Regulation of ER stress and insulin pathway by lipids in skeletal muscle
(2014)
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Details
- Authors
- Supervisors
- Francaux, Marc
- Abstract
- The endoplasmic reticulum (ER) functions as a protein folding factory, where polypeptide chains gain their native structure. Disruption of ER homeostasis, referred as ER stress, induces a cellular response called the unfolded protein response (UPR). In the context of obesity, UPR induced by high concentrations in lipids appears as a key actor in the development of insulin resistance in liver and adipose tissue. However, the mechanism of lipid-induced ER stress remains unclear and, the causal link between UPR and insulin resistance is controversial in skeletal muscle. In a first part, we investigated whether a plasma membrane receptor namely the toll-like receptor 4 (TLR4) could be a mediator of lipid-induced ER stress. Wild-type and TLR4-/- mice were fed with standard chow or high-fat diet (HFD). As shown by the UPR-regulated protein BiP, TLR4-/- mice were protected against ER stress induced by HFD in skeletal muscle, liver and adipose tissue. Contrary to our hypothesis, this does not seem due to a direct mechanism but probably arise from a protective effect of TLR4 deficiency on obesity. In a second part, C2C12 myotubes were incubated with hydrogen peroxide (H2O2). ER stress was activated by H2O2 as demonstrated by upregulation of UPR-inducible genes such as ATF4, CHOP and TRB3. This provides an argument to propose oxidative molecules as an intermediate by which lipids induce ER stress. In a third part, the link between UPR and insulin signaling was tested in C2C12 myotubes. Knockdown of TRB3 and IRE1α, two proteins at the interface of UPR and insulin signaling, did not prevent the disruption of insulin signaling caused by palmitate. Muscle cells, contrary to other cells types, do not seem to have the signaling mechanism linking UPR to insulin resistance.
- Affiliations
Citations
Pierre, N. (2014). Regulation of ER stress and insulin pathway by lipids in skeletal muscle. https://hdl.handle.net/2078.5/49734