Oxidized Low-Density Lipoproteins Trigger Hepatocellular Oxidative Stress with the Formation of Cholesteryl Ester Hydroperoxide-Enriched Lipid Droplets.

Abstract

Oxidized low-density lipoproteins (oxLDLs) induce oxidative stress in the liver tissue, leading to hepatic steatosis, inflammation, and fibrosis. Precise information on the role of oxLDL in this process is needed to establish strategies for the prevention and management of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). Here, we report the effects of native LDL (nLDL) and oxLDL on lipid metabolism, lipid droplet formation, and gene expression in a human liver-derived C3A cell line. The results showed that nLDL induced lipid droplets enriched with cholesteryl ester (CE) and promoted triglyceride hydrolysis and inhibited oxidative degeneration of CE in association with the altered expression of LIPE, FASN, SCD1, ATGL, and CAT genes. In contrast, oxLDL showed a striking increase in lipid droplets enriched with CE hydroperoxides (CE-OOH) in association with the altered expression of SREBP1, FASN, and DGAT1. Phosphatidylcholine (PC)-OOH/PC was increased in oxLDL-supplemented cells as compared with other groups, suggesting that oxidative stress increased hepatocellular damage. Thus, intracellular lipid droplets enriched with CE-OOH appear to play a crucial role in NAFLD and NASH, triggered by oxLDL. We propose oxLDL as a novel therapeutic target and candidate biomarker for NAFLD and NASH.

• Authors: Iku Sazaki, Toshihiro Sakurai, Arisa Yamahata, Sumire Mogi, Nao Inoue, Koutaro Ishida, Ami Kikkai, Hana Takeshita, Akiko Sakurai, Yuji Takahashi, Hitoshi Chiba, Shu-Ping Hui
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 24 Issue 5 (Feb 21 2023) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 36901709 (Publication Type: Journal Article)

Chemical References

• oxidized low density lipoprotein
• cholesteryl ester hydroperoxide
• Cholesterol Esters
• Lipoproteins, LDL

Topics

• Humans
• Cholesterol Esters (metabolism)
• Non-alcoholic Fatty Liver Disease (metabolism)
• Carcinoma, Hepatocellular (metabolism)
• Lipid Droplets (metabolism)
• Liver Neoplasms (metabolism)
• Lipoproteins, LDL (metabolism)
• Oxidative Stress