Lipidomic analysis identifies long-chain acylcarnitine as a target for ischemic stroke

Xin-Xin Huang; Lei Li; Run-Hao Jiang; Jian-Bing Yu; Yu-Qin Sun; Jinjun Shan; Jin Yang; Juan Ji; Shu-Qi Cheng; Yin-Feng Dong; Xi-Yue Zhang; Hai-Bin Shi; Sheng Liu; Xiu-Lan Sun

doi:10.1016/j.jare.2023.08.007

Lipidomic analysis identifies long-chain acylcarnitine as a target for ischemic stroke

J Adv Res. 2023 Aug 11:S2090-1232(23)00223-0. doi: 10.1016/j.jare.2023.08.007. Online ahead of print.

Authors

Xin-Xin Huang¹, Lei Li², Run-Hao Jiang³, Jian-Bing Yu², Yu-Qin Sun², Jinjun Shan⁴, Jin Yang², Juan Ji², Shu-Qi Cheng², Yin-Feng Dong⁴, Xi-Yue Zhang², Hai-Bin Shi³, Sheng Liu⁵, Xiu-Lan Sun⁶

Affiliations

¹ Neuroprotective Drug Discovery Key Laboratory, Jiangsu Key Laboratory of Neurodegeneration, Nanjing Medical University, Nanjing, China; Center of Interventional Radiology and Vascular Surgery, Department of Radiology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China.
² Neuroprotective Drug Discovery Key Laboratory, Jiangsu Key Laboratory of Neurodegeneration, Nanjing Medical University, Nanjing, China.
³ Department of Interventional Radiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
⁴ Nanjing University of Chinese Medicine, the Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China.
⁵ Department of Interventional Radiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China. Electronic address: liusheng@njmu.edu.cn.
⁶ Neuroprotective Drug Discovery Key Laboratory, Jiangsu Key Laboratory of Neurodegeneration, Nanjing Medical University, Nanjing, China; Nanjing University of Chinese Medicine, the Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China. Electronic address: xiulans@njmu.edu.cn.

PMID: 37572732
DOI: 10.1016/j.jare.2023.08.007

Abstract

Introduction: Lipid metabolism dysfunction is widely involved in the pathological process of acute ischemic stroke (AIS). The coordination of lipid metabolism between neurons and astrocytes is of great significance. However, the full scope of lipid dynamic changes and the function of key lipids during AIS remain unknown. Hence, identifying lipid alterations and characterizing their key roles in AIS is of great importance.

Methods: Untargeted and targeted lipidomic analyses were applied to profile lipid changes in the ischemic penumbra and peripheral blood of transient middle cerebral artery occlusion (tMCAO) mice as well as the peripheral blood of AIS patients. Infarct volume and neurological deficits were assessed after tMCAO. The cell viability and dendritic complexity of primary neurons were evaluated by CCK8 assay and Sholl analysis. Seahorse, MitoTracker Green, tetramethyl rhodamine methyl ester (TMRM), 2',7'-dichlorodihydrofluorescein diacetate (DCFH-DA) and MitoSOX were used as markers of mitochondrial health. Fluorescent and isotopic free fatty acid (FFA) pulse-chase assays were used to track FFA flux in astrocytes.

Results: Long-chain acylcarnitines (LCACs) were the lipids with the most dramatic changes in the ischemic penumbra and peripheral blood of tMCAO mice. LCACs were significantly elevated on admission in AIS patients and associated with poor outcomes in AIS patients. Increasing LCACs through a bolus administration of palmitoylcarnitine amplified stroke injury, while decreasing LCACs by overexpressing carnitine palmitoyltransferase 2 (CPT2) ameliorated stroke injury. Palmitoylcarnitine aggravated astrocytic mitochondrial damage after OGD/R, while CPT2 overexpression in astrocytes ameliorated cocultured neuron viability. Further study revealed that astrocytes stimulated by OGD/R liberated FFAs from lipid droplets into mitochondria to form LCACs, resulting in mitochondrial damage and lowered astrocytic metabolic support and thereby aggravated neuronal damage.

Conclusion: LCACs could accumulate and damage neurons by inducing astrocytic mitochondrial dysfunction in AIS. LCACs play a crucial role in the pathology of AIS and are novel promising diagnostic and prognostic biomarkers for AIS.

Keywords: Astrocytic mitochondrial; Biomarker; Ischemic stroke; Lipid droplet; Long-chain acylcarnitine.