PPARγ-Mediated and Arachidonic Acid–Dependent Signaling Is Involved in Differentiation and Lipid Production of Human Sebocytes

Abstract

The transcriptional basis of sebocyte differentiation and lipid production is mostly unclear. Peroxisome proliferator-activated receptor gamma (PPARγ), a lipid-activated transcription factor, has been implicated in differentiation and lipid metabolism of various cell types. Here, we show that PPARγ is differentially expressed in normal and pathological human sebocytes and appears to have roles in their differentiation and lipid production. We used laser-microdissected normal and pathological human sebaceous glands (SGs) and SZ95 cells (immortalized sebocyte cell line) analyzed by real-time quantitative PCR and immunohistochemistry. Lipids were analyzed by quantitative fluorimetry- and mass spectrometry-based approaches. We have observed that PPARγ and its target genes, ADRP (adipose differentiation-related protein) and PGAR (PPARγ angiopoietin-related protein), are expressed in sebocytes and show association with their level of differentiation. Also, PPARγ is present in normal and hyperplastic SG, whereas its expression levels are decreased in SG adenoma and SG carcinoma cells, reflecting a maturation-linked expression pattern. Furthermore, in SZ95 sebocytes, naturally occurring lipids, including arachidonic acid and arachidonic acid keto-metabolites (e.g., 5-KETE (5-oxo-6E,8Z,11Z,14Z-eicosatetraenoic acid), 12-KETE (12-oxo-5Z,8Z,10E,14Z-eicosatetraenoic acid)), appear to regulate PPARγ signaling pathways, which in turn modulate phospholipid biosynthesis and induce neutral lipid synthesis. Collectively, our findings highlight the importance of endogenous ligand-activated PPARγ signaling in human sebocyte biology and suggest that PPARγ might be a promising candidate for the clinical management of SG disorders.

Insulin and insulin-like growth factor-1 can modulate the phosphoinositide-3-kinase/Akt/FoxO1 pathway in SZ95 sebocytes in vitro

“…FoxO1 translocation via the growth factors activates peroxisome proliferator-activated receptor-g (PPAR-g) target genes (Fan et al, 2009;Fan et al, 2007) that regulate SZ95 sebocyte lipogenesis (Chen et al, 2003). Furthermore, FoxO1 antagonizes PPAR-g activity through disruption of DNA binding activity of PPAR-g/retinoid X receptora (RXRa) heterodimeric complex which is present in SZ95 ( (Dowell et al, 2003;Dozsa et al, 2014). Additionally, in SEB-1 sebocytes, IGF-1 stimulated sterol regulatory element binding protein-1 (SREBP-1) expression, as the most important transcription factor of lipogenesis, via activation of the PI3K/Akt pathway (assessed after 24 h-which is a long period time for signal transduction pathway readout) and hence increased lipogenesis a (Smith et al, 2006;Smith et al, 2007a,b).…”

Beyond acne: Current aspects of sebaceous gland biology and function

“…Treatment of these cells with linoleic acid, a ligand for PPARδ and γ, increases the intracellular content of lipids [60]. Arachidonic acid couples to PPARγ to induce differentiation and lipid production in human sebocytes [62,63]. However, the activity of PPAR agonists seems to be complex: PPARγ agonists have been shown to increase sebum production in adults with diabetes and hyperlipidemia [64].…”

Sebaceous Gland Atrophy in Psoriasis: An Explanation for Psoriatic Alopecia?

“…We identified one module of coordinately-expressed NN transcripts (module N5) that was highly enriched for genes involved in the metabolism of lipids and lipoproteins (p = 3 x 10 −40 ). Another module (N17) was enriched (p = 1.5 x 10 −11 ) for genes in the peroxisome proliferator activator receptor-γ (PPAR-γ) signaling pathway, which plays a central role in adipocyte differentiation (Alestas et al, 2006, Dozsa et al, 2014, Tontonoz and Spiegelman, 2008). Both modules manifested a high proportion of significantly down-regulated genes (28.8% and 52.5%, respectively) (Li, Tsoi, 2014).…”