Novel potential determinants in endoplasmic reticulum stress, inflammation and insulin resistance: Apo CIII and sAPPβ

Abstract

Diabetes represents one of the biggest health challenges of the 21st century. Insulin resistance is the primary defect in the most common form of diabetes, type 2 diabetes mellitus (T2D), and is defined as a failure in the capacity of insulin to drive glucose into its target tissues. This condition both predicts and precedes the development of T2D. Loss of insulin sensitivity in skeletal muscle is the major defect in T2D and is believed to be critical in the pathogenesis of this disease. Elucidating new molecular mechanisms involved in insulin resistance in skeletal muscle may lead to the development of new strategies for the prevention and treatment of T2D. Insulin resistance develops as the result of the expansion of adipose tissue in obese individuals, which releases increased amounts of fatty acids, hormones, pro-inflammatory cytokines and other factors. Most of these molecules induce the activation of a chronic low-level inflammatory process that contributes to insulin resistance and T2D. The molecular mechanisms by which these molecules induce a low-grade and chronic inflammatory process in obese patients are not completely understood. However, some studies have shown that alterations in the endoplasmic reticulum (ER) might contribute to the development of an inflammatory status and consequently to insulin resistance. Obesity and insulin resistance are also characterized by the presence of atherogenic dyslipidemia, which refers to elevated levels of triglycerides (TG) and the particles responsible for carrying these lipids in the plasma, the very low-density lipoproteins (VLDL), low levels of high-density lipoproteins (HDL), and increased levels of small, dense low-density lipoproteins (sdLDL). In addition to TG, VLDL also contain apolipoproteins, of which apolipoprotein CIII (Apo CIII) is one of the most abundant. Although plasma levels of VLDL and Apo CIII are increased in diabetic patients, little was known about whether the increase in the levels of these lipoproteins and apolipoproteins contributes to exacerbate insulin resistance and the mechanisms involved. Recent evidence indicates that subjects suffering T2D are at higher risk of developing Alzheimer’s Disease (AD). In addition, several evidences point out that the converse is also true, since cognitive impairment and Alzheimer’s dementia can induce central and peripheral insulin resistance, thus increasing the risk of T2D. The β-site Amyloid precursor protein Cleaving Enzyme 1 (BACE1) or β-secretase is a key enzyme involved in AD and is responsible for the cleavage of Amyloid Precursor Protein in the amyloidogenic pathway. It has been recently reported that BACE1 is also implicated in glucose metabolism. Thus, BACE1-deficient mice are protected against high fat diet (HFD)-induced glucose intolerance and inhibition of BACE1 activity increases insulin-independent glucose uptake. BACE1 is proteolytically active not only in the brain but also in skeletal muscle, suggesting that this enzyme might be involved in development of systemic insulin resistance. However, little was known about whether BACE1 contributes to ER stress, inflammation and insulin resistance. In this thesis, we report that the increase in the levels of VLDL can promote ER stress, inflammation, and insulin resistance in skeletal muscle through Apo CIII-mediated activation of the toll-like receptor 2. Moreover, BACE1 inhibition in myotubes results in an improvement in lipid-induced ER stress, inflammation, and insulin resistance. Further, the product of BACE1 enzymatic activity, soluble amyloid precursor protein β (sAPPβ), mimics the effects of palmitate and induces ER stress, inflammation and insulin resistance. Overall, these findings suggest that both VLDL-Apo CIII and sAPPβ are new determinants involved in ER stress, inflammation and insulin resistance in skeletal muscle.