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Role of Cholesterol and Phospholipids in Amylin Misfolding, Aggregation and Etiology of Islet Amyloidosis

  • Chapter
Lipids in Protein Misfolding

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 855))

Abstract

Amyloidosis is a biological event in which proteins undergo structural transitions from soluble monomers and oligomers to insoluble fibrillar aggregates that are often toxic to cells. Exactly how amyloid proteins, such as the pancreatic hormone amylin, aggregate and kill cells is still unclear. Islet amyloid polypeptide, or amylin, is a recently discovered hormone that is stored and co-released with insulin from pancreatic islet β-cells. The pathology of type 2 diabetes mellitus (T2DM) is characterized by an excessive extracellular and intracellular accumulation of toxic amylin species, soluble oligomers and insoluble fibrils, in islets, eventually leading to β-cell loss. Obesity and elevated serum cholesterol levels are additional risk factors implicated in the development of T2DM. Because the homeostatic balance between cholesterol synthesis and uptake is lost in diabetics, and amylin aggregation is a hallmark of T2DM, this chapter focuses on the biophysical and cell biology studies exploring molecular mechanisms by which cholesterol and phospholipids modulate secondary structure, folding and aggregation of human amylin and other amyloid proteins on membranes and in cells. Amylin turnover and toxicity in pancreatic cells and the regulatory role of cholesterol in these processes are also discussed.

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Abbreviations

AFM:

Atomic force microscopy

BCD:

Methylbetacyclodextrin

CD:

Circular dichroism

CTX:

Cholera toxin

DOPC:

1,2-dioleoyl-phosphatidylcholine

DOPS:

1,2-dioleoylphosphatidylserine

EM:

Electron microscopy

HFIP:

Hexafluoride isopropanol

hIAPP:

Human islet amyloid peptide

Lov:

Lovostatin

PM:

Plasma membranes

T2DM:

Type 2 diabetes mellitus

ThT:

Thioflavin-T

Trf:

Transferrin

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Acknowledgment

This work was supported by the NIH grant RO1DK091845 and the ICR Basic Science Islet Distribution Program (to A.J.).

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  1. Saurabh Trikha

    Present address: Endocrinology Division, Boston Children’s Hospital, Harvard Medical School, Boston, MA, 02115, USA

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  1. Department of Biological Sciences, The George Washington University, 2023 G Street NW, Washington, DC, 20052, USA

    Sanghamitra Singh, Saurabh Trikha, Diti Chatterjee Bhowmick, Anjali A. Sarkar & Aleksandar M. Jeremic

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  1. Dept. of Physiology and Biophysics, Boston University School of Medicine, Boston, Massachusetts, USA

    Olga Gursky

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Singh, S., Trikha, S., Bhowmick, D.C., Sarkar, A.A., Jeremic, A.M. (2015). Role of Cholesterol and Phospholipids in Amylin Misfolding, Aggregation and Etiology of Islet Amyloidosis. In: Gursky, O. (eds) Lipids in Protein Misfolding. Advances in Experimental Medicine and Biology, vol 855. Springer, Cham. https://doi.org/10.1007/978-3-319-17344-3_4

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