Biology subjects

Shih, A. Z. L.

Publications and source records attributed to Shih, A. Z. L..

2 recordsLinked to original sources

bioRxiv2022

SORLA mediates endocytic uptake of proIAPP and protects against islet amyloid deposition

Aims/ hypothesisSorting-related receptor with type A repeats (SORLA) is a neuronal sorting receptor that prevents accumulation of amyloid-beta peptides, the main constituent of senile plaques in Alzheimer disease. Recent transcriptomic studies show that SORLA transcripts are also found in pancreatic islet beta cells, yet the role of SORLA in islets is unclear so far. Based on its protective role in reducing amyloid burden in the brain, we hypothesized that SORLA may have a similar function in the pancreas, regulating islet amyloid plaque formation from islet amyloid polypeptide (IAPP). MethodsWe generated human IAPP transgenic mice lacking SORLA (hIAPP:SORLA KO) to assess the consequences of receptor deficiency for islet histopathology and function in vivo. Using both primary islet cells and established cell lines, we further investigated the molecular mechanisms whereby SORLA controls the cellular metabolism and accumulation of IAPP. ResultsLoss of SORLA activity in hIAPP:SORLA KO resulted in a significant increase in islet amyloid deposits and associated islet cell death as compared to hIAPP:SORLA WT animals expressing the receptor. Aggravated islet amyloid deposition was observed in mice fed a normal chow diet, not requiring high-fat diet feeding typically needed to induce islet amyloidosis in mouse models. Further in vitro studies showed that SORLA binds to and mediates the endocytic uptake of proIAPP, but not mature IAPP, delivering the propeptide to an endolysosomal fate. Conclusions/interpretationSORLA functions as a clearance receptor specific for proIAPP, protecting against islet amyloid deposition and associated cell death caused by IAPP.

cell biology↗

bioRxiv2021

Bcl-xL restricts transcriptional, morphological and functional decompensation of β-cell mitochondria under chronic glucose excess

In the progression of diabetes, pancreatic islet {beta}-cells respond to increased metabolic demand with functional compensation, followed by pathogenic decompensation of mitochondria-dependent insulin secretion. It is not clear what mechanisms drive, or control, mitochondrial decompensation. Here, we report that anti-apoptotic Bcl-xL maintains mitochondrial integrity in {beta}-cells under non-apoptotic levels of glucose stress. Prolonged glucose excess causes transcriptional reprogramming of glycolysis and {beta}-cell identity genes, while sensitizing glucose-stimulated Ca2+ signaling and insulin secretion. Deletion of Bcl-xL amplifies this insulin hypersecretion and increases mitochondrial fusion, mitochondrial volume, and oxygen consumption, whereas ATP-coupled respiration and mitochondrial hyperpolarization become impaired. Of note, Bcl-xL-deficient {beta}-cells have impaired Pgc-1 expression, and develop specific defects in the expression of Tfam, mitochondrial ribosomal genes, and OXPHOS components under glucose stress. Bcl-xL limits high glucose-induced mitochondrial ROS (mitoROS) levels and pharmacological normalization of mitoROS in Bcl-xL KO cells rescues glucose-induced defects in mitochondrial gene expression and changes to {beta}-cell identity. Our data identify mitoROS as a primary retrograde driver of transcriptional re-wiring in {beta}-cells exposed to excess glucose, and reveal Bcl-xL as an important safeguard against transcriptional and functional decompensation of {beta}-cell mitochondria. Bcl-xL and mitoROS may thus be viable targets to prevent early {beta}-cell dysfunction and the progression of diabetes.

cell biology↗