👤 Claudia Bellomo

The pathways linking lipoprotein(a) (Lp[a]) to atherosclerotic cardiovascular disease (ASCVD) are unclear. This study aimed to discover Lp(a)-associated plasma proteins and estimate their associations with incident ASCVD. We analyzed 48,859 UK Biobank participants with measured Lp(a) and proteomic profiles, with replication in 9,416 individuals in the Atherosclerosis Risk in Communities (ARIC) study cohort utilizing a separate proteomic platform. Linear models assessed associations between Lp(a) and protein concentrations adjusted for age, sex, cigarette smoking, diabetes diagnosis, body mass index, systolic blood pressure, hypertension, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol, triglycerides, estimated glomerular filtration rate, statin prescription, and the first 10 components of genetic ancestry. Multiple testing correction was performed using the Benjamini-Hochberg FDR method (P < 0.05). We examined how the protein effect sizes from the primary analysis using the outcome of Lp(a) aligned with those for the outcomes of an LPA genetic risk score (GRS) and LDL-C. Cox proportional hazards models quantified hazard ratios (HRs) for protein associations with incident ASCVD. Participants were a mean age of 57 years (SD 8.22), 93.9% European, and 53.8% male, with median follow-up of 8.9 years (IQR 8.3-9.7). Of 1,459 circulating proteins, 164 were significantly associated with Lp(a) after FDR correction, with enrichment for lipid degradation, metabolism, and insulin secretion. In the ARIC study, 10 proteins were replicated with consistent effect estimates. Of these replicated proteins, there were no significant associations observed with an Using high-throughput proteomics, we discovered and replicated 10 proteins associated with circulating Lp(a), several of which were independent of genetically-predicted Lp(a). While Lp(a) is highly heritable, these atherogenic proteins represent a non-heritable Lp(a) axis. Show less

The roles of lipoprotein(a) [Lp(a)] and related oxidized phospholipids (OxPLs) in the development and progression of coronary disease is known, but their influence on extracoronary vascular disease is not well-established. We sought to evaluate associations between Lp(a), OxPL apolipoprotein B (OxPL-apoB), and apolipoprotein(a) (OxPL-apo(a)) with angiographic extracoronary vascular disease and incident major adverse limb events (MALEs). Four hundred forty-six participants who underwent coronary and/or peripheral angiography were followed up for a median of 3.7 years. Lp(a) and OxPLs were measured before angiography. Elevated Lp(a) was defined as ≥150 nmol/L. Elevated OxPL-apoB and OxPL-apo(a) were defined as greater than or equal to the 75th percentile (OxPL-apoB ≥8.2 nmol/L and OxPL-apo(a) ≥35.8 nmol/L, respectively). Elevated Lp(a) had a stronger association with the presence of extracoronary vascular disease compared to OxPLs and was minimally improved with the addition of OxPLs in multivariable models. Compared to participants with normal Lp(a) and OxPL concentrations, participants with elevated Lp(a) levels were twice as likely to experience a MALE (odds ratio: 2.14, 95% confidence interval: 1.03, 4.44), and the strength of the association as well as the C statistic of 0.82 was largely unchanged with the addition of OxPL-apoB and OxPL-apo(a). Elevated Lp(a) and OxPLs are risk factors for progression and complications of extracoronary vascular disease. However, the addition of OxPLs to Lp(a) does not provide additional information about risk of extracoronary vascular disease. Therefore, Lp(a) alone captures the risk profile of Lp(a), OxPL-apoB, and OxPL-apo(a) in the development and progression of atherosclerotic plaque in peripheral arteries. Show less

Protein tyrosine phosphatases (PTPs) are a family of enzymes essential for numerous cellular processes, such as cell growth, inflammation, differentiation, immune-mediated responses and oncogenic transformation. The aim of this review is to review the literature concerning the role of several PTPs-PTPN22, PTPN2, PTPN6, PTPN11, PTPσ, DUSP2, DUSP6 and PTPRK-at the level of the intestinal mucosa in inflammatory bowel disease (IBD), celiac disease (CeD) and type 1 diabetes (T1D) in both in vitro and in vivo models. The results revealed shared features, at the level of the intestinal mucosa, between these diseases characterized by alterations of different biological processes, such as proliferation, autoimmunity, cell death, autophagy and inflammation. PTPs are now actively studied to develop new drugs. Also considering the availability of organoids as models to test new drugs in personalized ways, it is very likely that soon these proteins will be the targets of useful drugs. Show less

Understanding the complexity of changes in differentiation and cell survival in hepatocellular carcinoma (HCC) is essential for the design of new diagnostic tools and therapeutic modalities. In this context, we have analyzed the crosstalk between transforming growth factor β (TGFβ) and liver X receptor α (LXRα) pathways. TGFβ is known to promote cytostatic and pro-apoptotic responses in HCC, and to facilitate mesenchymal differentiation. We here demonstrate that stimulation of the nuclear LXRα receptor system by physiological and clinically useful agonists controls the HCC response to TGFβ. Specifically, LXRα activation antagonizes the mesenchymal, reactive oxygen species and pro-apoptotic responses to TGFβ and the mesenchymal transcription factor Snail mediates this crosstalk. In contrast, LXRα activation and TGFβ cooperate in enforcing cytostasis in HCC, which preserves their epithelial features. LXRα influences Snail expression transcriptionally, acting on the Snail promoter. These findings propose that clinically used LXR agonists may find further application to the treatment of aggressive, mesenchymal HCCs, whose progression is chronically dependent on autocrine or paracrine TGFβ. Show less