脂质过氧化在糖脂代谢紊乱中的作用研究进展

doi:10.3969/j.issn.1673-8640.2025.06.017

摘要/Abstract

摘要：

脂质过氧化是指细胞中的多不饱和脂肪酸（PUFA）在酶促或者非酶促的作用下产生一系列过氧化产物的过程。脂质过氧化会导致生物膜结构紊乱和功能损伤，进而引起多种疾病，尤其是糖脂代谢紊乱相关疾病，如2型糖尿病、非酒精性脂肪性肝病和心血管疾病。文章总结了脂质过氧化的3种途径，介绍每种途径中发生的主要反应，提炼主要的氧化代谢产物。同时，阐述了3种脂质过氧化途径与疾病发生的关系，重点阐述多种氧化代谢产物对疾病发生、发展的影响。文章旨在对未来脂代谢紊乱相关疾病的治疗，以及新型生物标志物研究提供理论指导。

关键词: 脂质过氧化, 多不饱和脂肪酸, 环氧合酶, 脂氧合酶, 细胞色素P450

Abstract:

Lipid peroxidation means the generation process of a series of peroxidation products from polyunsaturated fatty acids（PUFA） within cells under enzymatic or non-enzymatic processes. This process disrupts the structure and function of biological membranes，consequently leading to various diseases，particularly those associated with disrupted glucose and lipid metabolism such as type 2 diabetes mellitus，non-alcoholic fatty liver disease and cardiovascular diseases. The present study provides comprehensive summary of the 3 pathways of lipid peroxidation，elucidating the primary reactions occurring within each pathway and identifying key oxidative metabolites. Furthermore，it examines the connections between these lipid peroxidation pathways and disease development，with a specific focus on the effects of multiple oxidative metabolites on the progression of diseases. This review aims to offer theoretical guidance for future treatments of disorders related to lipid metabolism and the exploration of novel biomarkers.

Key words: Lipid peroxidation, Polyunsaturated fatty acid, Cyclooxygenase, Lipoxygenase, Cytochrome P450

中图分类号:

R446.1

曹姝贤, 高毅男, 宋御繁, 逯素梅. 脂质过氧化在糖脂代谢紊乱中的作用研究进展[J]. 检验医学, 2025, 40(6): 615-620.

CAO Shuxian, GAO Yinan, SONG Yufan, LU Sumei. Research progress of lipid peroxidation in dysregulation of glucose and lipid metabolism[J]. Laboratory Medicine, 2025, 40(6): 615-620.

图/表 4

参考文献 47

[1]	JEON S, CARR R. Alcohol effects on hepatic lipid metabolism[J]. J Lipid Res, 2020, 61(4):470-479. DOI PMID
[2]	PENG Y, LI Z, ZHANG Z, et al. Bromocriptine protects perilesional spinal cord neurons from lipotoxicity after spinal cord injury[J]. Neural Regen Res, 2024, 19(5):1142-1149. DOI PMID
[3]	BADMUS O O, HILLHOUSE S A, ANDERSON C D, et al. Molecular mechanisms of metabolic associated fatty liver disease(MAFLD):functional analysis of lipid metabolism pathways[J]. Clin Sci(Lond), 2022, 136(18):1347-1366.
[4]	VIGOR C, BERTRAND-MICHEL J, PINOT E, et al. Non-enzymatic lipid oxidation products in biological systems:assessment of the metabolites from polyunsaturated fatty acids[J]. J Chromatogr B Analyt Technol Biomed Life Sci, 2014, 964:65-78.
[5]	MORITA M, NAITO Y, YOSHIKAWA T, et al. Plasma lipid oxidation induced by peroxynitrite,hypochlorite,lipoxygenase and peroxyl radicals and its inhibition by antioxidants as assessed by diphenyL^-1-pyrenylphosphine[J]. Redox Biol, 2016, 8:127-135.
[6]	ALVAREZ M L, LORENZETTI F. Role of eicosanoids in liver repair,regeneration and cancer[J]. Biochem Pharmacol, 2021, 192:114732.
[7]	MITCHELL J A, KIRKBY N S. Eicosanoids, prostacyclin and cyclooxygenase in the cardiovascular system[J]. Br J Pharmacol, 2019, 176(8):1038-1050.
[8]	FREJBORG E, SALO T, SALEM A. Role of cyclooxygenase-2 in head and neck tumorigenesis[J]. Int J Mol Sci, 2020, 21(23):9246.
[9]	HAJEYAH A A, GRIFFITHS W J, WANG Y, et al. The biosynthesis of enzymatically oxidized lipids[J]. Front Endocrinol(Lausanne), 2020, 11:591819.
[10]	FEUSSNER I, WASTERNACK C. The lipoxygenase pathway[J]. Annu Rev Plant Biol, 2002, 53:275-297. PMID
[11]	JANSEN C, HOFHEINZ K, VOGEL R, et al. Stereocontrol of arachidonic acid oxygenation by vertebrate lipoxygenases:newly cloned zebrafish lipoxygenase 1 does not follow the Ala-versus-Gly concept[J]. J Biol Chem, 2011, 286(43):37804-37812.
[12]	PANG Y, LIU X, ZHAO C, et al. LC-MS/MS-based arachidonic acid metabolomics in acute spinal cord injury reveals the upregulation of 5-LOX and COX-2 products[J]. Free Radic Biol Med, 2022, 193(Pt 1):363-372.
[13]	BALDWIN W S. Phase 0 of the xenobiotic response:nuclear receptors and other transcription factors as a first step in protection from xenobiotics[J]. Nucl Receptor Res, 2019, 6:101447.
[14]	ZHOU M, LI J, XU J, et al. Exploring human CYP4 enzymes:physiological roles,function in diseases and focus on inhibitors[J]. Drug Discov Today, 2023, 28(5):103560.
[15]	BERGMANN C B, HAMMOCK B D, WAN D, et al. TPPU treatment of burned mice dampens inflammation and generation of bioactive DHET which impairs neutrophil function[J]. Sci Rep, 2021, 11(1):16555. DOI PMID
[16]	KELLY K A, HAVRILLA C M, BRADY T C, et al. Oxidative stress in toxicology:established mammalian and emerging piscine model systems[J]. Environ Health Perspect, 1998, 106(7):375-384.
[17]	NONO NANKAM P A, NGUELEFACK T B, GOEDECKE J H, et al. Contribution of adipose tissue oxidative stress to obesity-associated diabetes risk and ethnic differences:focus on women of African ancestry[J]. Antioxidants(Basel), 2021, 10(4):622.
[18]	PAN Y, CAO S, TANG J, et al. Cyclooxygenase-2 in adipose tissue macrophages limits adipose tissue dysfunction in obese mice[J]. J Clin Invest, 2022, 132(9):e152391.
[19]	KARPISHEH V, NIKKHOO A, HOJJAT-FARSANGI M, et al. Prostaglandin E2 as a potent therapeutic target for treatment of colon cancer[J]. Prostaglandins Other Lipid Mediat, 2019, 144:106338.
[20]	ZHU R, WANG X H, WANG B W, et al. Prostaglandin F2α regulates adipogenesis by modulating extracellular signal-regulated kinase signaling in Graves' ophthalmopathy[J]. Int J Mol Sci, 2023, 24(8):7012.
[21]	RICHELSEN B. Prostaglandin E2 action and binding in human adipocytes:effects of sex,age,and obesity[J]. Metabolism, 1988, 37(3):268-275.
[22]	RAHMAN M S. Prostacyclin:a major prostaglandin in the regulation of adipose tissue development[J]. J Cell Physiol, 2019, 234(4):3254-3262.
[23]	DOMINGO C, PALOMARES O, SANDHAM D A, et al. The prostaglandin D₂ receptor 2 pathway in asthma:a key player in airway inflammation[J]. Respir Res, 2018, 19(1):189.
[24]	SAMUCHIWAL S K, BOYCE J A. Role of lipid mediators and control of lymphocyte responses in type 2 immunopathology[J]. J Allergy Clin Immunol, 2018, 141(4):1182-1190. DOI PMID
[25]	NAJAR M, OUHADDI Y, PARÉ F, et al. Role of lipocalin-type prostaglandin D synthase in experimental osteoarthritis[J]. Arthritis Rheumatol, 2020, 72(9):1524-1533.
[26]	YAMANE S, AMANO H, ITO Y, et al. The role of thromboxane prostanoid receptor signaling in gastric ulcer healing[J]. Int J Exp Pathol, 2022, 103(1):4-12.
[27]	ZHANG Y, LIU Y, SUN J, et al. Arachidonic acid metabolism in health and disease[J]. MedComm(2020), 2023, 4(5):e363.
[28]	SINGH N K, RAO G N. Emerging role of 12/15-lipoxygenase(ALOX15)in human pathologies[J]. Prog Lipid Res, 2019, 73:28-45.
[29]	任咪咪, 孙宏志, 马莉, 等. 12/15-脂氧合酶在糖尿病肾脏疾病中的研究进展[J]. 中华肾脏病杂志, 2022, 38(8):754-759.
[30]	DOBRIAN A D, LIEB D C, MA Q, et al. Differential expression and localization of 12/15 lipoxygenases in adipose tissue in human obese subjects[J]. Biochem Biophys Res Commun, 2010, 403(3):485-490.
[31]	WANG B, WU L, CHEN J, et al. Metabolism pathways of arachidonic acids:mechanisms and potential therapeutic targets[J]. Signal Transduct Target Ther, 2021, 6(1):94.
[32]	HAEGGSTRÖM J Z. Leukotriene biosynthetic enzymes as therapeutic targets[J]. J Clin Invest, 2018, 128(7):2680-2690. DOI PMID
[33]	刘充, 刘迎迎, 郭兆安. 特异性促炎消退介质在糖尿病肾脏疾病中的研究进展[J]. 基础医学与临床, 2023, 43(7):1152-1156.
[34]	DAS U N. Beneficial role of bioactive lipids in the pathobiology,prevention,and management of HBV,HCV and alcoholic hepatitis,NAFLD,and liver cirrhosis:a review[J]. J Adv Res, 2018, 17:17-29.
[35]	SOTÁK M, RAJAN M R, CLARK M, et al. Lipoxins reduce obesity-induced adipose tissue inflammation in 3D-cultured human adipocytes and explant cultures[J]. iScience, 2022, 25(7):104602.
[36]	ZHA W, EDIN M L, VENDROV K C, et al. Functional characterization of cytochrome P450-derived epoxyeicosatrienoic acids in adipogenesis and obesity[J]. J Lipid Res, 2014, 55(10):2124-2136. DOI PMID
[37]	KROGSTAD V, PERIC A, ROBERTSEN I, et al. A comparative analysis of cytochrome P450 activities in paired liver and small intestinal samples from patients with obesity[J]. Drug Metab Dispos, 2020, 48(1):8-17. DOI PMID
[38]	ROCIC P, SCHWARTZMAN M L. 20-HETE in the regulation of vascular and cardiac function[J]. Pharmacol Ther, 2018, 192:74-87.
[39]	YEN H C, WEI H J, LIN C L. Unresolved issues in the analysis of F2-isoprostanes,F4-neuroprostanes,isofurans,neurofurans,and F2-dihomo-isoprostanes in body fluids and tissue using gas chromatography/negative-ion chemical-ionization mass spectrometry[J]. Free Radic Res, 2015, 49(7):861-880.
[40]	DALLE-DONNE I, ROSSI R, COLOMBO R, et al. Biomarkers of oxidative damage in human disease[J]. Clin Chem, 2006, 52(4):601-623.
[41]	ITO F, SONO Y, ITO T. Measurement and clinical significance of lipid peroxidation as a biomarker of oxidative stress:oxidative stress in diabetes,atherosclerosis,and chronic inflammation[J]. Antioxidants(Basel), 2019, 8(3):72.
[42]	ZHONG S, LI L, SHEN X, et al. An update on lipid oxidation and inflammation in cardiovascular diseases[J]. Free Radic Biol Med, 2019, 144:266-278.
[43]	SETHIYA N K, GHILORIA N, SRIVASTAV A, et al. Therapeutic potential of myricetin in the treatment of neurological,neuropsychiatric,and neurodegenerative disorders[J]. CNS Neurol Disord Drug Targets, 2024, 23(7):865-882.
[44]	REDDY P H, OLIVER D M. Amyloid beta and phosphorylated tau-induced defective autophagy and mitophagy in Alzheimer's disease[J]. Cells, 2019, 8(5):488.
[45]	BREITZIG M, BHIMINENI C, LOCKEY R, et al. 4-Hydroxy-2-nonenal:a critical target in oxidative stress?[J] Am J Physiol Cell Physiol, 2016, 311(4):C537-C543.
[46]	麻京豫, 魏经汉, 赵洛沙. 急性冠状动脉综合征8-异前列腺素F2α与血脂、体重指数及腰臀比的相关性研究[J]. 中国综合临床, 2005, 21(9):781-783.
[47]	DHAM D, ROY B, GOWDA A, et al. 4-Hydroxy-2-nonenal,a lipid peroxidation product,as a biomarker in diabetes and its complications:challenges and opportunities[J]. Free Radic Res, 2021, 55(5):547-561.

同工酶	氧化代谢产物	酶的分布	功能
COX	PGG₂、PGH₂、PGX₂、TXA₂	全身各处	血小板活化，抑癌或促癌，抑炎，水盐平衡或激素分泌
LOX	HPETE^①、HETE、EET、LX、LT	表皮、白细胞、肥大细胞、树突状细胞、淋巴细胞等	参与哮喘的形成，参与动脉粥样硬化的发生，促炎，抑炎，参与鱼鳞病的发生
CYP450	EET、HETE	全身各处	抑炎或促炎，参与高血压、糖尿病、肿瘤的发展

同工酶	氧化代谢产物	酶的分布	功能
COX	PGG₂、PGH₂、PGX₂、TXA₂	全身各处	血小板活化，抑癌或促癌，抑炎，水盐平衡或激素分泌
LOX	HPETE^①、HETE、EET、LX、LT	表皮、白细胞、肥大细胞、树突状细胞、淋巴细胞等	参与哮喘的形成，参与动脉粥样硬化的发生，促炎，抑炎，参与鱼鳞病的发生
CYP450	EET、HETE	全身各处	抑炎或促炎，参与高血压、糖尿病、肿瘤的发展

代谢产物	功能	参考文献
PGI₂	促炎，促进脂肪细胞分化	[27]
PGE₂	抑制前脂肪细胞分化，促进结肠癌发生、发展，抑制癌细胞凋亡，促进癌细胞增殖、侵袭和转移	[22]
PGD₂	参与哮喘形成，促炎	[24]
PGF2α	使血管收缩、血压升高，参与抑制脂肪生成	[20]
TX	诱导血小板活性、诱导血管生成	[26]

代谢产物	功能	参考文献
PGI₂	促炎，促进脂肪细胞分化	[27]
PGE₂	抑制前脂肪细胞分化，促进结肠癌发生、发展，抑制癌细胞凋亡，促进癌细胞增殖、侵袭和转移	[22]
PGD₂	参与哮喘形成，促炎	[24]
PGF2α	使血管收缩、血压升高，参与抑制脂肪生成	[20]
TX	诱导血小板活性、诱导血管生成	[26]