Activation of Peroxisome Proliferator-Activated Receptor-β/δ (PPARβ/δ) in Keratinocytes by Endogenous Fatty Acids

• Published in: Biomolecules (Basel, Switzerland) Vol. 14; no. 6; p. 606
• Main Authors: Zhu, Bokai, Zhu, Xiaoyang, Borland, Michael G, Ralph, Douglas H, Chiaro, Christopher R, Krausz, Kristopher W, Ntambi, James M, Glick, Adam B, Patterson, Andrew D, Perdew, Gary H, Gonzalez, Frank J, Peters, Jeffrey M
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 21.05.2024; MDPI
• Subjects: Angiopoietin; Angiopoietin-Like Protein 4 - genetics; Angiopoietin-Like Protein 4 - metabolism; Animals; Biotechnology; Carcinogenesis; Cell activation; Cell cycle; Cell proliferation; Chromatin; Desaturase; DNA binding proteins; Fatty acids; Fatty Acids - metabolism; Fatty Acids, Monounsaturated - metabolism; Fatty Acids, Monounsaturated - pharmacology; Genes; Humans; Keratinocytes; Keratinocytes - drug effects; Keratinocytes - metabolism; Ligands; Lipids; Melanoma; Mice; Monounsaturated fatty acids; Nuclear receptors; Oleic acid; Oleic Acid - pharmacology; peroxisome proliferator-activated receptor; Peroxisome proliferator-activated receptors; Polymerase chain reaction; PPAR delta - genetics; PPAR delta - metabolism; PPAR-beta - genetics; PPAR-beta - metabolism; Proteins; Proto-Oncogene Proteins p21(ras) - genetics; Proto-Oncogene Proteins p21(ras) - metabolism; RNA polymerase; Skin; Skin cancer; Skin Neoplasms - genetics; Skin Neoplasms - metabolism; Skin Neoplasms - pathology; Solvents; Stearoyl-CoA Desaturase - genetics; Stearoyl-CoA Desaturase - metabolism; Transcription factors; UVB-induced non-melanoma skin cancer; United States > US; ligands; UVB-induced non-melanoma skin cancer; peroxisome proliferator-activated receptor; fatty acids; cell cycle
• ISSN: 2218-273X; 2218-273X
• DOI: 10.3390/biom14060606

Nuclear hormone receptors exist in dynamic equilibrium between transcriptionally active and inactive complexes dependent on interactions with ligands, proteins, and chromatin. The present studies examined the hypothesis that endogenous ligands activate peroxisome proliferator-activated receptor-β/δ (PPARβ/δ) in keratinocytes. The phorbol ester treatment or HRAS infection of primary keratinocytes increased fatty acids that were associated with enhanced PPARβ/δ activity. Fatty acids caused PPARβ/δ-dependent increases in chromatin occupancy and the expression of angiopoietin-like protein 4 ( ) mRNA. Analyses demonstrated that stearoyl Co-A desaturase 1 ( ) mediates an increase in intracellular monounsaturated fatty acids in keratinocytes that act as PPARβ/δ ligands. The activation of PPARβ/δ with palmitoleic or oleic acid causes arrest at the G2/M phase of the cell cycle of HRAS-expressing keratinocytes that is not found in similarly treated HRAS-expressing -null keratinocytes. HRAS-expressing -null mouse keratinocytes exhibit enhanced cell proliferation, an effect that is mitigated by treatment with palmitoleic or oleic acid. Consistent with these findings, the ligand activation of PPARβ/δ with GW0742 or oleic acid prevented UVB-induced non-melanoma skin carcinogenesis, an effect that required PPARβ/δ. The results from these studies demonstrate that PPARβ/δ has endogenous roles in keratinocytes and can be activated by lipids found in diet and cellular components.