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

Lipoproteins and lipid metabolism: lipoprotein metabolism. ldl receptor (ldlr) expression and function in human pancreatic beta cells

Lipoproteins and lipid metabolism: lipoprotein metabolism. ldl receptor (ldlr) expression and function in human pancreatic beta cells. Congress of the European-Atherosclerosis-Society (EAS

LDL receptor expression and function in human pancreatic beta cells

LDL receptor expression and function in human pancreatic beta cells. 52nd Annual Meeting of th

Lipoproteins and lipid metabolism: lipoprotein metabolism. stable isotope kinetic study of apolipoprotein m in healthy subjects

Lipoproteins and lipid metabolism: lipoprotein metabolism. stable isotope kinetic study of apolipoprotein m in healthy subjects. Congress of the European-Atherosclerosis-Society (EAS

Apolipoprotein A-I glycation by Glucose and Reactive Aldehydes Alters Phospholipid Affinity but Not Cholesterol Export from Lipid-Laden Macrophages

Increased protein glycation in people with diabetes may promote atherosclerosis. This study examined the effects of non-enzymatic glycation on the association of lipid-free apolipoproteinA-I (apoA-I) with phospholipid, and cholesterol efflux from lipid-loaded macrophages to lipid-free and lipid-associated apoA-I. Glycation of lipid-free apoA-I by methylglyoxal and glycolaldehyde resulted in Arg, Lys and Trp loss, advanced glycation end-product formation and protein cross-linking. The association of apoA-I glycated by glucose, methylglyoxal or glycolaldehyde with phospholipid multilamellar vesicles was impaired in a glycating agent dose-dependent manner, with exposure of apoA-I to both 30 mM glucose (42% decrease in kslow) and 3 mM glycolaldehyde (50% decrease in kfast, 60% decrease in kslow) resulting is significantly reduced affinity. Cholesterol efflux to control or glycated lipid-free apoA-I, or discoidal reconstituted HDL containing glycated apoA-I (drHDL), was examined using cholesterol-loaded murine (J774A.1) macrophages treated to increase expression of ATP binding cassette transporters A1 (ABCA1) or G1 (ABCG1). Cholesterol efflux from J774A.1 macrophages to glycated lipid-free apoA-I via ABCA1 or glycated drHDL via an ABCG1-dependent mechanism was unaltered, as was efflux to minimally modified apoA-I from people with Type 1 diabetes, or controls. Changes to protein structure and function were prevented by the reactive carbonyl scavenger aminoguanidine. Overall these studies demonstrate that glycation of lipid-free apoA-I, particularly late glycation, modifies its structure, its capacity to bind phospholipids and but not ABCA1- or ABCG1-dependent cholesterol efflux from macrophages

Inhibition of glycation of lipid-free apoA-I by aminoguanidine.

<p>(A) Arg, Lys and Trp loss in lipid-free apoA-I exposed to 0 (black bars) or 15 mM glycolaldehyde in the absence (white bars) or presence (spotted bars) of 15 mM aminoguanidine (24 h, 37°C). (B) SDS-PAGE of lipid-free apoA-I exposed to 0 mM glycolaldehyde (lane 2), 3 mM glycolaldehyde (lane 3), 3 mM glycolaldehyde and 3 mM aminoguanidine (lane 4), 15 mM glycolaldehyde (lane 5), 15 mM glycolaldehyde and 15 mM aminoguanidine (lane 6) for 24 h. Lane 1: molecular mass markers. Representative gel of 3. (C) Cholesterol efflux after 4 h to lipid-free apoA-I exposed (24 h, 37°C) to 0 or 15 mM glycolaldehyde (GA) ± aminoguanidine (AMG, 15 mM). Columns with different superscript letters are significantly different (one-way ANOVA).</p