Transcytosis of Albumin in Astrocytes Activates the Sterol Regulatory Element-binding Protein-1, Which Promotes the Synthesis of the Neurotrophic Factor Oleic Acid

Abstract

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.

Glial transcytosis of a photoreceptor‐secreted signaling protein, retinoschisin

“…Although Mü ller cell transport of proteins secreted by other cells has not been shown before, it is known that glial cells, having an elaborate system for protein trafficking (Larocca and Rodriguez-Gabin, 2002), can deliver serum albumin across the blood-brain barrier into the gray matter (Tabernero et al, 2002). Our results suggest that Mü ller cells take in retinoschisin from their distal processes, and then deliver it into the inner retina where it interacts with bipolar cells (Reid et al, 2003) and other retinal components.…”

Serum albumin protects from cytokine-induced pancreatic β cell death by a phosphoinositide 3-kinase-dependent mechanism

“…It might therefore be speculated that albumin contrary to ovalbumin might protect against cytokines through binding of fatty acids. Preincubation of INS-1E cells for 4 h with bovine serum albumin (11 mg/ml) for extraction and binding of fatty acids [14,35] or culture in serum free media did, however, not decrease the ensuing sensitivity to cytokines or affect the protective effect of albumin during cytokine exposure (results not given).…”

“…With plasma levels ranging from 35 to 50 mg/ml [10], albumin is the most important antioxidant in serum. In addition, albumin is also present at appreciable, although lower levels in the extra vascular compartment [11], and cellular uptake of albumin by receptor-mediated endocytosis is well documented [12][13][14]. In this context, albumin binding to cell surface receptors like megalin may protect from apoptosis through activation of intracellular signaling cascades and activate PI3K and/or p44/p42 MAPK as observed in some cell types [15][16][17][18][19].…”

Endogenous Agents That Contribute to Generate or Prevent Ischemic Damage

“…It is shown that albumin affects metabolism of cultured astrocytes (Tabernero et al, 1999). Albumin up on transcytosis into cultured astrocytes stimulates the synthesis of neurotrophic factor oleic acid which promotes neuronal differentiation (Tabernero et al, 2002). Megalin is a receptor for albumin in astrocytes and is required for the synthesis of the neurotrophic factor oleic acid (BentoAbreu et al, 2008).…”