title: 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.
authors: Department of Physiology & Biophysics, Boston University School of Medicine, Boston, USA.
authors: Shobini
authors: S
authors: Jayaraman
authors: Cardiovascular Biochemistry Group, Biomedical Research Institute IIB-Sant Pau, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
authors: Jose Luis
authors: JL
authors: Sánchez-Quesada
authors: Department of Physiology & Biophysics, Boston University School of Medicine, Boston, USA. Electronic address: gursky@bu.edu.
authors: Olga
authors: O
authors: Gursky
mesh_terms: D000682:Amyloid / Q000097:blood / Q000378:metabolism*; D016632:Apolipoprotein A-I / Q000097:blood / Q000378:metabolism*; D003920:Diabetes Mellitus / Q000097:blood / Q000378:metabolism; D006801:Humans; D008066:Lipolysis; D008075:Lipoproteins, HDL / Q000097:blood / Q000378:metabolism*; D008958:Models, Molecular; D010084:Oxidation-Reduction; D055550:Protein Stability; D059748:Proteolysis; D014280:Triglycerides / Q000097:blood / Q000378:metabolism*
chemical_list: C505693:APOA1 protein, human; D000682:Amyloid; D016632:Apolipoprotein A-I; D008075:Lipoproteins, HDL; D014280:Triglycerides
keywords: Cardiovascular and amyloid diseases; Fibrates, statins and low-fat diets; Lipid-lowering therapies; Oxidation and hydrolysis; Protein-lipid interactions and protein misfolding