We have recently reported that albumin, a serum protein present in the developing brain, stimulates the synthesis of oleic acid by astrocytes, which promotes neuronal differentiation. In this work, we gain insight into the mechanism by which albumin induces the synthesis of this neurotrophic factor. Our results show that astrocytes internalize albumin in vesicle-like structures by receptor-mediated endocytosis. Albumin uptake was followed by transcytosis, including passage through the endoplasmic reticulum, which was required to induce the synthesis of oleic acid. Oleic acid synthesis is feedback-regulated by the sterol regulatory element-binding protein-1, which induces the transcription of stearoylCoA 9-desaturase, the key rate-limiting enzyme for oleic acid synthesis. In our research, the presence of albumin activated the sterol regulatory element-binding protein-1 and increased stearoyl-CoA 9-desaturase mRNA. Moreover, when the activity of sterol regulatory element-binding protein-1 was inhibited by overexpression of a truncated form of this protein, albumin did not affect stearoyl-CoA 9-desaturase mRNA, indicating that the effect of albumin is mediated by this transcription factor. The effect of albumin was abolished when traffic to the endoplasmic reticulum was prevented or when albumin was accompanied with oleic acid. In conclusion, our results suggest that the transcytosis of albumin includes passage through the endoplasmic reticulum, where oleic acid is sequestrated, initiating the signal cascade leading to an increase in its own synthesis.Astrocytes, the main glial cell population in the central nervous system, play a major role in supporting the development of neurons. In fact, astrocytes synthesize and release extracellular matrix proteins and adhesion molecules, which participate not only in the migration of neurons but also in the formation of neuronal aggregates. In addition, astrocytes produce a broad spectrum of growth factors and cytokines, which can regulate the morphology, proliferation, differentiation, and survival of neurons (for a review, see Ref.