Excess fatty acids can disrupt membrane and organelle function. Cells buffer fatty acid toxicity by synthesizing and storing triglycerides (TGs) in lipid droplets, but their capacity for TG storage is limited. Here, using hepatocytes with impaired TG synthesis, we identified adaptive pathways that restore homeostasis during lipid overload. One arm of the response is transcriptional activation of peroxisome proliferator-activated receptors to promote fatty acid oxidation. The other suppresses sterol regulatory element-binding protein 1 (SREBP1)-mediated lipogenesis, reducing fatty acid synthesis and desaturation. Mechanistically, SREBP1 cleavage-activation occurs with changes in membrane fluidity: impaired TG synthesis increased membrane fluidity and suppressed SREBP1 activation, whereas saturated fatty acids exerted opposite effects. These findings reveal feedback regulation that maintains fatty acid homeostasis by coordinating their synthesis and oxidation. They also support a model in which ER membrane fluidity regulates SREBP1 activity to maintain membrane lipid homeostasis, a finding with broad implications for physiology and disease.
Xiang, X., Ambaw, Y. A., Tok, O., Hui, S., Tang, W.-c., Mizrak, A., Zhang, Q., Cohen-Abeles, L., Farese, R. C., Walther, T. C.
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