The role of mitofusin 2 in saturated fatty acid induced ER stress in H4IIE liver cells (1116.4)

Abstract

Genetic ablation of mitofusin 2 (Mfn2) in mice results in ER stress and insulin resistance in the liver. In liver cells, saturated fatty acids (SFA) induce ER stress and activate c‐Jun NH2 terminal kinase (JNK) which can mediate Mfn2 degradation. We hypothesized that SFA would reduce Mfn2 expression. We examined the effects of the unsaturated fatty acid oleate (O250µM) and the SFA palmitate (P250 µM) on Mfn2 mRNA, translation and protein expression in H4IIE liver cells (n=3). O250 µM and P250 µM had no significant effect on Mfn2 mRNA. P250 µM significantly increased Mfn2 translational efficiency based on polysome profiling, however no increase in Mfn2 protein expression was observed. JNK‐mediated degradation of Mfn2 involves serine phosphorylation (pSer) and ubiquitination (Ub), however P250 µM did not increase pSer or Ub of Mfn2. These data suggest that either the increase in translational efficiency was not sufficient to alter Mfn2 protein levels or that Mfn2 degradation occurs via mechanisms independent of pSer and Ub. We utilized si‐RNA mediated knockdown of Mfn2 to determine whether Mfn2 could protect against palmitate‐induced ER stress (n=3). Knockdown of Mfn2 had no significant effect on thapsigargin (Thap) or P250 µM ‐induced ER stress in H4IIE cells. These findings indicate that Mfn2 does not appear to play a protective role in Thap or P250 µM mediated ER stress in H4IIE cells.Grant Funding Source: NIH DK 072017