Bosma Madeleen, Dapito Dianne H, Drosatos-Tampakaki Zoi, Huiping-Son Ni, Huang Li-Shin, Kersten Sander, Drosatos Konstantinos, Goldberg Ira J
Biochim Biophys Acta. 2014 Dec;1841(12):1648-55. doi: 10.1016/j.bbalip.2014.09.012.
We used human cardiomyocyte-derived cells to create an in vitro model to study lipid metabolism and explored the effects of PPARγ; ACSL1 and ATGL on fatty acid-induced ER stress. Compared to oleate, palmitate treatment resulted in less intracellular accumulation of lipid droplets and more ER stress, as measured by upregulation of CHOP, ATF6 and GRP78 gene expression and phosphorylation of eukaryotic initiation factor 2a (EIF2a). Both ACSL1 and PPARγ adenovirus-mediated expression augmented neutral lipid accumulation and reduced palmitate-induced upregulation of ER stress markers to levels similar to those in the oleate and control treatment groups. This suggests that increased channeling of non-esterified free fatty acids (NEFA) towards storage in the form of neutral lipids in lipid droplets protects against palmitate-induced ER stress. Overexpression of ATGL in cells incubated with oleate-containing medium increased NEFA release and stimulated expression of ER stress markers. Thus, inefficient creation of lipid droplets as well greater release of stored lipids induces ER stress.
我们使用人源心肌细胞衍生细胞构建了一个体外模型来研究脂质代谢，并探究过氧化物酶体增殖物激活受体γ（PPARγ）、长链脂酰辅酶A合成酶1（ACSL1）和脂肪甘油三酯脂肪酶（ATGL）对脂肪酸诱导的内质网应激的影响。与油酸处理相比，棕榈酸处理导致脂滴的细胞内积累减少，内质网应激增加，这通过CHOP、ATF6和GRP78基因表达上调以及真核起始因子2α（EIF2α）磷酸化来衡量。ACSL1和PPARγ腺病毒介导的表达均增加了中性脂质积累，并将棕榈酸诱导的内质网应激标志物上调降低至与油酸和对照处理组相似的水平。这表明，增加非酯化游离脂肪酸（NEFA）以中性脂质形式储存于脂滴中的通道化作用可预防棕榈酸诱导的内质网应激。在含油酸培养基中培养的细胞中过表达ATGL会增加NEFA释放并刺激内质网应激标志物的表达。因此，脂滴生成效率低下以及储存脂质释放增加会诱导内质网应激。
