. All LPA assays and comparison of LPA levels and CA125 (an ovarian cancer biomarker) levels were performed by observers blinded to patient status or group.Setting.-The Cleveland Clinic Foundation.Participants.-A convenience sample of 48 healthy control women, 48 women with ovarian cancer, 36 women with other gynecologic cancers, 17 women with benign gynecologic diseases, 11 women with breast cancer, and 5 women with leukemias.Main Outcome Measures.-Total LPA levels in plasma samples from patients and controls.Results.-Patients in the ovarian cancer group had significantly higher plasma LPA levels (mean, 8.6 µmol/L; range, 1.0-43.1 µmol/L) compared with the healthy control group (mean, 0.6 µmol/L; range, Ͻ0.1-6.3 µmol/L) (PϽ.001). Elevated plasma LPA levels were detected in 9 of 10 patients with stage I ovarian cancer, 24 of 24 patients with stage II, III, and IV ovarian cancer, and 14 of 14 patients with recurrent ovarian cancer. Of 36 patients with other gynecologic cancers, 33 also showed higher LPA levels (mean, 14.9 µmol/L; range, Ͻ0.1-63.2 µmol/L), compared with healthy controls (PϽ.001). Elevated plasma LPA levels were detected in 5 of 48 controls and 4 of 17 patients with benign gynecologic diseases and in no women with breast cancer or leukemia. In comparison, among a subset of patients with ovarian cancer, 28 of 47 had elevated CA125 levels, including 2 of 9 patients with stage I disease.Conclusions.-Plasma LPA levels may represent a potential biomarker for ovarian cancer and other gynecologic cancers. However, these findings are preliminary and require confirmation in larger studies.

SUMMARY Emerging evidence suggests that microbes resident in the human intestine represent a key environmental factor contributing to obesity-associated disorders. Here we demonstrate that the gut microbiota-initiated trimethylamine-N-oxide (TMAO)-generating pathway is linked to obesity and energy metabolism. In multiple clinical cohorts, systemic levels of TMAO were observed to strongly associate with type 2 diabetes. In addition, circulating TMAO levels were associated with obesity traits in the different inbred strains represented in the Hybrid Mouse Diversity Panel. Further, antisense oligonucleotide-mediated knockdown or genetic deletion of the TMAO-producing enzyme, flavin-containing monooxygenase 3 (FMO3), conferred protection against obesity in mice. Complimentary mouse and human studies indicate a negative regulatory role for FMO3 in the beiging of white adipose tissue. Collectively, our studies reveal a link between the TMAO-producing enzyme FMO3 and obesity and the beiging of white adipose tissue.

AimsObesity and hyperlipidaemia are associated with insulin resistance (IR); however, the mechanisms responsible remain incompletely understood. Pro-atherogenic hyperlipidaemic states are characterized by inflammation, oxidant stress, and pathophysiologic oxidized lipids, including ligands for the scavenger receptor CD36. Here we tested the hypothesis that the absence of CD36 protects mice from IR associated with diet-induced obesity and hyperlipidaemia.Methods and resultsAdipose tissue from CD36−/− mice demonstrated a less inflammatory phenotype and improved insulin signalling in vivo and at the level of the adipocyte and macrophage. The pathophysiologic ligand oxidized low-density lipoprotein (oxLDL) activated c-Jun N-terminal kinase (JNK) and disrupted insulin signalling in both adipocytes and macrophages in a CD36-dependent manner. Macrophages isolated from CD36−/− mice after high-fat diet feeding elicited less JNK activation and inhibition of insulin signalling in adipocytes after co-culture compared with wild-type macrophages.ConclusionThese data suggest that a CD36-dependent inflammatory paracrine loop between adipocytes and macrophages facilitates chronic inflammation and contributes to IR common in obesity and dyslipidaemia.

These results provide new insights into the pro-atherogenic mechanisms of CD36 by implicating processes other than modified lipoprotein uptake.

Lipid transfer protein (LTP) activity is modulated by a distinct plasma protein termed lipid transfer inhibitor protein (LTIP). The objective of this study was to establish an assay for LTIP that could be used to quantify its activity in lipoprotein-deficient plasma. A straightforward heating protocol (56°C for 60 minutes) was found to inactivate more than 90% of LTIP activity. The responses of individual lipoprotein-deficient plasma samples to this heating procedure were unique. Among normolipidemic donors, inactivation of LTIP caused a 230% to 600% increase in LTP activity. Essentially all measurable transfer activity in native and heated samples was inhibited by an antibody to LTP. Whole-plasma samples from these donors were spiked with radiolabeled lipoproteins to measure the rates of lipid transfer among the major lipoprotein classes. In general, plasma lipid transfer rates were negatively correlated with LTIP activity in these samples. However, the decrease in lipid transfers from very-lowdensity lipoprotein (VLDL) to low-density lipoprotein (LDL) and from LDL to VLDL was from 2.4-to 5.1-fold greater than in the transfers from VLDL to high-density lipoprotein (HDL) or from HDL to VLDL. In these samples, the molecular weight of HDL 2 was negatively correlated with LTIP activity. Thus, LTIP activities among normolipidemic individuals were observed to vary severalfold; compared with other lipoprotein transfers, higher LTIP activities were associated with a relative reduction in LDL-VLDL lipid transfer events. 13 In concerted action with lipolytic activities, LTP is a key component in the normal intravascular metabolism of lipoproteins in humans. 4 Individuals who are genetically deficient in LTP show marked alterations in their lipoprotein composition, which is characterized by elevated high-density lipoprotein cholesterol (HDL-C) levels and the accumulation of high-density lipoprotein (HDL) enriched in apolipoprotein E, 56 much like the HDL-C noted in cholesterol-fed animals that lack detectable plasma LTP activity. 7In the plasma of individuals not genetically deficient in LTP, variations in lipid transfer activity can result from many factors. In some instances, activity appears to reflect changes in the level or quality of lipoprotein substrates present. 8 -10 In other cases, the lipoproteinfree fraction of plasma is the source of altered LTP activity."13 In these cases, however, variations in the concentration of LTP mass account for only a portion of