Lipoproteins Contribute to β Cell Death

Abstract

Cholesterol is carried in the circulation bound to lipoprotein particles. Low density lipoproteins (LDLs) and very low density lipoproteins (VLDLs) are relatively high in cholesterol content and high density lipoproteins are comparatively low in cholesterol content, thus the names "good" cholesterol (HDL) and "bad" cholesterol (VLDL and LDL). VLDLs and LDLs have been implicated in various pathological conditions. Roehrich et al. show that pancreatic β cells have receptors for all of the lipoproteins and that application of VLDL or LDL to isolated mouse islets increases the appearance of apoptotic cells, an affect that was confirmed in a transformed insulin-secreting cell line (βTC3 cells). The apoptotic effect of VLDL and LDL was inhibited by application of HDL and was reduced in islets from LDL receptor-deficient mice. In addition VLDL and LDL reduced production of insulin transcripts, an effect that was not inhibited by HDL. Apoptosis appeared to be triggered by two different mechanisms: VLDL stimulated caspase-3 cleavage and reduced the amount of a Jun amino-terminal kinase (JNK) scaffold protein (JIP-1). VLDL-induced death was decreased in the presence of a JNK inhibitor. LDL did not produce these same effects, nor was cell death caused by LDL inhibited by the JNK inhibitor. HDL inhibited caspase-3 cleavage and stimulated the activity of Akt, a kinase that functions in cell survival pathways. Thus, the balance between the good and the bad cholesterol-containing lipoproteins may contribute to the progression of type 2 diabetes by contributing to decreased insulin production and increased islet cell death. M.-E. Roehrich, V. Mooser, V. Lenain, J. Herz, J. Nimpf, S. Azhar, M. Bideau, A. Capponi, P. Nicod, J.-A. Haefliger, G. Waeber, Insulin-secreting β-cell dysfunction induced by human lipoproteins. J. Biol. Chem. 278 , 18368 (2003). [Abstract] [Full Text]