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

The cellular mechanisms that determine whether excess lipid accumulation is tolerated or cytotoxic remain poorly understood. The present study examined the effects of fatty acid composition on endoplasmic reticulum (ER) homeostasis and apoptosis in liver cells. Primary rat hepatocytes or a rat hepatoma cell line, H4IIE, were exposed to varying concentrations (25–500 μM) of albumin‐bound saturated (palmitate or stearate) or unsaturated fatty acids (oleate or linoleate) for 6 or 16 h (n=5–7/cell type/treatment). Apoptosis was monitored using expression of the pro‐apoptotic gene, CHOP; caspase‐3 activity; DNA laddering. ER stress was monitored using known markers of the ER stress response pathway: phosphorylation of eIF2α, splicing of XBP1; expression of ER chaperones, GRP78, GRP94. In both cell types, palmitate and stearate, at a fatty acid to albumin ratio of 1:1, increased ER stress, CHOP expression and caspase‐3 activity at 6 h and DNA laddering at 16 h. No effects were observed when cells were incubated with unsaturated fatty acids. Increasing the saturated fatty acid to albumin ratio (1:1, 2:1, 4:1, 6:1) lead to a dose‐dependent increase in ER stress and apoptosis. In contrast, no effects were observed when cells were incubated with unsaturated fatty acids at similar fatty acid to albumin ratios. In summary, saturated fatty acids potently induce ER stress and apoptosis in liver cells. These effects were exacerbated by an increased fatty acid to albumin ratio. Thus, saturated fatty acids and the saturated fatty acid to albumin ratio combine to promote liver cell stress and injury. Supported by NIH grant DK072017.