Triglyceride increase in the core of high-density lipoproteins augments apolipoprotein dissociation from the surface: Potential implications for treatment of apolipoprotein deposition diseases

Abstract

Lipids in the body are transported via lipoproteins that are nanoparticles comprised of lipids and amphipathic proteins termed apolipoproteins. This family of lipid surface-binding proteins is over-represented in human amyloid diseases. In particular, all major proteins of high-density lipoproteins (HDL), including apoA-I, apoA-II and serum amyloid A, can cause systemic amyloidoses in humans upon protein mutations, post-translational modifications or overproduction. Here, we begin to explore how the HDL lipid composition influences amyloid deposition by apoA-I and related proteins. First, we summarize the evidence that, in contrast to lipoproteins that are stabilized by kinetic barriers, free apolipoproteins are labile to misfolding and proteolysis. Next, we report original biochemical and biophysical studies showing that increase in triglyceride content in the core of plasma or reconstituted HDL destabilizes the lipoprotein assembly, making it more labile to various perturbations (oxidation, thermal and chemical denaturation and enzymatic hydrolysis), and promotes apoA-I release in a lipid-poor/free aggregation-prone form. Together, the results suggest that decreasing plasma levels of triglycerides will shift the dynamic equilibrium from the lipid-poor/free (labile) to the HDL-bound (protected) apolipoprotein state, thereby decreasing the generation of the protein precursor of amyloid. This prompts us to propose that triglyceride-lowering therapies may provide a promising strategy to alleviate amyloid diseases caused by the deposition of HDL proteins.

Relation of High‐Density Lipoprotein Charge Heterogeneity, Cholesterol Efflux Capacity, and the Expression of High‐Density Lipoprotein‐Related Genes in Mononuclear Cells to the HDL‐Cholesterol Level

“…Previously, Söderlund et al observed a positive correlation between the level of preβ‐HDL and TAG in subjects with familial hypoalphalipoproteinemia (Soderlund et al, ). The increased dissociation of lipid‐free apoA‐I from HDL at hypertriglyceridemia was described recently (Jayaraman et al, ). Overall, the atheroprotective effect of preβ‐HDL at hypertriglyceridemia may be suggested thus explaining the discordance between HDL‐C and cholesterol efflux (Koekemoer et al, ).…”

Synergy between serum amyloid A and secretory phospholipase A2

“…Our focus was on the FFA that are elevated in diabetes, inflammation and other diseases. LDL was isolated from the pooled plasma of subjects who were either normolipidemic or had diabetes mellitus, as previously described (Jayaraman et al, 2017b). The content of endogenous FFA in these diabetic LDL was 20% higher than that in normolipidemic LDL (Jayaraman et al, 2017b).…”

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10.7554/eLife.46630.016Figure 6—figure supplement 1.SAA and albumin sequester naturally occurring FFA from human plasma LDL at pH 7.5.LDL were obtained from pooled plasma of diabetic and from healthy normolipidemic patients as previously described (Jayaraman et al, 2017b). Diabetic LDL had 20% higher content of endogenous FFA compared to normolipidemic LDL.

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Structural Basis for Vital Function and Malfunction of Serum Amyloid A: an Acute-Phase Protein that Wears Hydrophobicity on Its Sleeve

“…Other approaches propose to block amyloidogenic segments of SAA by using complementary peptides [ 95 ] or lipids. In particular, decreasing triglyceride levels in the core of HDL helps retain SAA and other apolipoproteins on the HDL surface and thereby retard fibrillogenesis [ 96 ]. If so, existing triglyceride-lowering therapies hold promise for treating AA amyloidosis, including cases without the underlying inflammation.…”