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2018-03-09

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cc-by-nc-nd (c) W.B. Saunders, 2018
Si us plau utilitzeu sempre aquest identificador per citar o enllaçar aquest document: https://hdl.handle.net/2445/164869

The Bace1 product sAPPβ induces ER stress and inflammation and impairs insulin signaling

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Recurs relacionat

https://doi.org/10.1016/j.metabol.2018.03.005

Resum

Objective -secretase/-site amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1) is a key enzyme involved in Alzheimer's disease that has recently been implicated in insulin-independent glucose uptake in myotubes. However, it is presently unknown whether BACE1 and the product of its activity, soluble APPsAPPcontribute to lipid-induced inflammation and insulin resistance in skeletal muscle cells. Materials/Methods Studies were conducted in mouse C2C12 myotubes, skeletal muscle from Bace1-/-mice and mice treated with sAPP and adipose tissue and plasma from obese and type 2 diabetic patients. Results We show that BACE1 inhibition or knockdown attenuates palmitate-induced endoplasmic reticulum (ER) stress, inflammation, and insulin resistance and prevents the reduction in Peroxisome Proliferator- Activated Receptor  Co-activator 1 (PGC-1) and fatty acid oxidation caused by palmitate in myotubes. The effects of palmitate on ER stress, inflammation, insulin resistance, PGC-1 down-regulation, and fatty acid oxidation were mimicked by soluble APP in vitro. BACE1 expression was increased in subcutaneous adipose tissue of obese and type 2 diabetic patients and this was accompanied by a decrease in PGC-1 mRNA levels and by an increase in sAPPplasma levels of obese type 2 diabetic patients compared to obese non-diabetic subjects. Acute sAPP administration to mice reduced PGC-1 levels and increased inflammation in skeletal muscle and decreased insulin sensitivity. Conclusions Collectively, these findings indicate that the BACE1 product sAPP is a key determinant in ER stress, inflammation and insulin resistance in skeletal muscle and gluconeogenesis in liver.

Matèries

Insulina, Farmacologia, Farmacocinètica, Fisiologia, Resistència a la insulina, Metabolisme, Inflamació, Reticle endoplasmàtic, Ratolins (Animals de laboratori)

Matèries (anglès)

Insulin, Pharmacology, Pharmacokinetics, Physiology, Insulin resistance, Metabolism, Inflammation, Endoplasmic reticulum, Mice (Laboratory animals)

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Articles publicats en revistes (Farmacologia, Toxicologia i Química Terapèutica)
Articles publicats en revistes (Bioquímica i Biomedicina Molecular)
Articles publicats en revistes (Institut de Biomedicina (IBUB))

Citació

BOTTERI, Gaia, et al. The Bace1 product sAPPβ induces ER stress and inflammation and impairs insulin signaling. Metabolism-Clinical and Experimental. 2018. Vol. 85, num. 59-75. ISSN 0026-0495. [consulted: 9 of September of 2026]. Available at: https://hdl.handle.net/2445/164869

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