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Am J Physiol Endocrinol Metab (February 21, 2006). doi:10.1152/ajpendo.00644.2005
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Submitted on December 21, 2005
Accepted on February 13, 2006

Saturated fatty acids induce endoplasmic reticulum stress and apoptosis independently of ceramide in liver cells

Yuren Wei1, Dong Wang1, Farran Topczewski1, and Michael J Pagliassotti1*

1 Department of Food Science and Human Nutrition, Colorado State University, Fort Collins, CO, USA

* To whom correspondence should be addressed. E-mail: pagliasm{at}cahs.colostate.edu.

Accumulation of lipids in non-adipose tissues can lead to cell dysfunction and cell death, a phenomenon known as lipotoxicity. However, the signaling pathways and mechanisms linking lipid accumulation to cell death are poorly understood. The present study examined the hypothesis that saturated fatty acids disrupt endoplasmic reticulum (ER) homeostasis and promote apoptosis in liver cells via accumulation of ceramide. H4IIE liver cells were exposed to varying concentrations of saturated (palmitate or stearate) or unsaturated (oleate or linoleate) fatty acids. ER homeostasis was monitored using markers of the ER stress response pathway including phosphorylation of IRE1{alpha} and eIF2{alpha}, splicing of XBP1 mRNA, and expression of molecular chaperone (e.g. GRP78) and pro-apoptotic (CHOP) genes. Apoptosis was monitored using caspase activity and DNA laddering. Palmitate and stearate induced ER stress, caspase activity and DNA laddering. Inhibition of caspase activation prevented DNA laddering. Unsaturated fatty acids did not induce ER stress or apoptosis. Saturated fatty acids increased ceramide concentration; however, inhibition of de novo ceramide synthesis did not prevent saturated fatty acid-induced ER stress and apoptosis. Unsaturated fatty acids rescued palmitate-induced ER stress and apoptosis. These data demonstrate that saturated fatty acids disrupt ER homeostasis and induce apoptosis in liver cells via mechanisms that do not involve ceramide accumulation.




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