Abstract
Cell dysfunction and death induced by lipid accumulation in nonadipose tissues, or lipotoxicity, may contribute to the pathogenesis of obesity and type 2 diabetes. However, the mechanisms leading to lipotoxic cell death are poorly understood. We recently reported that, in Chinese hamster ovary (CHO) cells and in H9c2 cardiomyoblasts, lipid overload induced by incubation with 500 muM palmitate leads to intracellular accumulation of reactive oxygen species, which subsequently induce endoplasmic reticulum (ER) stress and cell death. Here, we show that palmitate also impairs ER function through a more direct mechanism. Palmitate was rapidly incorporated into saturated phospholipid and triglyceride species in microsomal membranes of CHO cells. The resulting membrane remodeling was associated with dramatic dilatation of the ER and redistribution of protein-folding chaperones to the cytosol within 5 h, indicating compromised ER membrane integrity. Increasing beta-oxidation, through the activation of AMP-activated protein kinase, decreased palmitate incorporation into microsomes, decreased the escape of chaperones to the cytosol, and decreased subsequent caspase activation and cell death. Thus, palmitate rapidly increases the saturated lipid content of the ER, leading to compromised ER morphology and integrity, suggesting that impairment of the structure and function of this organelle is involved in the cellular response to fatty acid overload.
Highlights
Cell dysfunction and death induced by lipid accumulation in nonadipose tissues, or lipotoxicity, may contribute to the pathogenesis of obesity and type 2 diabetes
A significant proportion of [3H]palmitate was associated with the relatively pure rough microsomal fraction, composed predominantly of rough endoplasmic reticulum (ER), the crude mitochondria were contaminated with rough microsomes (Fig. 1C), indicating that the calculated percentage distribution underestimates the incorporation of palmitate into the rough ER
Exogenous saturated and unsaturated FAs are channeled quickly to the ER as well as to the mitochondria. This distribution is independent of lipotoxicity, which occurs in Chinese hamster ovary (CHO) cells treated with palmitate but not in CHO cells treated with oleate or SCD1overexpressing cells treated with palmitate [27]
Summary
Cell dysfunction and death induced by lipid accumulation in nonadipose tissues, or lipotoxicity, may contribute to the pathogenesis of obesity and type 2 diabetes. Relatively few studies have focused on mechanisms of palmitateinduced cell death in cardiomyocytes, recent evidence obtained using primary cardiomyocyte cultures from embryonic chicks and neonatal rats suggests that incubation with palmitate is associated with the loss of mitochondrial membrane potential, mitochondrial swelling, and cytochrome c release [9,10,11] These events may be initiated via several mechanisms, including decreased synthesis of the signature mitochondrial membrane phospholipid, cardiolipin [11], increased ceramide synthesis [9, 12], and increased generation of reactive oxygen species (ROS) [13, 14]. Our studies revealed that palmitate-induced ER stress was mediated, in part, through the generation of ROS [14]
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