D25V apolipoprotein C-III variant causes dominant hereditary systemic amyloidosis and confers cardiovascular protective lipoprotein profile

Apolipoprotein C-III deficiency provides cardiovascular protection, but apolipoprotein C-III is not known to be associated with human amyloidosis. Here we report a form of amyloidosis characterized by renal insufficiency caused by a new apolipoprotein C-III variant, D25V. Despite their uremic state, the D25V-carriers exhibit low triglyceride (TG) and apolipoprotein C-III levels, and low very-low-density lipoprotein (VLDL)/high high-density lipoprotein (HDL) profile. Amyloid fibrils comprise the D25V-variant only, showing that wild-type apolipoprotein C-III does not contribute to amyloid deposition in vivo. The mutation profoundly impacts helical structure stability of D25V-variant, which is remarkably fibrillogenic under physiological conditions in vitro producing typical amyloid fibrils in its lipid-free form. D25V apolipoprotein C-III is a new human amyloidogenic protein and the first conferring cardioprotection even in the unfavourable context of renal failure, extending the evidence for an important cardiovascular protective role of apolipoprotein C-III deficiency. Thus, fibrate therapy, which reduces hepatic APOC3 transcription, may delay amyloid deposition in affected patients

GH Administration Rescues Fatty Liver Regeneration Impairment by Restoring GH/EGFR Pathway Deficiency

International audienc

Multiple Roles of Membrane Lipids: Implications for Health and Disease

Lipids are a major class of molecules which fulfil several functions. Cell membrane lipid composition can vary substantially, suggesting that different lipids are required for different functions. The lipid matrix is not simply the physical scaffold for proteins or the structural barrier that isolates and defines cells and organelles, but, it is also active in many cellular functions. Caveolae represent membrane compartments enriched with sphingolipids, cholesterol and signaling molecules whose structural integrity is essential for the cellular response. Levels of lipid species can change in response to diet, physiological and environmental factors. In human blood, transport of lipids is exerted by lipoproteins.Alterations of membrane and/or lipoprotein lipid composition, associated either with adaptive responses or with the aetiology of the disease, have been described in several pathologies. The current understanding of lipids, the structures they form, their roles in cells and lipoproteins, and their physico-chemical properties are the result of many years of our research. Aim of the paper is to review the history, current status, and future of lipids in cell and lipoprotein biology. A promising field of research is the study of structures derived from lipids as carriers of bioactive molecules to deliver site-specific targeting ligands in vivo

Lipoprotein hydrophobic core lipids are partially extruded to surface in smaller HDL: “Herniated” HDL, a common feature in diabetes

Recent studies have shown that pharmacological increases in HDL cholesterol concentrations do not necessarily translate into clinical benefits for patients, raising concerns about its predictive value for cardiovascular events. Here we hypothesize that the size-modulated lipid distribution within HDL particles is compromised in metabolic disorders that have abnormal HDL particle sizes, such as type 2 diabetes mellitus (DM2). By using NMR spectroscopy combined with a biochemical volumetric model we determined the size and spatial lipid distribution of HDL subclasses in a cohort of 26 controls and 29 DM2 patients before and after two drug treatments, one with niacin plus laropiprant and another with fenofibrate as an add-on to simvastatin. We further characterized the HDL surface properties using atomic force microscopy and fluorescent probes to show an abnormal lipid distribution within smaller HDL particles, a subclass particularly enriched in the DM2 patients. The reduction in the size, force cholesterol esters and triglycerides to emerge from the HDL core to the surface, making the outer surface of HDL more hydrophobic. Interestingly, pharmacological interventions had no effect on this undesired configuration, which may explain the lack of clinical benefits in DM2 subjects