Cover Story

The pancreas is a mixed gland primarily composed of exocrine tissue, which secretes digestive enzymes into the digestive tract, and an endocrine component organized into small clusters known as islets of Langerhans, constituting approximately 1% of the pancreatic mass. Each adult islet contains an average of 1,500 cells, including beta-, alpha- and delta-cells, which produce and secrete insulin (INS), glucagon (GCG), and somatostatin (SST) respectively. The destruction of insulin-producing beta-cells or the defective insulin secretion give rise to type 1 and type 2 diabetes mellitus, respectively. These chronic metabolic disorders are characterized by the dysregulation of glucose homeostasis. The pathophysiology of diabetes has been extensively studied and beta-cell biology is now described in great details. Glucose is taken up by beta-cells, metabolized and generates an increase in the intracellular ATP:ADP ratio that drives the closure of ATP-sensitive potassium (KATP) channels. This causes membrane depolarization, leading to the activation of voltage-gated calcium channels, which increases intracellular calcium level and initiates insulin secretion. This secretory process is enhanced by signals mediated by insulinotropic Gαs coupled G Protein Coupled Receptors (GPCRs) that increase cAMP levels. For example, this occurs through GCG-, Glucagon-like Peptide 1- (GLP1) and Glucose-dependent insulinotropic polypeptide (GIP)-Receptors, all of which are expressed at the beta-cell surface. In parallel, SST secreted by delta-cells, by acting through its receptors expressed on beta-cells, decreases cAMP levels and insulin secretion. Drugs targeting beta-cell secretion are used to treat patients suffering of type 2 diabetes. They increase insulin secretion by closing the KATP channels (sulfonylureas) or by increasing intracellular cAMP (GLP1R agonists). However, many aspects of pancreatic islet function remain to be further understood. Specifically, more needs to be learned about the role of signals from alpha- and delta-cells on beta-cells within the islets.

Full text

All Articles

HSP70 induces liver X receptor pathway activation and cholesterol reduction in vitro and in vivo

Burcin Gungor, Lauri Vanharanta, Maarit Hölttä-Vuori, Juho Pirhonen, Nikolaj H.T. Petersen, Silvia Gramolelli, Päivi M. Ojala, Thomas Kirkegaard, Elina Ikonen

Heat shock protein 70 (HSP70) is a chaperone that facilitates protein folding and transport, with essential roles in maintaining cell homeostasis and survival. In addition to its chaperone function in proteostasis, HSP70 can act as a signaling molecule. Gungor, Vanharanta, et al. studied the effects of rHSP70 on human primary monocyte-derived macrophage foam cells that accumulate cholesterol, which leads to artherosclerosis. They found that HSP70 exerts atheroprotective effects and that this can be mechanistically explained by HSP70 mediated stimulation of the liver X receptor, the master regulator of cholesterol removal.

Objective: Heat Shock Proteins (HSPs) maintain cellular homeostasis under stress. HSP70 represents a major stress-inducible family member and has been identified as a druggable target in inherited cholesterol-sphingolipid storage diseases. We investigated if HSP70 modulates cholesterol accumulation in more common conditions related to atherogenesis.

Methods: We studied the effects of recombinant HSP70 in cholesterol-laden primary macrophages from human blood donors and pharmacological HSP70 upregulation in high-cholesterol diet fed zebrafish.

Results: Recombinant HSP70 facilitated cholesterol removal from primary human macrophage foam cells. RNA sequencing revealed that HSP70 induced a robust transcriptional re-programming, including upregulation of key targets of liver X receptors (LXR), master regulators of whole-body cholesterol removal. Mechanistically, HSP70 interacted with the macrophage LXRalpha promoter, increased LXRalpha and its target mRNAs, and led to elevated levels of key proteins facilitating cholesterol efflux, including ATP-binding cassette transporters A1 and G1. Pharmacological augmentation of endogenous HSP70 in high-cholesterol diet fed zebrafish activated LXR and its target mRNAs and reduced cholesterol storage at the whole organism level.

Conclusions: These data demonstrate that HSP70 exerts a cholesterol lowering effect in primary human cells and animals and uncover a nuclear action of HSP70 in mediating cross-talk between HSP and LXR transcriptional regulation.