Elevated plasma concentration of the pro-atherogenic oxidized low density lipoprotein cholesterol (LDL) triggers adverse effects in pancreatic beta-cells and is associated with type 2 diabetes. Here, we investigated whether the endoplasmic reticulum (ER) stress is a key player coupling oxidative stress to beta-cell dysfunction and death elicited by human oxidized LDL. We found that human oxidized LDL activates ER stress as evidenced by the activation of the inositol requiring 1α, and the elevated expression of both DDIT3 (also called CHOP) and DNAJC3 (also called P58IPK) ER stress markers in isolated human islets and the mouse insulin secreting MIN6 cells. Silencing of Chop and inhibition of ER stress markers by the chemical chaperone phenyl butyric acid (PBA) prevented cell death caused by oxidized LDL. Finally, we found that oxidative stress accounts for activation of ER stress markers induced by oxidized LDL. Induction of Chop/CHOP and p58IPK/P58IPK by oxidized LDL was mimicked by hydrogen peroxide and was blocked by co-treatment with the N-acetylcystein antioxidant. As a conclusion, the harmful effects of oxidized LDL in beta-cells requires ER stress activation in a manner that involves oxidative stress. This mechanism may account for impaired beta-cell function in diabetes and can be reversed by antioxidant treatment.
The impact of the amount of dietary α‐linolenic acid (ALA) on its own tissue accumulation and conversion to longer n‐3 polyunsaturated fatty acids (PUFAs) remains controversial and may depend on the other dietary fatty acids mixed with ALA. Whereas linoleic acid (LA) is well known to compete with ALA for its conversion to longer n‐3 PUFAs, the concomitant presence of dietary ALA with dairy saturated fatty acids (C4:0–C14:0) that are highly susceptible to β‐oxidation may inversely lead to its increased cellular storage and better conversion to long‐chain n‐3 PUFAs. The present study was therefore aimed at investigating further the putative beneficial effect of dietary dairy fat on n‐3 PUFA tissue levels in the rat. Firstly, we showed that when combined with a well‐defined dietary level of ALA (0.6% energy), substitution of olive oil for butterfat improved ALA storage in adipose tissue and liver, and had moderate effects on its conversion to n‐3 long‐chain PUFAs. Secondly, we showed that, when mixed with dairy fat, a small increase in dietary ALA (from 0.6 to 0.8% of energy) enhanced the ALA storage in adipose tissue only but conversely significantly increased its conversion to highly unsaturated n‐3 PUFAs in the liver. Practical applications: α‐linolenic acid (ALA) is the most accessible source of n‐3 PUFAs in the global diet. However, the intake of ALA is currently lower than dietary guidelines and the rate of ALA conversion to longer chain n‐3 PUFAs is low. The results from this study showed that a small enrichment in dietary ALA combined with dairy fat increased adipose tissue ALA storage, which represents a slow releasable pool that may be utilized over time by other tissues and greatly increased the conversion of ALA to highly unsaturated n‐3 PUFAs in the liver. This knowledge may possibly result in the development of new dietary strategies to increase the cellular level of n‐3 PUFAs in animals and humans. When mixed with dairy fat, a small increase in dietary α‐linolenic acid (from 0.6 to 0.8% of energy) enhances the α‐linolenic acid storage in adipose tissue and significantly increases its conversion to highly unsaturated n‐3 polyunsaturated fatty acids in the liver.
Preservation of beta cell against apoptosis is one of the therapeutic benefits of the glucagon-like peptide-1 (GLP1) antidiabetic mimetics for preserving the functional beta cell mass exposed to diabetogenic condition including proinflammatory cytokines. The mitogen activated protein kinase 10 also called c-jun amino-terminal kinase 3 (JNK3) plays a protective role in insulin-secreting cells against death caused by cytokines. In this study, we investigated whether the JNK3 expression is associated with the protective effect elicited by the GLP1 mimetic exendin 4. We found an increase in the abundance of JNK3 in isolated human islets and INS-1E cells cultured with exendin 4. Induction of JNK3 by exendin 4 was associated with an increased survival of INS-1E cells. Silencing of JNK3 prevented the cytoprotective effect of exendin 4 against apoptosis elicited by culture condition and cytokines. These results emphasize the requirement of JNK3 in the antiapoptotic effects of exendin 4.
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