The role of very-long-chain fatty acids in the pathogenesis of metabolic dysfunction-associated fatty liver disease

Jiaqi Kong; Tingting Ren; Rui Liu; Guizhong Zhou; Chuanlong Zhu

doi:10.12449/JCH260830

Volume 42 Issue 8

Aug. 2026

Turn off MathJax

Article Contents

Article Navigation > Journal of Clinical Hepatology > 2026 > 42(8): 1946-1951

PDF( 751 KB)

The role of very-long-chain fatty acids in the pathogenesis of metabolic dysfunction-associated fatty liver disease

DOI: 10.12449/JCH260830

Jiaqi Kong¹,
Tingting Ren¹,
Rui Liu^{1, 2},
Guizhong Zhou²,
Chuanlong Zhu^{1, 2
,
,
,}

1.
Department of Infectious Diseases，The First Affiliated Hospital of Nanjing Medical University，Nanjing 210029，China
2.
Department of Infectious and Tropical Diseases，The Second Affiliated Hospital of Hainan Medical University，Haikou 570100，China

Research funding:

National Natural Science Foundation of China (82472167);

Science and Technology Plan of Hainan Province （Clinical Research Center） (LCYX202204);

Science and Technology Plan of Hainan Province （Clinical Research Center） (LCYX202306);

Science and Technology Plan of Hainan Province （Clinical Research Center） (LCYX202408);

Natural Science Foundation of Jiangsu Province (BK20241982)

More Information

Corresponding author: Zhu Chuanlong， zhuchuanlong@jsph.org.cn （ORCID： 0000-0001-6557-1654）
Received Date: 2026-01-21
Accepted Date: 2026-03-16
Published Date: 2026-08-25

Abstract

Abstract

Metabolic dysfunction-associated fatty liver disease （MAFLD） is the most common chronic liver disease， and it has become a major global health issue. Excessive lipid accumulation in the liver is the core pathological event of MAFLD， which triggers lipotoxicity and leads to cell apoptosis， necrosis， and inflammatory cascades by mediating endoplasmic reticulum stress， oxidative stress， organelle dysfunction， and ferroptosis， thereby promoting the progression of simple hepatic steatosis to steatohepatitis and fibrosis. In this process， very-long-chain fatty acids （VLCFAs）， as essential components of cell membranes and lipid metabolism， have attracted increasing attention for their role in lipotoxicity mechanisms. This article reviews the role of VLCFAs in lipid metabolism processes and lipotoxicity mechanisms， focusing on how VLCFAs participate in metabolic regulation through key proteins and disrupt cell membranes to induce oxidative stress， and how their metabolites and derivatives drive inflammatory responses， ultimately promoting the progression of MAFLD.
- Metabolic Dysfunction-Associated Fatty Liver Disease,
- Fatty Acids,
- Pathologic Processes

FullText(HTML)

References(47)

References

[1]	Riazi K, Azhari H, Charette J H, et al. The prevalence and incidence of NAFLD worldwide: A systematic review and meta-analysis[J]. Lancet Gastroenterol Hepatol, 2022, 7( 9): 851- 861. DOI: 10.1016/S2468-1253(22)00165-0.
[2]	Rinella M E, Lazarus J V, Ratziu V, et al. A multisociety Delphi consensus statement on new fatty liver disease nomenclature[J]. J Hepatol, 2023, 79( 6): 1542- 1556. DOI: 10.1016/j.jhep.2023.06.003.
[3]	Powell E E, Wong V W, Rinella M. Non-alcoholic fatty liver disease[J]. Lancet, 2021, 397( 10290): 2212- 2224. DOI: 10.1016/S0140-6736(20)32511-3.
[4]	Iturbe-Rey S, Maccali C, Arrese M, et al. Lipotoxicity-driven metabolic dysfunction-associated steatotic liver disease(MASLD)[J]. Atherosclerosis, 2025, 400: 119053. DOI: 10.1016/j.atherosclerosis.2024.119053.
[5]	Lu Q Y, Zong W C, Zhang M, et al. The overlooked transformation mechanisms of VLCFAs: Peroxisomal β-oxidation[J]. Agriculture, 2022, 12( 7): 947. DOI: 10.3390/agriculture12070947.
[6]	Lu D L, He A Y, Tan M, et al. Liver ACOX1 regulates levels of circulating lipids that promote metabolic health through adipose remodeling[J]. Nat Commun, 2024, 15( 1): 4214. DOI: 10.1038/s41467-024-48471-2.
[7]	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. DOI: 10.1042/CS20220572.
[8]	Geng Y N, Faber K N, de Meijer V E, et al. How does hepatic lipid accumulation lead to lipotoxicity in non-alcoholic fatty liver disease?[J]. Hepatol Int, 2021, 15( 1): 21- 35. DOI: 10.1007/s12072-020-10121-2.
[9]	Perez V M, Gabell J, Behrens M, et al. Deletion of fatty acid transport protein 2(FATP2) in the mouse liver changes the metabolic landscape by increasing the expression of PPARα-regulated genes[J]. J Biol Chem, 2020, 295( 17): 5737- 5750. DOI: 10.1074/jbc.RA120.012730.
[10]	Melton E M, Cerny R L, Watkins P A, et al. Human fatty acid transport protein 2a/very long chain acyl-CoA synthetase 1(FATP2a/Acsvl1) has a preference in mediating the channeling of exogenous n-3 fatty acids into phosphatidylinositol[J]. J Biol Chem, 2011, 286( 35): 30670- 30679. DOI: 10.1074/jbc.M111.226316.
[11]	Zou Z Y, DiRusso C C, Ctrnacta V, et al. Fatty acid transport in Saccharomyces cerevisiae[J]. J Biol Chem, 2002, 277( 34): 31062- 31071. DOI: 10.1074/jbc.m205034200.
[12]	Zhang X, Luo L J, Wu Y W, et al. The role of CD36 in immune function: Bridging innate and adaptive responses[J]. Front Immunol, 2026, 17: 1728509. DOI: 10.3389/fimmu.2026.1728509.
[13]	Hao J W, Wang J, Guo H L, et al. CD36 facilitates fatty acid uptake by dynamic palmitoylation-regulated endocytosis[J]. Nat Commun, 2020, 11( 1): 4765. DOI: 10.1038/s41467-020-18565-8.
[14]	Drover V A, Nguyen D V, Bastie C C, et al. CD36 mediates both cellular uptake of very long chain fatty acids and their intestinal absorption in mice[J]. J Biol Chem, 2008, 283( 19): 13108- 13115. DOI: 10.1074/jbc.M708086200.
[15]	Moon Y A, Hammer R E, Horton J D. Deletion of ELOVL5 leads to fatty liver through activation of SREBP-1c in mice[J]. J Lipid Res, 2009, 50( 3): 412- 423. DOI: 10.1194/jlr.M800383-JLR200.
[16]	Ferrero E, Vaz F M, Cheillan D, et al. The ELOVL proteins: Very and ultra long-chain fatty acids at the crossroads between metabolic and neurodegenerative disorders[J]. Mol Genet Metab, 2025, 144( 3): 109050. DOI: 10.1016/j.ymgme.2025.109050.
[17]	Morita M, Imanaka T. Peroxisomal ABC transporters: Structure, function and role in disease[J]. Biochim Biophys Acta, 2012, 1822( 9): 1387- 1396. DOI: 10.1016/j.bbadis.2012.02.009.
[18]	Wiesinger C, Kunze M, Regelsberger G, et al. Impaired very long-chain acyl-CoA β-oxidation in human X-linked adrenoleukodystrophy fibroblasts is a direct consequence of ABCD1 transporter dysfunction[J]. J Biol Chem, 2013, 288( 26): 19269- 19279. DOI: 10.1074/jbc.M112.445445.
[19]	Yagita Y, Shinohara K, Abe Y, et al. Deficiency of a retinal dystrophy protein, acyl-CoA binding domain-containing 5(ACBD5), impairs peroxisomal β-oxidation of very-long-chain fatty acids[J]. J Biol Chem, 2017, 292( 2): 691- 705. DOI: 10.1074/jbc.M116.760090.
[20]	Ferdinandusse S, Falkenberg K D, Koster J, et al. ACBD5 deficiency causes a defect in peroxisomal very long-chain fatty acid metabolism[J]. J Med Genet, 2017, 54( 5): 330- 337. DOI: 10.1136/jmedgenet-2016-104132.
[21]	Deng X L, Luo Y Q, Gao Y, et al. Long-chain acyl-CoA synthetases: Biological functions, diseases and therapeutic targets[J]. Mol Biomed, 2025, 6( 1): 117. DOI: 10.1186/s43556-025-00366-4.
[22]	Wu L Z, Wang J Q, Wang Y W, et al. CLCC1 governs ER bilayer equilibration to maintain lipid homeostasis[J]. Nature, 2026, 652( 8109): 471- 480. DOI: 10.1038/s41586-026-10161-y.
[23]	Stilkerich A, Schicht G, Seidemann L, et al. Cell homeostasis or cell death-the balancing act between autophagy and apoptosis caused by steatosis-induced endoplasmic reticulum(ER) stress[J]. Cells, 2025, 14( 6): 449. DOI: 10.3390/cells14060449.
[24]	Elsaid S, Wu X D, Hu J K, et al. Beyond fructolysis: Ketohexokinase orchestrates ER proteostasis in nutrient-stressed hepatocytes[J]. Am J Physiol Gastrointest Liver Physiol, 2025, 329( 6): G708- G719. DOI: 10.1152/ajpgi.00235.2025.
[25]	Ali H, Yamanishi M, Hasi R Y, et al. Different effects of Lorenzo's oil components against very long-chain fatty acid-induced endoplasmic reticulum stress in peroxisome-deficient CHO cells[J]. Biochim Biophys Acta Mol Cell Biol Lipids, 2025, 1870( 7): 159670. DOI: 10.1016/j.bbalip.2025.159670.
[26]	Micoogullari Y, Basu S S, Ang J, et al. Dysregulation of very-long-chain fatty acid metabolism causes membrane saturation and induction of the unfolded protein response[J]. Mol Biol Cell, 2020, 31( 1): 7- 17. DOI: 10.1091/mbc.E19-07-0392.
[27]	van de Beek M C, Ofman R, Dijkstra I, et al. Lipid-induced endoplasmic reticulum stress in X-linked adrenoleukodystrophy[J]. Biochim Biophys Acta Mol Basis Dis, 2017, 1863( 9): 2255- 2265. DOI: 10.1016/j.bbadis.2017.06.003.
[28]	Summers S A, Chaurasia B, Holland W L. Metabolic messengers: Ceramides[J]. Nat Metab, 2019, 1( 11): 1051- 1058. DOI: 10.1038/s42255-019-0134-8.
[29]	Kim Y R, Lee E J, Shin K O, et al. Hepatic triglyceride accumulation via endoplasmic reticulum stress-induced SREBP-1 activation is regulated by ceramide synthases[J]. Exp Mol Med, 2019, 51( 11): 1- 16. DOI: 10.1038/s12276-019-0340-1.
[30]	Contreras C, González-García I, Martínez-Sánchez N, et al. Central ceramide-induced hypothalamic lipotoxicity and ER stress regulate energy balance[J]. Cell Rep, 2014, 9( 1): 366- 377. DOI: 10.1016/j.celrep.2014.08.057.
[31]	McNally B D, Ashley D F, Hänschke L, et al. Long-chain ceramides are cell non-autonomous signals linking lipotoxicity to endoplasmic reticulum stress in skeletal muscle[J]. Nat Commun, 2022, 13( 1): 1748. DOI: 10.1038/s41467-022-29363-9.
[32]	Tanaka H, Okazaki T, Aoyama S, et al. Peroxisomes control mitochondrial dynamics and the mitochondrion-dependent apoptosis pathway[J]. J Cell Sci, 2019, 132( 11): jcs224766. DOI: 10.1242/jcs.224766.
[33]	Marten L M, Lüttgens M S, Berečić B, et al. Mitochondrial dysfunction and impaired oxidative stress defense as potential trigger of cerebral X-linked adrenoleukodystrophy[J]. Free Radic Biol Med, 2026, 242: 654- 666. DOI: 10.1016/j.freeradbiomed.2025.10.289.
[34]	Zhou J, Terluk M R, Orchard P J, et al. N-acetylcysteine reverses the mitochondrial dysfunction induced by very long-chain fatty acids in murine oligodendrocyte model of adrenoleukodystrophy[J]. Biomedicines, 2021, 9( 12): 1826. DOI: 10.3390/biomedicines9121826.
[35]	Nury T, Doria M, Lizard G, et al. Docosahexaenoic acid attenuates mitochondrial alterations and oxidative stress leading to cell death induced by very long-chain fatty acids in a mouse oligodendrocyte model[J]. Int J Mol Sci, 2020, 21( 2): 641. DOI: 10.3390/ijms21020641.
[36]	Han Z N, Yan Z B, Ma Z H, et al. Targeting ABCD1-ACOX1-MET/IGF1R axis suppresses multiple myeloma[J]. Leukemia, 2025, 39( 3): 720- 733. DOI: 10.1038/s41375-025-02522-9.
[37]	Reyna-Bolaños I, Solís-García E P, Vargas-Vargas M A, et al. Polydatin prevents electron transport chain dysfunction and ROS overproduction paralleled by an improvement in lipid peroxidation and cardiolipin levels in iron-overloaded rat liver mitochondria[J]. Int J Mol Sci, 2024, 25( 20): 11104. DOI: 10.3390/ijms252011104.
[38]	Panov A V, Dikalov S I. Cardiolipin, perhydroxyl radicals, and lipid peroxidation in mitochondrial dysfunctions and aging[J]. Oxid Med Cell Longev, 2020, 2020: 1323028. DOI: 10.1155/2020/1323028.
[39]	Parisi L R, Sowlati-Hashjin S, Berhane I A, et al. Membrane disruption by very long chain fatty acids during necroptosis[J]. ACS Chem Biol, 2019, 14( 10): 2286- 2294. DOI: 10.1021/acschembio.9b00616.
[40]	Dong L W, Xiao J, Liu S, et al. Lysosomal cholesterol accumulation is commonly found in most peroxisomal disorders and reversed by 2-hydroxypropyl-β-cyclodextrin[J]. Sci China Life Sci, 2023, 66( 8): 1786- 1799. DOI: 10.1007/s11427-022-2260-4.
[41]	Ma C, Wang S, Dong B, et al. Metabolic reprogramming of immune cells in MASH[J]. Hepatology, 2025. DOI: 10.1097/HEP.0000000000001371.[ Epub ahead of print]
[42]	Raas Q, Tawbeh A, Tahri-Joutey M, et al. Peroxisomal defects in microglial cells induce a disease-associated microglial signature[J]. Front Mol Neurosci, 2023, 16: 1170313. DOI: 10.3389/fnmol.2023.1170313.
[43]	He A Y, Chen X W, Tan M, et al. Acetyl-CoA derived from hepatic peroxisomal β-oxidation inhibits autophagy and promotes steatosis via mTORC1 activation[J]. Mol Cell, 2020, 79( 1): 30- 42. DOI: 10.1016/j.molcel.2020.05.007.
[44]	Ross D, Siegel D. The diverse functionality of NQO1 and its roles in redox control[J]. Redox Biol, 2021, 41: 101950. DOI: 10.1016/j.redox.2021.101950.
[45]	Petrillo S, D’Amico J, Nicita F, et al. Antioxidant response in human X-linked adrenoleukodystrophy fibroblasts[J]. Antioxidants(Basel), 2022, 11( 11): 2125. DOI: 10.3390/antiox11112125.
[46]	Kanoh H, Nitta T, Go S, et al. Homeostatic and pathogenic roles of GM3 ganglioside molecular species in TLR4 signaling in obesity[J]. EMBO J, 2020, 39( 12): e101732. DOI: 10.15252/embj.2019101732.
[47]	Yanagisawa N, Shimada K, Miyazaki T, et al. Enhanced production of nitric oxide, reactive oxygen species, and pro-inflammatory cytokines in very long chain saturated fatty acid-accumulated macrophages[J]. Lipids Health Dis, 2008, 7: 48. DOI: 10.1186/1476-511X-7-48.

Relative Articles

Supplements(0)

Cited By

Proportional views

Proportional views

通讯作者: 陈斌, bchen63@163.com

1.
沈阳化工大学材料科学与工程学院沈阳 110142

Figures(1)

Get Citation

PDF

XML

Article Metrics

Article views (10) PDF downloads(0)

The role of very-long-chain fatty acids in the pathogenesis of metabolic dysfunction-associated fatty liver disease

DOI: 10.12449/JCH260830

Abstract

References

Proportional views

Catalog

通讯作者: 陈斌, bchen63@163.com

Article Metrics

Proportional views

Related

The role of very-long-chain fatty acids in the pathogenesis of metabolic dysfunction-associated fatty liver disease

DOI: 10.12449/JCH260830

Abstract

References

Proportional views

Catalog

通讯作者: 陈斌, bchen63@163.com

Article Metrics

Proportional views

Related

About Journal

Submission Guideline

Journal Online

Hepatobiliary College

Guidelines

Export File

Citation

Format

Content