7-Ketocholesterol Induces Lipid Metabolic Reprogramming and Enhances Cholesterol Ester Accumulation in Cardiac Cells.

Mei-Ling Cheng,Cheng-Hung Yang,Jui-Fen Lin,Chi-Jen Lo,Hung-Yao Ho,Pei-Ting Wu,Hsiang-Yu Tang

doi:10.3390/cells10123597

Mei-Ling Cheng, Cheng-Hung Yang + Show 5 more

Open Access

https://doi.org/10.3390/cells10123597

Copy DOI

Journal: Cells	Publication Date: Dec 20, 2021
Citations: 6	License type: CC BY 4.0

Affiliation: Chang Gung University, Chang Gung Memorial Hospital

Abstract

7-Ketocholesterol (7KCh) is a major oxidized cholesterol product abundant in lipoprotein deposits and atherosclerotic plaques. Our previous study has shown that 7KCh accumulates in erythrocytes of heart failure patients, and further investigation centered on how 7KCh may affect metabolism in cardiomyocytes. We applied metabolomics to study the metabolic changes in cardiac cell line HL-1 after treatment with 7KCh. Mevalonic acid (MVA) pathway-derived metabolites, such as farnesyl-pyrophosphate and geranylgeranyl-pyrophosphate, phospholipids, and triacylglycerols levels significantly declined, while the levels of lysophospholipids, such as lysophosphatidylcholines (lysoPCs) and lysophosphatidylethanolamines (lysoPEs), considerably increased in 7KCh-treated cells. Furthermore, the cholesterol content showed no significant change, but the production of cholesteryl esters was enhanced in the treated cells. To explore the possible mechanisms, we applied mRNA-sequencing (mRNA-seq) to study genes differentially expressed in 7KCh-treated cells. The transcriptomic analysis revealed that genes involved in lipid metabolic processes, including MVA biosynthesis and cholesterol transport and esterification, were differentially expressed in treated cells. Integrated analysis of both metabolomic and transcriptomic data suggests that 7KCh induces cholesteryl ester accumulation and reprogramming of lipid metabolism through altered transcription of such genes as sterol O-acyltransferase- and phospholipase A2-encoding genes. The 7KCh-induced reprogramming of lipid metabolism in cardiac cells may be implicated in the pathogenesis of cardiovascular diseases.

Highlights

The oxidized low-density lipoprotein (LDL) in the artery wall is known to participate in atherogenesis [1,2]
To examine whether 7KCh impairs the physiology of cardiomyocytes, we tested the changes in the growth of HL-1 cells after 7KCh treatments
The concentration of 7KCh used for cell treatment ranged from 10 μM to 20 μM. 7KCh caused a dose-dependent reduction in cell number at concentrations ranging from 10 μM to 20 μM in HL-1 cells at 24 h post-treatment (Figure 1F)

Summary

Introduction

The oxidized low-density lipoprotein (LDL) in the artery wall is known to participate in atherogenesis [1,2]. A cytotoxic component of oxidized low-density lipoproteins— 7-Ketocholesterol (7KCh)—is believed to contribute to the atherosclerotic process. High levels of 7KCh are detected in advanced atherosclerotic plaques [3] and in the plasma of patients with increased risk for cardiovascular diseases [4,5]. Lowered expression of SOAT1 and SOAT2 in heart tissue [8] may lead to an accumulation of 7KCh and exacerbate heart damage in patients with cardiovascular disease. We demonstrate that 7KCh promotes reactive oxygen species (ROS) formation and induces growth inhibition or death in cardiomyocytes [9]

Methods

Results

Conclusion