V- Therapeutic targeting of ER dysfunction
Recent studies provide strong evidence in support of a role for ER stress in human metabolic disease. For example, a significant positive correlation between increasing body mass index and expression of various ER stress markers has been evidenced in human subcutaneous adipose tissue. Interestingly when obese patients undergo marked weight loss due to gastric bypass surgery, ER stress markers are decreased in liver and adipose tissue.32 ER stress indicators have been observed in human atherosclerotic lesions, in a manner similar to the vascular lesions in mouse, suggesting that the causal disease mechanisms discovered in mice are also present in human disease and exhibit similar regulation. Therefore, the ER could be an important new target for treating the metabolic complications of obesity. One of the central ER stress defense strategies of the cell is to coordinately up-regulate its chaperoning capacity. Chaperones are specialized proteins that play a key role in cellular homeostasis by assisting in protein folding, assembly of the macromolecular complexes, protein transport, and cellular signaling. There are currently three types of molecules that show chaperone-like activities, namely, the molecular, pharmacological, and chemical chaperones (Hotamisligil, Lecture). Molecular chaperones recognize and bind to their substrates in their non-native states and their main role is to assist protein stabilization, assembly, and translocation across membranes. Many chaperones prevent unstable proteins from aggregating under stress conditions and present the misfolded proteins to the proteolytic machinery for disposal. Molecular chaperones are composed of several distinct classes of proteins called nucleoplasmins, chaperonins, and heat shock proteins (HSP). Pharmacological chaperones are small molecules, generally a ligand or an inhibitor of a mutant protein that reversibly binds and stabilizes the protein rather than assisting the general folding properties. Chemical chaperones are small orally active molecules that modulate ER folding capacity. For example, phenyl butyric acid (PBA) and tauro-ursodeoxycholic acid (TUDCA) have been shown to increase systemic insulin sensitivity, establish normoglycemia, and reduce fatty liver disease in a mouse model of type 2 diabetes. PBA has been approved by US Food and Drug Administration (FDA) for clinical use in urea-cycle disorders in humans and TUDCA has
been used as a liver-protecting agent in human cholestatic liver diseases, which is currently under clinical testing. Additional work is needed to determine whether these molecules can be used for treatments of human obesity and diabetes.1 Alternative therapies to reduce ER stress or to modify organelle function may also involve directly targeting molecules that regulate the UPR. Salubrinal is a small molecule that prevents dephosphorylation of eIF2 alpha. Treatment of cells with salubrinal leads to protection against ER stress induced cell death in vitro and in vivo. However, it is unclear whether this chemical strategy could be beneficial for treating metabolic disease as different cell types respond differently to salubrinal. Intriguingly, some chemicals, such as PPAR agonists or salicylates, that are in clinical trials or currently used for treating type 2 diabetes affect the activity of critical ER molecules. Similar arguments, although speculative, could be made for metformin, rapamycin, or AMP-K activators, which modulate nutrient-sensing and related pathways.
One wonders whether at least some of the metabolically beneficial effects of these agents are due to their ability to modulate ER function or the UPR.2 Finally, another way of relieving ER stress may be through the action of metabolic hormones. Recent data have shown that activation of the receptor for GLP-1 reduces ER stress in pancreatic beta-cells.
A reciprocal relationship may exist wherein some hormones, which depend upon the ER for their translation and secretion, may act on target cells in ways that protect the biological function of that cell thus ensuring continued hormone action, a self-preserving activity. Given the example of GLP-1 receptor activation in relieving ER stressinduced apoptosis, it will be interesting to investigate other hormones for such potential protective effects.2
“The Stressed Beta-Cell”
I- ER and the canonical unfolded protein response (UPR)
II- When UPR leads to cell death
III- Cellular stress in type 2 diabetes
IV- The mitochondria and cellular stress
V- Therapeutic targeting of ER dysfunction