PUBLICATION
27-Hydroxycholesterol induces liver fibrosis via down-regulation of trimethylation of histone H3 at lysine 27 by activating oxidative stress; effect of nutrient interventions
- Authors
- Jiao, K., Yang, K., Wang, J., Ni, Y., Hu, C., Liu, J., Zhou, M., Zheng, J., Li, Z.
- ID
- ZDB-PUB-231207-8
- Date
- 2023
- Source
- Free radical biology & medicine 210: 462-477 (Journal)
- Registered Authors
- Keywords
- 27-Hydroxycholesterol, Folic acid, Hepatic stellate cells, Liver fibrosis, Trimethylation of histone H3 at lysine 27
- MeSH Terms
-
- Animals
- Cholesterol/metabolism
- Down-Regulation
- Hepatic Stellate Cells/metabolism
- Histones*/genetics
- Histones*/metabolism
- Liver Cirrhosis/chemically induced
- Liver Cirrhosis/genetics
- Liver Cirrhosis/metabolism
- Lysine*/metabolism
- Nutrients
- Oxidative Stress
- Reactive Oxygen Species/metabolism
- Transforming Growth Factor beta/genetics
- Transforming Growth Factor beta/metabolism
- Zebrafish/metabolism
- PubMed
- 38056577 Full text @ Free Radic. Biol. Med.
Citation
Jiao, K., Yang, K., Wang, J., Ni, Y., Hu, C., Liu, J., Zhou, M., Zheng, J., Li, Z. (2023) 27-Hydroxycholesterol induces liver fibrosis via down-regulation of trimethylation of histone H3 at lysine 27 by activating oxidative stress; effect of nutrient interventions. Free radical biology & medicine. 210:462-477.
Abstract
Background Chronic liver injury caused by activation of hepatic stellate cells (HSCs) is a key event in the development of liver fibrosis (LF). A high-cholesterol diet can prompt accumulation of free cholesterol in HSCs, which promotes HSC activation and progression of LF.
Objective 27-Hydroxycholesterol (27HC) is the most abundant cholesterol metabolite. Here, we investigated whether the HSC activation and LF induced by high cholesterol is caused by its metabolite 27HC, and whether TGFβ classical signaling were involved in these processes.
Methods In vitro, LX2 and HSC-T6 cells were used to explore the effects of 27HC on activation of HSCs, while LSECs were used to observe the effects of 27HC on capillarization. In vivo, zebrafish were used to assess the effect of 27HC on LF.
Results The cholesterol metabolite 27HC promoted the proliferation of HSCs and up-regulated expression of COL-1 and α-SMA as well as CTGF and TIMP1. Also, 27HC up-regulated expression of Smad2/3 and phosphorylated Smad2/3 in HSCs. Furthermore, 27HC-induced up-regulation of COL-1, α-SMA, CTGF, and TIMP1 protein levels was inhibited by Smad2/3 knockout. In addition, 27HC down-regulated H3K27me3 by inhibition of EZH2 and promotion of UTX and JMJD3 expression via the TGFβ signaling, thereby inducing activation of HSCs. Notably, 27HC significantly aggravated the pathological damage induced by DEN, and induced deposition of collagen fibers in zebrafish liver. Folic acid (FA) and resveratrol (RES) both reduced 27HC-induced production of reactive oxygen species (ROS) and inhibited the effects of TGFβ signaling on EZH2, UTX, and JMJD3, thereby increasing H3K27me3, and finally jointly inhibiting LF.
Conclusion Cholesterol is metabolized to 27HC, which mediates activation of HSCs and onset of LF. Reduced expression of H3k27me3 by TGFβ signaling is crucial to 27HC-induced LF. FA and RES ameliorated activation of HSCs and LF by reducing 27HC-induced production of ROS and regulating of H3K27me3.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping