Oxidative stress and calcium dysregulation by palmitate in type 2 diabetes

Abstract

Free fatty acids (FFAs) are important substrates for mitochondrial oxidative metabolism and ATP synthesis but also cause serious stress to various tissues, contributing to the development of metabolic diseases. CD36 is a major mediator of cellular FFA uptake. Inside the cell, saturated FFAs are able to induce the production of cytosolic and mitochondrial reactive oxygen species (ROS), which can be prevented by co-exposure to unsaturated FFAs. There are close connections between oxidative stress and organellar Ca2+ homeostasis. Highly oxidative conditions induced by palmitate trigger aberrant endoplasmic reticulum (ER) Ca2+ release and thereby deplete ER Ca2+ stores. The resulting ER Ca2+ deficiency impairs chaperones of the protein folding machinery, leading to the accumulation of misfolded proteins. This ER stress may further aggravate oxidative stress by augmenting ER ROS production. Secondary to ER Ca2+ release, cytosolic and mitochondrial matrix Ca2+ concentrations can also be altered. In addition, plasmalemmal ion channels operated by ER Ca2+ depletion mediate persistent Ca2+ influx, further impairing cytosolic and mitochondrial Ca2+ homeostasis. Mitochondrial Ca2+ overload causes superoxide production and functional impairment, culminating in apoptosis. This vicious cycle of lipotoxicity occurs in multiple tissues, resulting in β-cell failure and insulin resistance in target tissues, and further aggravates diabetic complications.

The role of Cox‐2 and prostaglandin E 2 receptor EP3 in pancreatic β‐cell death

“…This ER stress may further aggravate oxidative stress by augmenting ROS production. This vicious cycle of lipotoxicity results in β‐cell failure and apoptosis (5).…”

Iron overload by transferrin receptor protein 1 regulation plays an important role in palmitate‐induced insulin resistance in human skeletal muscle cells

“…At a single nerve terminal, calcium/ calmodulin can initiate various forms of endocytosis (20). Calcium levels are often increased by PA treatment, subsequently inducing insulin resistance (22,23) through the following possible mechanisms. PA inhibits calcium entering the ER (55) or activates calcium release from the ER (56,57), thus further augmenting extracellular calcium influx through store-operated channels, subsequently increasing cytosolic and mitochondrial Ca 2+ overload (57), triggering mitochondrial damage and reactive oxygen species generation, and, ultimately, inducing insulin resistance (22).…”

“…PA may induce ER stress and ER Ca 2+ depletion, thus accelerating persistent calcium influx. This process can induce mitochondrial damage and generate reactive oxygen species, resulting in insulin resistance (22,23). Thus, PA may influence intracellular calcium to regulate intracellular iron levels through tfR1 modulation, ultimately resulting in insulin resistance.…”

<b><i>Euodia daniellii</i></b> Hemsl. (Bee-Bee Tree) Oil Attenuates Palmitate-Induced Lipid Accumulation and Apoptosis in Hepatocytes

“…Palmitate induces ER stress through palmitoyl CoA-mediated reactive oxygen species production and calcium dysregulation [27]. Furthermore, ER stress plays a causative role in the development of hepatic steatosis [28].…”