👤 Gerhard M Kostner

Lipoprotein(a) [Lp(a)] is a genetically determined, highly atherogenic lipoprotein that contributes to cardiovascular disease and calcific aortic valve stenosis. Increased Lp(a) levels warrant intensified management of cardiovascular risk factors. With targeted Lp(a)-lowering therapies in clinical development, identification of individuals with increased levels has increasing therapeutic implications. Guidelines differ, recommending testing in either high-risk groups or universally once in a lifetime, yet testing rates remain low. We performed a retrospective analysis of laboratory data from a large tertiary referral centre in Queensland, Australia, evaluating trends in Lp(a) testing between 1 January 2015 and 31 December 2024. Lp(a) testing increased markedly over the 10-year study period. In Queensland, annual test volumes rose from 652 in 2015 to 4,364 in 2024. Including interstate referrals, test numbers increased from 2,686 in 2015 to 23,135 in 2024. The steepest rise occurred in the final 2 years of observation. Despite these increases, testing rates relative to the screened population remained low, and testing generally occurred late in individuals in their 50s. Lp(a) testing has grown substantially in Queensland and Australia over the past decade, likely reflecting increased recognition of its causal role in cardiovascular disease, evolving guideline recommendations, test accessibility, and the emergence of novel therapies. However, overall testing remains limited. Broader implementation of guideline-based testing and greater clinician awareness will be critical to ensure timely identification of individuals who may benefit from available and emerging therapeutic strategies. Show less

NLRP3-inflammasome-driven inflammation is involved in the pathogenesis of a variety of diseases. Identification of endogenous inflammasome activators is essential for the development of new anti-inflammatory treatment strategies. Here, we identified that apolipoprotein C3 (ApoC3) activates the NLRP3 inflammasome in human monocytes by inducing an alternative NLRP3 inflammasome via caspase-8 and dimerization of Toll-like receptors 2 and 4. Alternative inflammasome activation in human monocytes is mediated by the Toll-like receptor adapter protein SCIMP. This triggers Lyn/Syk-dependent calcium entry and the production of reactive oxygen species, leading to activation of caspase-8. In humanized mouse models, ApoC3 activated human monocytes in vivo to impede endothelial regeneration and promote kidney injury in an NLRP3- and caspase-8-dependent manner. These data provide new insights into the regulation of the NLRP3 inflammasome and the pathophysiological role of triglyceride-rich lipoproteins containing ApoC3. Targeting ApoC3 might prevent organ damage and provide an anti-inflammatory treatment for vascular and kidney diseases. Show less

Liver X receptors (LXRα and LXRβ) are key transcription factors in cholesterol metabolism that regulate cholesterol biosynthesis/efflux and bile acid metabolism/excretion in the liver and numerous organs. In macrophages, LXR signaling modulates cholesterol handling and the inflammatory response, pathways involved in atherosclerosis. Since regulatory pathways of LXR transcription control are well understood, in the present study we aimed at identifying post-transcriptional regulators of LXR activity. MicroRNAs (miRs) are such post-transcriptional regulators of genes that in the canonical pathway mediate mRNA inactivation. In silico analysis identified miR-206 as a putative regulator of LXRα but not LXRβ. Indeed, as recently shown, we found that miR-206 represses LXRα activity and expression of LXRα and its target genes in hepatic cells. Interestingly, miR-206 regulates LXRα differently in macrophages. Stably overexpressing miR-206 in THP-1 human macrophages revealed an up-regulation and miR-206 knockdown led to a down-regulation of LXRα and its target genes. In support of these results, bone marrow-derived macrophages (BMDMs) from miR-206 KO mice also exhibited lower expression of LXRα target genes. The physiological relevance of these findings was proven by gain- and loss-of-function of miR-206; overexpression of miR-206 enhanced cholesterol efflux in human macrophages and knocking out miR-206 decreased cholesterol efflux from MPMs. Moreover, we show that miR-206 expression in macrophages is repressed by LXRα activation, while oxidized LDL and inflammatory stimuli profoundly induced miR-206 expression. We therefore propose a feed-back loop between miR-206 and LXRα that might be part of an LXR auto-regulatory mechanism to fine tune LXR activity. Show less