Kahweol activates the Nrf2/HO-1 pathway by decreasing Keap1 expression independently of p62 and autophagy pathways

• Published in: PloS one 2020-10, Vol.15 (10), p.e0240478
• Main Authors: Seo, Hye-Young, Lee, So-Hee, Lee, Ji-Ha, Hwang, Jae Seok, Kim, Mi Kyung, Jang, Byoung Kuk
• Format: Article
• Language: English
• Subjects: Animals; Antibodies; Antioxidants; Antioxidants - pharmacology; Apoptosis; Autophagy; Autophagy (Cytology); Autophagy-Related Protein 7 - physiology; Beans; Beverages; Biology and Life Sciences; Care and treatment; Cell death; Cell Survival; Cells, Cultured; Cellular signal transduction; Coffee; Coffee (Beverage); Diterpenes; Diterpenes - pharmacology; Engineering and Technology; Gene expression; Genetic aspects; Health aspects; Heme oxygenase (decyclizing); Heme Oxygenase-1 - genetics; Heme Oxygenase-1 - metabolism; Hepatocytes; Hepatocytes - drug effects; Hepatocytes - metabolism; Hepatocytes - pathology; Homeostasis; Hydrogen Peroxide - metabolism; Internal medicine; Liver diseases; Male; Medicine; Medicine and Health Sciences; Membrane Proteins - genetics; Membrane Proteins - metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; mRNA; NF-E2-Related Factor 2 - genetics; NF-E2-Related Factor 2 - metabolism; Oxidative stress; p62 Protein; Phagocytosis; Proteins; Reactive Oxygen Species - metabolism; Research and Analysis Methods; RNA-Binding Proteins - genetics; RNA-Binding Proteins - metabolism; Signaling peptides and proteins; Transcription factors; Ubiquitin - metabolism; Ubiquitination
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0240478

Kahweol is a diterpene found in coffee beans and unfiltered coffee drinks. Several studies have demonstrated that kahweol induces the nuclear factor erythroid-2 related factor 2/ hemeoxygenase-1 (Nrf2/HO-1) pathway; however, the mechanisms involved are currently unknown. Kelch-like ECH-associated protein 1 (Keap1) is a major regulator of Nrf2 expression and is degraded mostly by autophagy. The p62 protein enhances binding to Keap1 and contributes to the activation of Nrf2. Here, we examined the role of Keap1 regulation in the effect of kahweol on the Nrf2/HO-1 pathway in hepatocytes. In AML12 cells and primary mouse hepatocytes, kahweol increased the levels of Nrf2 and HO-1 protein without increasing expression of the Nrf2 mRNA. In addition, kahweol reduced Keap1 protein levels significantly without decreasing Keap1 mRNA levels. Although regulation of the Keap1-Nrf2-pathway by p62-dependent autophagy is well known, we confirmed here that the reduction of Keap1 protein levels by kahweol does not involve p62-dependent autophagy degradation or ubiquitination. In conclusion, kahweol increases the expression of Nrf2 in hepatocytes by inhibiting translation of the Keap1 mRNA.