Lipidome Changes Associated with a Diet-Induced Reduction in Hepatic Fat among Adolescent Boys with Metabolic Dysfunction-Associated Steatotic Liver Disease
Abstract
:1. Introduction
2. Materials and Methods
2.1. Study Design
2.2. Untargeted High-Resolution Lipidomics
2.3. Targeted Lipidomics (Oxylipins Assay)
2.4. Untargeted Lipidomic Data Processing
2.5. Targeted Oxylipins Data Processing
2.6. Statistical Analyses
2.6.1. Univariate Analysis
2.6.2. Multivariate Analysis
2.6.3. Pairwise Differential Expression Analysis
2.6.4. Correlation Analysis of Lipids with Hepatic Steatosis and DNL
2.6.5. Weighted Lipid Co-Expression Network Analysis
2.6.6. Over-Representation Analysis
2.6.7. Lipid Set Enrichment Analysis (LSEA)
2.6.8. Dietary Fat Intake Analysis
3. Results
3.1. Changes in Dietary Fat Intake and Fatty Acid Composition
3.2. Lipidome Changes Associated with the LFSD Treatment
3.3. Correlations between Hepatic Steatosis and DNL with the Untargeted Lipidomics Data
3.4. Construction of a Lipid Coexpression Network
3.5. Oxylipin Changes Associated with the LFSD Treatment
3.6. Subgroup Analysis: Untargeted Lipidomic Data
4. Discussion
4.1. Changes in Lipid Classes and Individual Lipid Features with the LFSD Treatment
4.2. Lipid Co-Expression Network Analysis
4.3. Clinical and Lipidome Differences between Responders and Non-Responders to the LFSD
4.4. Changes in Oxylipin Species
4.5. Strengths and Limitations
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
- Rinella, M.E.; Lazarus, J.V.; Ratziu, V.; Francque, S.M.; Sanyal, A.J.; Kanwal, F.; Romero, D.; Abdelmalek, M.F.; Anstee, Q.M.; Arab, J.P.; et al. A multi-society Delphi consensus statement on new fatty liver disease nomenclature. Ann. Hepatol. 2023, 29, 101133. [Google Scholar] [CrossRef] [PubMed]
- Schwimmer, J.B.; Deutsch, R.; Kahen, T.; Lavine, J.E.; Stanley, C.; Behling, C. Prevalence of fatty liver in children and adolescents. Pediatrics 2006, 118, 1388–1393. [Google Scholar] [CrossRef] [PubMed]
- Goldner, D.; Lavine, J.E. Nonalcoholic Fatty Liver Disease in Children: Unique Considerations and Challenges. Gastroenterology 2020, 158, 1967–1983.e1961. [Google Scholar] [CrossRef] [PubMed]
- Mischel, A.K.; Liao, Z.; Cao, F.; Dunn, W.; Lo, J.C.; Newton, K.P.; Goyal, N.P.; Yu, E.L.; Schwimmer, J.B. Prevalence of Elevated ALT in Adolescents in the US 2011–2018. J. Pediatr. Gastroenterol. Nutr. 2023, 77, 103–109. [Google Scholar] [CrossRef] [PubMed]
- Yu, E.L.; Golshan, S.; Harlow, K.E.; Angeles, J.E.; Durelle, J.; Goyal, N.P.; Newton, K.P.; Sawh, M.C.; Hooker, J.; Sy, E.Z.; et al. Prevalence of Nonalcoholic Fatty Liver Disease in Children with Obesity. J. Pediatr. 2019, 207, 64–70. [Google Scholar] [CrossRef] [PubMed]
- Welsh, J.A.; Karpen, S.; Vos, M.B. Increasing prevalence of nonalcoholic fatty liver disease among United States adolescents, 1988–1994 to 2007–2010. J. Pediatr. 2013, 162, 496–500.e491. [Google Scholar] [CrossRef] [PubMed]
- Grønbæk, H.; Lange, A.; Birkebæk, N.H.; Holland-Fischer, P.; Solvig, J.; Hørlyck, A.; Kristensen, K.; Rittig, S.; Vilstrup, H. Effect of a 10-week weight loss camp on fatty liver disease and insulin sensitivity in obese Danish children. J. Pediatr. Gastroenterol. Nutr. 2012, 54, 223–228. [Google Scholar] [CrossRef]
- Ramon-Krauel, M.; Salsberg, S.L.; Ebbeling, C.B.; Voss, S.D.; Mulkern, R.V.; Apura, M.M.; Cooke, E.A.; Sarao, K.; Jonas, M.M.; Ludwig, D.S. A low-glycemic-load versus low-fat diet in the treatment of fatty liver in obese children. Child. Obes. 2013, 9, 252–260. [Google Scholar] [CrossRef]
- Nobili, V.; Marcellini, M.; Devito, R.; Ciampalini, P.; Piemonte, F.; Comparcola, D.; Sartorelli, M.R.; Angulo, P. NAFLD in children: A prospective clinical-pathological study and effect of lifestyle advice. Hepatology 2006, 44, 458–465. [Google Scholar] [CrossRef]
- Reinehr, T.; Schmidt, C.; Toschke, A.M.; Andler, W. Lifestyle intervention in obese children with non-alcoholic fatty liver disease: 2-year follow-up study. Arch. Dis. Child. 2009, 94, 437–442. [Google Scholar] [CrossRef]
- Pozzato, C.; Verduci, E.; Scaglioni, S.; Radaelli, G.; Salvioni, M.; Rovere, A.; Cornalba, G.; Riva, E.; Giovannini, M. Liver fat change in obese children after a 1-year nutrition-behavior intervention. J. Pediatr. Gastroenterol. Nutr. 2010, 51, 331–335. [Google Scholar] [CrossRef] [PubMed]
- Koot, B.G.P.; van der Baan-Slootweg, O.H.; Vinke, S.; Bohte, A.E.; Tamminga-Smeulders, C.L.J.; Jansen, P.L.M.; Stoker, J.; Benninga, M.A. Intensive lifestyle treatment for non-alcoholic fatty liver disease in children with severe obesity: Inpatient versus ambulatory treatment. Int. J. Obes. 2016, 40, 51–57. [Google Scholar] [CrossRef] [PubMed]
- Draijer, L.; Benninga, M.; Koot, B. Pediatric NAFLD: An overview and recent developments in diagnostics and treatment. Expert. Rev. Gastroenterol. Hepatol. 2019, 13, 447–461. [Google Scholar] [CrossRef] [PubMed]
- Geng, Y.; Faber, K.N.; de Meijer, V.E.; Blokzijl, H.; Moshage, H. How does hepatic lipid accumulation lead to lipotoxicity in non-alcoholic fatty liver disease? Hepatol. Int. 2021, 15, 21–35. [Google Scholar] [CrossRef] [PubMed]
- Ipsen, D.H.; Lykkesfeldt, J.; Tveden-Nyborg, P. Molecular mechanisms of hepatic lipid accumulation in non-alcoholic fatty liver disease. Cell. Mol. Life Sci. CMLS 2018, 75, 3313–3327. [Google Scholar] [CrossRef] [PubMed]
- Lipke, K.; Kubis-Kubiak, A.; Piwowar, A. Molecular Mechanism of Lipotoxicity as an Interesting Aspect in the Development of Pathological States-Current View of Knowledge. Cells 2022, 11, 844. [Google Scholar] [CrossRef] [PubMed]
- Liangpunsakul, S.; Chalasani, N. Lipid mediators of liver injury in nonalcoholic fatty liver disease. Am. J. Physiol. Gastrointest. Liver Physiol. 2019, 316, G75–G81. [Google Scholar] [CrossRef]
- Rada, P.; González-Rodríguez, Á.; García-Monzón, C.; Valverde, Á.M. Understanding lipotoxicity in NAFLD pathogenesis: Is CD36 a key driver? Cell Death Dis. 2020, 11, 802. [Google Scholar] [CrossRef]
- Jensen, T.; Abdelmalek, M.F.; Sullivan, S.; Nadeau, K.J.; Green, M.; Roncal, C.; Nakagawa, T.; Kuwabara, M.; Sato, Y.; Kang, D.H.; et al. Fructose and sugar: A major mediator of non-alcoholic fatty liver disease. J. Hepatol. 2018, 68, 1063–1075. [Google Scholar] [CrossRef]
- Maersk, M.; Belza, A.; Stødkilde-Jørgensen, H.; Ringgaard, S.; Chabanova, E.; Thomsen, H.; Pedersen, S.B.; Astrup, A.; Richelsen, B. Sucrose-sweetened beverages increase fat storage in the liver, muscle, and visceral fat depot: A 6-mo randomized intervention study. Am. J. Clin. Nutr. 2011, 95, 283–289. [Google Scholar] [CrossRef]
- Parry, S.A.; Hodson, L. Influence of dietary macronutrients on liver fat accumulation and metabolism. J. Investig. Med. 2017, 65, 1102. [Google Scholar] [CrossRef] [PubMed]
- Schwarz, J.-M.; Noworolski, S.M.; Wen, M.J.; Dyachenko, A.; Prior, J.L.; Weinberg, M.E.; Herraiz, L.A.; Tai, V.W.; Bergeron, N.; Bersot, T.P.; et al. Effect of a High-Fructose Weight-Maintaining Diet on Lipogenesis and Liver Fat. J. Clin. Endocrinol. Metab. 2015, 100, 2434–2442. [Google Scholar] [CrossRef] [PubMed]
- Schwimmer, J.B.; Ugalde-Nicalo, P.; Welsh, J.A.; Angeles, J.E.; Cordero, M.; Harlow, K.E.; Alazraki, A.; Durelle, J.; Knight-Scott, J.; Newton, K.P.; et al. Effect of a Low Free Sugar Diet vs. Usual Diet on Nonalcoholic Fatty Liver Disease in Adolescent Boys: A Randomized Clinical Trial. JAMA 2019, 321, 256–265. [Google Scholar] [CrossRef]
- Cohen, C.C.; Li, K.W.; Alazraki, A.L.; Beysen, C.; Carrier, C.A.; Cleeton, R.L.; Dandan, M.; Figueroa, J.; Knight-Scott, J.; Knott, C.J.; et al. Dietary sugar restriction reduces hepatic de novo lipogenesis in adolescent boys with fatty liver disease. J. Clin. Investig. 2021, 131, e150996. [Google Scholar] [CrossRef]
- Cohen, C.C.; Huneault, H.; Accardi, C.J.; Jones, D.P.; Liu, K.; Maner-Smith, K.M.; Song, M.; Welsh, J.A.; Ugalde-Nicalo, P.A.; Schwimmer, J.B.; et al. Metabolome × Microbiome Changes Associated with a Diet-Induced Reduction in Hepatic Fat among Adolescent Boys. Metabolites 2023, 13, 401. [Google Scholar] [CrossRef] [PubMed]
- Khusial, R.D.; Cioffi, C.E.; Caltharp, S.A.; Krasinskas, A.M.; Alazraki, A.; Knight-Scott, J.; Cleeton, R.; Castillo-Leon, E.; Jones, D.P.; Pierpont, B.; et al. Development of a Plasma Screening Panel for Pediatric Nonalcoholic Fatty Liver Disease Using Metabolomics. Hepatol. Commun. 2019, 3, 1311–1321. [Google Scholar] [CrossRef] [PubMed]
- Yang, K.; Han, X. Lipidomics: Techniques, Applications, and Outcomes Related to Biomedical Sciences. Trends Biochem. Sci. 2016, 41, 954–969. [Google Scholar] [CrossRef]
- Züllig, T.; Trötzmüller, M.; Köfeler, H.C. Lipidomics from sample preparation to data analysis: A primer. Anal. Bioanal. Chem. 2020, 412, 2191–2209. [Google Scholar] [CrossRef] [PubMed]
- Perakakis, N.; Stefanakis, K.; Mantzoros, C.S. The role of omics in the pathophysiology, diagnosis and treatment of non-alcoholic fatty liver disease. Metabolism 2020, 111, 154320. [Google Scholar] [CrossRef]
- Kartsoli, S.; Kostara, C.E.; Tsimihodimos, V.; Bairaktari, E.T.; Christodoulou, D.K. Lipidomics in non-alcoholic fatty liver disease. World J. Hepatol. 2020, 12, 436–450. [Google Scholar] [CrossRef]
- Misheva, M.; Johnson, J.; McCullagh, J. Role of Oxylipins in the Inflammatory-Related Diseases NAFLD, Obesity, and Type 2 Diabetes. Metabolites 2022, 12, 1238. [Google Scholar] [CrossRef] [PubMed]
- Gabbs, M.; Leng, S.; Devassy, J.G.; Monirujjaman, M.; Aukema, H.M. Advances in Our Understanding of Oxylipins Derived from Dietary PUFAs. Adv. Nutr. 2015, 6, 513–540. [Google Scholar] [CrossRef] [PubMed]
- Yamaguchi, A.; Botta, E.; Holinstat, M. Eicosanoids in inflammation in the blood and the vessel. Front. Pharmacol. 2022, 13, 997403. [Google Scholar] [CrossRef] [PubMed]
- Santoro, N.; Feldstein, A.E. The role of oxidized lipid species in insulin resistance and NASH in children. Front. Endocrinol. 2022, 13, 1019204. [Google Scholar] [CrossRef] [PubMed]
- Santoro, N.; Caprio, S.; Giannini, C.; Kim, G.; Kursawe, R.; Pierpont, B.; Shaw, M.M.; Feldstein, A.E. Oxidized Fatty Acids: A Potential Pathogenic Link Between Fatty Liver and Type 2 Diabetes in Obese Adolescents? Antioxid. Redox Signal. 2014, 20, 383–389. [Google Scholar] [CrossRef]
- Mann, J.P.; Jenkins, B.; Furse, S.; Snowden, S.G.; Alisi, A.; Draijer, L.G.; Karnebeek, K.; Kelly, D.A.; Koot, B.G.; Mosca, A.; et al. Comparison of the Lipidomic Signature of Fatty Liver in Children and Adults: A Cross-Sectional Study. J. Pediatr. Gastroenterol. Nutr. 2022, 74, 734–741. [Google Scholar] [CrossRef]
- Di Sessa, A.; Riccio, S.; Pirozzi, E.; Verde, M.; Passaro, A.P.; Umano, G.R.; Guarino, S.; Miraglia Del Giudice, E.; Marzuillo, P. Advances in paediatric nonalcoholic fatty liver disease: Role of lipidomics. World J. Gastroenterol. 2021, 27, 3815–3824. [Google Scholar] [CrossRef] [PubMed]
- Matthews, D.R.; Hosker, J.P.; Rudenski, A.S.; Naylor, B.A.; Treacher, D.F.; Turner, R.C. Homeostasis model assessment: Insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 1985, 28, 412–419. [Google Scholar] [CrossRef] [PubMed]
- Simental-Mendía, L.E.; Rodríguez-Morán, M.; Guerrero-Romero, F. The product of fasting glucose and triglycerides as surrogate for identifying insulin resistance in apparently healthy subjects. Metab. Syndr. Relat. Disord. 2008, 6, 299–304. [Google Scholar] [CrossRef]
- Brunt, E.M.; Kleiner, D.E.; Wilson, L.A.; Belt, P.; Neuschwander-Tetri, B.A. Nonalcoholic fatty liver disease (NAFLD) activity score and the histopathologic diagnosis in NAFLD: Distinct clinicopathologic meanings. Hepatology 2011, 53, 810–820. [Google Scholar] [CrossRef]
- Walker, D.I.; Lane, K.J.; Liu, K.; Uppal, K.; Patton, A.P.; Durant, J.L.; Jones, D.P.; Brugge, D.; Pennell, K.D. Metabolomic assessment of exposure to near-highway ultrafine particles. J. Expo. Sci. Environ. Epidemiol. 2018, 29, 469–483. [Google Scholar] [CrossRef]
- Walker, D.I.; Perry-Walker, K.; Finnell, R.H.; Pennell, K.D.; Tran, V.; May, R.C.; McElrath, T.F.; Meador, K.J.; Pennell, P.B.; Jones, D.P. Metabolome-wide association study of anti-epileptic drug treatment during pregnancy. Toxicol. Appl. Pharmacol. 2019, 363, 122–130. [Google Scholar] [CrossRef]
- Collins, J.M.; Jones, D.P.; Sharma, A.; Khadka, M.; Liu, K.H.; Kempker, R.R.; Prideaux, B.; Maner-Smith, K.; Tukvadze, N.; Shah, N.S.; et al. TCA cycle remodeling drives proinflammatory signaling in humans with pulmonary tuberculosis. PLoS Pathog. 2021, 17, e1009941. [Google Scholar] [CrossRef]
- Maner-Smith, K.M.; Goll, J.B.; Khadka, M.; Jensen, T.L.; Colucci, J.K.; Gelber, C.E.; Albert, C.J.; Bosinger, S.E.; Franke, J.D.; Natrajan, M.; et al. Alterations in the Human Plasma Lipidome in Response to Tularemia Vaccination. Vaccines 2020, 8, 414. [Google Scholar] [CrossRef]
- Strassburg, K.; Huijbrechts, A.M.; Kortekaas, K.A.; Lindeman, J.H.; Pedersen, T.L.; Dane, A.; Berger, R.; Brenkman, A.; Hankemeier, T.; van Duynhoven, J.; et al. Quantitative profiling of oxylipins through comprehensive LC-MS/MS analysis: Application in cardiac surgery. Anal. Bioanal. Chem. 2012, 404, 1413–1426. [Google Scholar] [CrossRef]
- Gouveia-Figueira, S.; Späth, J.; Zivkovic, A.M.; Nording, M.L. Profiling the Oxylipin and Endocannabinoid Metabolome by UPLC-ESI-MS/MS in Human Plasma to Monitor Postprandial Inflammation. PLoS ONE 2015, 10, e0132042. [Google Scholar] [CrossRef]
- Wei, R.; Wang, J.; Su, M.; Jia, E.; Chen, S.; Chen, T.; Ni, Y. Missing Value Imputation Approach for Mass Spectrometry-based Metabolomics Data. Sci. Rep. 2018, 8, 663. [Google Scholar] [CrossRef]
- Liquet, B.; Cao, K.-A.L.; Hocini, H.; Thiébaut, R. A novel approach for biomarker selection and the integration of repeated measures experiments from two assays. BMC Bioinform. 2012, 13, 325. [Google Scholar] [CrossRef]
- Kucheryavskiy, S. mdatools—R package for chemometrics. Chemom. Intell. Lab. Syst. 2020, 198, 103937. [Google Scholar] [CrossRef]
- Ritchie, M.E.; Phipson, B.; Wu, D.; Hu, Y.; Law, C.W.; Shi, W.; Smyth, G.K. limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res. 2015, 43, e47. [Google Scholar] [CrossRef]
- Slowikowski, K.; Schep, A.; Hughes, S.; Lukauskas, S.; Irisson, J.-O.; Kamvar, Z.N.; Ryan, T.; Christophe, D.; Hiroaki, Y.; Gramme, P. Automatically Position Non-Overlapping Text Labels with ‘ggplot2’, version 0.9.5, Package Ggrepel; GitHub: San Francisco, CA, USA, 2018. [Google Scholar]
- Gagolewski, M. Stringi: Fast and portable character string processing in R. J. Stat. Softw. 2022, 103, 1–59. [Google Scholar] [CrossRef]
- Bakdash, J.Z.; Marusich, L.R. Repeated Measures Correlation. Front. Psychol. 2017, 8, 456. [Google Scholar] [CrossRef]
- Gu, Z.; Eils, R.; Schlesner, M. Complex heatmaps reveal patterns and correlations in multidimensional genomic data. Bioinformatics 2016, 32, 2847–2849. [Google Scholar] [CrossRef] [PubMed]
- Kolde, R. Pheatmap: Pretty Heatmaps, Version 1.0.12; R Package Version; CRAN: Bogota, Colombia, 2012. [Google Scholar]
- Langfelder, P.; Horvath, S. WGCNA: An R package for weighted correlation network analysis. BMC Bioinform. 2008, 9, 559. [Google Scholar] [CrossRef] [PubMed]
- Csárdi, G.; Nepusz, T. Igraph Reference Manual. Available online: https://igraph.org/c/doc/ (accessed on 20 April 2010).
- Pedersen, T.L.; Pedersen, M.; LazyData, T.; Rcpp, I.; Rcpp, L. An Implementation of Grammar of Graphics for Graphs and Networks, version 2.2.1; Package ’ggraph’; GitHub: San Francisco, CA, USA, 2017. [Google Scholar]
- Subramanian, A.; Tamayo, P.; Mootha, V.K.; Mukherjee, S.; Ebert, B.L.; Gillette, M.A.; Paulovich, A.; Pomeroy, S.L.; Golub, T.R.; Lander, E.S.; et al. Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles. Proc. Natl. Acad. Sci. USA 2005, 102, 15545–15550. [Google Scholar] [CrossRef] [PubMed]
- Sergushichev, A. An algorithm for fast preranked gene set enrichment analysis using cumulative statistic calculation. bioRxiv 2016. [Google Scholar]
- Puri, P.; Wiest, M.M.; Cheung, O.; Mirshahi, F.; Sargeant, C.; Min, H.-K.; Contos, M.J.; Sterling, R.K.; Fuchs, M.; Zhou, H.; et al. The plasma lipidomic signature of nonalcoholic steatohepatitis. Hepatology 2009, 50, 1827–1838. [Google Scholar] [CrossRef]
- Puri, P.; Baillie, R.A.; Wiest, M.M.; Mirshahi, F.; Choudhury, J.; Cheung, O.; Sargeant, C.; Contos, M.J.; Sanyal, A.J. A lipidomic analysis of nonalcoholic fatty liver disease. Hepatology 2007, 46, 1081–1090. [Google Scholar] [CrossRef]
- Kumashiro, N.; Erion, D.M.; Zhang, D.; Kahn, M.; Beddow, S.A.; Chu, X.; Still, C.D.; Gerhard, G.S.; Han, X.; Dziura, J.; et al. Cellular mechanism of insulin resistance in nonalcoholic fatty liver disease. Proc. Natl. Acad. Sci. USA 2011, 108, 16381–16385. [Google Scholar] [CrossRef]
- Gorden, D.L.; Ivanova, P.T.; Myers, D.S.; McIntyre, J.O.; VanSaun, M.N.; Wright, J.K.; Matrisian, L.M.; Brown, H.A. Increased diacylglycerols characterize hepatic lipid changes in progression of human nonalcoholic fatty liver disease; comparison to a murine model. PLoS ONE 2011, 6, e22775. [Google Scholar] [CrossRef]
- Byrne, C.D.; Targher, G. NAFLD: A multisystem disease. J. Hepatol. 2015, 62, S47–S64. [Google Scholar] [CrossRef] [PubMed]
- Samuel, V.T.; Shulman, G.I. Nonalcoholic Fatty Liver Disease as a Nexus of Metabolic and Hepatic Diseases. Cell Metab. 2018, 27, 22–41. [Google Scholar] [CrossRef]
- Petersen, M.C.; Shulman, G.I. Roles of Diacylglycerols and Ceramides in Hepatic Insulin Resistance. Trends Pharmacol. Sci. 2017, 38, 649–665. [Google Scholar] [CrossRef] [PubMed]
- Van der Veen, J.N.; Kennelly, J.P.; Wan, S.; Vance, J.E.; Vance, D.E.; Jacobs, R.L. The critical role of phosphatidylcholine and phosphatidylethanolamine metabolism in health and disease. Biochim. Biophys. Acta (BBA)—Biomembr. 2017, 1859, 1558–1572. [Google Scholar] [CrossRef]
- Tiwari-Heckler, S.; Gan-Schreier, H.; Stremmel, W.; Chamulitrat, W.; Pathil, A. Circulating Phospholipid Patterns in NAFLD Patients Associated with a Combination of Metabolic Risk Factors. Nutrients 2018, 10, 649. [Google Scholar] [CrossRef] [PubMed]
- Hollie, N.I.; Cash, J.G.; Matlib, M.A.; Wortman, M.; Basford, J.E.; Abplanalp, W.; Hui, D.Y. Micromolar changes in lysophosphatidylcholine concentration cause minor effects on mitochondrial permeability but major alterations in function. Biochim. Biophys. Acta (BBA)—Mol. Cell Biol. Lipids 2014, 1841, 888–895. [Google Scholar] [CrossRef] [PubMed]
- Chin, C.F.; Galam, D.; Gao, L.; Tan, B.C.; Wong, B.H.; Chua, G.L.; Loke, R.Y.; Lim, Y.C.; Wenk, M.R.; Lim, M.S.; et al. Blood-derived lysophospholipid sustains hepatic phospholipids and fat storage necessary for hepatoprotection in overnutrition. J. Clin. Investig. 2023, 133, e171267. [Google Scholar] [CrossRef] [PubMed]
- Cantero, I.; Abete, I.; del Bas, J.M.; Caimari, A.; Arola, L.; Zulet, M.A.; Martinez, J.A. Changes in lysophospholipids and liver status after weight loss: The RESMENA study. Nutr. Metab. 2018, 15, 51. [Google Scholar] [CrossRef] [PubMed]
- Kerr, T.A.; Davidson, N.O. Cholesterol and nonalcoholic fatty liver disease: Renewed focus on an old villain. Hepatology 2012, 56, 1995–1998. [Google Scholar] [CrossRef]
- Gorden, D.L.; Myers, D.S.; Ivanova, P.T.; Fahy, E.; Maurya, M.R.; Gupta, S.; Min, J.; Spann, N.J.; McDonald, J.G.; Kelly, S.L.; et al. Biomarkers of NAFLD progression: A lipidomics approach to an epidemic. J. Lipid Res. 2015, 56, 722–736. [Google Scholar] [CrossRef] [PubMed]
- Trapani, L.; Segatto, M.; Pallottini, V. Regulation and deregulation of cholesterol homeostasis: The liver as a metabolic “power station”. World J. Hepatol. 2012, 4, 184–190. [Google Scholar] [CrossRef] [PubMed]
- Mensenkamp, A.R.; Havekes, L.M.; Romijn, J.A.; Kuipers, F. Hepatic steatosis and very low density lipoprotein secretion: The involvement of apolipoprotein E. J. Hepatol. 2001, 35, 816–822. [Google Scholar] [CrossRef] [PubMed]
- Simon, J.; Ouro, A.; Ala-Ibanibo, L.; Presa, N.; Delgado, T.C.; Martínez-Chantar, M.L. Sphingolipids in Non-Alcoholic Fatty Liver Disease and Hepatocellular Carcinoma: Ceramide Turnover. Int. J. Mol. Sci. 2019, 21, 40. [Google Scholar] [CrossRef] [PubMed]
- Musso, G.; Cassader, M.; Paschetta, E.; Gambino, R. Bioactive Lipid Species and Metabolic Pathways in Progression and Resolution of Nonalcoholic Steatohepatitis. Gastroenterology 2018, 155, 282–302.e288. [Google Scholar] [CrossRef] [PubMed]
- Hajduch, E.; Lachkar, F.; Ferré, P.; Foufelle, F. Roles of Ceramides in Non-Alcoholic Fatty Liver Disease. J. Clin. Med. 2021, 10, 792. [Google Scholar] [CrossRef]
- Gadgil, M.D.; Sarkar, M.; Sands, C.; Lewis, M.R.; Herrington, D.M.; Kanaya, A.M. Associations of NAFLD with circulating ceramides and impaired glycemia. Diabetes Res. Clin. Pract. 2022, 186, 109829. [Google Scholar] [CrossRef]
- Poss, A.M.; Summers, S.A. Too Much of a Good Thing? An Evolutionary Theory to Explain the Role of Ceramides in NAFLD. Front. Endocrinol. 2020, 11, 505. [Google Scholar] [CrossRef]
- Hanamatsu, H.; Ohnishi, S.; Sakai, S.; Yuyama, K.; Mitsutake, S.; Takeda, H.; Hashino, S.; Igarashi, Y. Altered levels of serum sphingomyelin and ceramide containing distinct acyl chains in young obese adults. Nutr. Diabetes 2014, 4, e141. [Google Scholar] [CrossRef]
- Torretta, E.; Barbacini, P.; Al-Daghri, N.M.; Gelfi, C. Sphingolipids in Obesity and Correlated Co-Morbidities: The Contribution of Gender, Age and Environment. Int. J. Mol. Sci. 2019, 20, 5901. [Google Scholar] [CrossRef]
- Green, C.D.; Maceyka, M.; Cowart, L.A.; Spiegel, S. Sphingolipids in metabolic disease: The good, the bad, and the unknown. Cell Metab. 2021, 33, 1293–1306. [Google Scholar] [CrossRef]
- Couttas, T.A.; Rustam, Y.H.; Song, H.; Qi, Y.; Teo, J.D.; Chen, J.; Reid, G.E.; Don, A.S. A Novel Function of Sphingosine Kinase 2 in the Metabolism of Sphinga-4,14-Diene Lipids. Metabolites 2020, 10, 236. [Google Scholar] [CrossRef]
- Raichur, S.; Wang, S.T.; Chan, P.W.; Li, Y.; Ching, J.; Chaurasia, B.; Dogra, S.; Öhman, M.K.; Takeda, K.; Sugii, S.; et al. CerS2 haploinsufficiency inhibits β-oxidation and confers susceptibility to diet-induced steatohepatitis and insulin resistance. Cell Metab. 2014, 20, 687–695. [Google Scholar] [CrossRef] [PubMed]
- Gault, C.R.; Obeid, L.M.; Hannun, Y.A. An overview of sphingolipid metabolism: From synthesis to breakdown. In Sphingolipids as Signaling and Regulatory Molecules; Advances in Experimental Medicine and Biology; Springer: New York, NY, USA, 2010; Volume 688, pp. 1–23. [Google Scholar] [CrossRef]
- Gao, X.; Lee, K.; Reid, M.A.; Sanderson, S.M.; Qiu, C.; Li, S.; Liu, J.; Locasale, J.W. Serine Availability Influences Mitochondrial Dynamics and Function through Lipid Metabolism. Cell Rep. 2018, 22, 3507–3520. [Google Scholar] [CrossRef] [PubMed]
- Zhou, X.; He, L.; Zuo, S.; Zhang, Y.; Wan, D.; Long, C.; Huang, P.; Wu, X.; Wu, C.; Liu, G.; et al. Serine prevented high-fat diet-induced oxidative stress by activating AMPK and epigenetically modulating the expression of glutathione synthesis-related genes. Biochim Biophys Acta Mol Basis Dis 2018, 1864, 488–498. [Google Scholar] [CrossRef]
- Papandreou, C.; Bullò, M.; Tinahones, F.J.; Martínez-González, M.Á.; Corella, D.; Fragkiadakis, G.A.; López-Miranda, J.; Estruch, R.; Fitó, M.; Salas-Salvadó, J. Serum metabolites in non-alcoholic fatty-liver disease development or reversion; a targeted metabolomic approach within the PREDIMED trial. Nutr. Metab. 2017, 14, 58. [Google Scholar] [CrossRef]
- Carta, G.; Murru, E.; Banni, S.; Manca, C. Palmitic Acid: Physiological Role, Metabolism and Nutritional Implications. Front. Physiol. 2017, 8, 902. [Google Scholar] [CrossRef] [PubMed]
- Vvedenskaya, O.; Rose, T.D.; Knittelfelder, O.; Palladini, A.; Wodke, J.A.H.; Schuhmann, K.; Ackerman, J.M.; Wang, Y.; Has, C.; Brosch, M.; et al. Nonalcoholic fatty liver disease stratification by liver lipidomics. J Lipid Res 2021, 62, 100104. [Google Scholar] [CrossRef]
- Montgomery, M.K.; Brown, S.H.; Lim, X.Y.; Fiveash, C.E.; Osborne, B.; Bentley, N.L.; Braude, J.P.; Mitchell, T.W.; Coster, A.C.; Don, A.S.; et al. Regulation of glucose homeostasis and insulin action by ceramide acyl-chain length: A beneficial role for very long-chain sphingolipid species. Biochim. Biophys. Acta 2016, 1861, 1828–1839. [Google Scholar] [CrossRef]
- Song, Z.; Xiaoli, A.M.; Yang, F. Regulation and Metabolic Significance of De Novo Lipogenesis in Adipose Tissues. Nutrients 2018, 10, 1383. [Google Scholar] [CrossRef]
- Wunderling, K.; Zurkovic, J.; Zink, F.; Kuerschner, L.; Thiele, C. Triglyceride cycling enables modification of stored fatty acids. Nat. Metab. 2023, 5, 699–709. [Google Scholar] [CrossRef]
- Rhee, E.P.; Cheng, S.; Larson, M.G.; Walford, G.A.; Lewis, G.D.; McCabe, E.; Yang, E.; Farrell, L.; Fox, C.S.; O’Donnell, C.J.; et al. Lipid profiling identifies a triacylglycerol signature of insulin resistance and improves diabetes prediction in humans. J. Clin. Investig. 2011, 121, 1402–1411. [Google Scholar] [CrossRef] [PubMed]
- Han, M.S.; Lim, Y.M.; Quan, W.; Kim, J.R.; Chung, K.W.; Kang, M.; Kim, S.; Park, S.Y.; Han, J.S.; Park, S.Y.; et al. Lysophosphatidylcholine as an effector of fatty acid-induced insulin resistance. J. Lipid. Res. 2011, 52, 1234–1246. [Google Scholar] [CrossRef]
- Prada, M.; Wittenbecher, C.; Eichelmann, F.; Wernitz, A.; Drouin-Chartier, J.P.; Schulze, M.B. Association of the odd-chain fatty acid content in lipid groups with type 2 diabetes risk: A targeted analysis of lipidomics data in the EPIC-Potsdam cohort. Clin. Nutr. 2021, 40, 4988–4999. [Google Scholar] [CrossRef]
- Livingstone, K.M.; Ramos-Lopez, O.; Pérusse, L.; Kato, H.; Ordovas, J.M.; Martínez, J.A. Precision nutrition: A review of current approaches and future endeavors. Trends Food Sci. Technol. 2022, 128, 253–264. [Google Scholar] [CrossRef]
- Lonardo, A.; Arab, J.P.; Arrese, M. Perspectives on Precision Medicine Approaches to NAFLD Diagnosis and Management. Adv. Ther. 2021, 38, 2130–2158. [Google Scholar] [CrossRef]
- Samuel, V.T.; Shulman, G.I. The pathogenesis of insulin resistance: Integrating signaling pathways and substrate flux. J. Clin. Investig. 2016, 126, 12–22. [Google Scholar] [CrossRef]
- Pagadala, M.; Kasumov, T.; McCullough, A.J.; Zein, N.N.; Kirwan, J.P. Role of ceramides in nonalcoholic fatty liver disease. Trends Endocrinol. Metab. 2012, 23, 365–371. [Google Scholar] [CrossRef] [PubMed]
- Kim, J.Y.; Lee, J.W.; Youn, Y.J.; Ahn, M.S.; Ahn, S.G.; Yoo, B.S.; Lee, S.H.; Yoon, J.; Choe, K.H. Urinary levels of 8-iso-prostaglandin f2α and 8-hydroxydeoxyguanine as markers of oxidative stress in patients with coronary artery disease. Korean Circ. J. 2012, 42, 614–617. [Google Scholar] [CrossRef]
- Gopaul, N.K.; Anggård, E.E.; Mallet, A.I.; Betteridge, D.J.; Wolff, S.P.; Nourooz-Zadeh, J. Plasma 8-epi-PGF2 alpha levels are elevated in individuals with non-insulin dependent diabetes mellitus. FEBS Lett. 1995, 368, 225–229. [Google Scholar] [CrossRef]
- Morrow, J.D.; Frei, B.; Longmire, A.W.; Gaziano, J.M.; Lynch, S.M.; Shyr, Y.; Strauss, W.E.; Oates, J.A.; Roberts, L.J., 2nd. Increase in circulating products of lipid peroxidation (F2-isoprostanes) in smokers. Smoking as a cause of oxidative damage. N. Engl. J. Med. 1995, 332, 1198–1203. [Google Scholar] [CrossRef]
- Sampson, M.J.; Gopaul, N.; Davies, I.R.; Hughes, D.A.; Carrier, M.J. Plasma F2 isoprostanes: Direct evidence of increased free radical damage during acute hyperglycemia in type 2 diabetes. Diabetes Care 2002, 25, 537–541. [Google Scholar] [CrossRef] [PubMed]
- Konishi, M.; Iwasa, M.; Araki, J.; Kobayashi, Y.; Katsuki, A.; Sumida, Y.; Nakagawa, N.; Kojima, Y.; Watanabe, S.; Adachi, Y.; et al. Increased lipid peroxidation in patients with non-alcoholic fatty liver disease and chronic hepatitis C as measured by the plasma level of 8-isoprostane. J. Gastroenterol. Hepatol. 2006, 21, 1821–1825. [Google Scholar] [CrossRef] [PubMed]
- Schuck, R.N.; Zha, W.; Edin, M.L.; Gruzdev, A.; Vendrov, K.C.; Miller, T.M.; Xu, Z.; Lih, F.B.; DeGraff, L.M.; Tomer, K.B.; et al. The cytochrome P450 epoxygenase pathway regulates the hepatic inflammatory response in fatty liver disease. PLoS ONE 2014, 9, e110162. [Google Scholar] [CrossRef] [PubMed]
- Wells, M.A.; Vendrov, K.C.; Edin, M.L.; Ferslew, B.C.; Zha, W.; Nguyen, B.K.; Church, R.J.; Lih, F.B.; DeGraff, L.M.; Brouwer, K.L.; et al. Characterization of the Cytochrome P450 epoxyeicosanoid pathway in non-alcoholic steatohepatitis. Prostaglandins Other Lipid Mediat. 2016, 125, 19–29. [Google Scholar] [CrossRef] [PubMed]
- Loomba, R.; Quehenberger, O.; Armando, A.; Dennis, E.A. Polyunsaturated fatty acid metabolites as novel lipidomic biomarkers for noninvasive diagnosis of nonalcoholic steatohepatitis. J. Lipid Res. 2015, 56, 185–192. [Google Scholar] [CrossRef] [PubMed]
- Zeldin, D.C. Epoxygenase pathways of arachidonic acid metabolism. J. Biol. Chem. 2001, 276, 36059–36062. [Google Scholar] [CrossRef] [PubMed]
- Kalveram, L.; Schunck, W.H.; Rothe, M.; Rudolph, B.; Loddenkemper, C.; Holzhütter, H.G.; Henning, S.; Bufler, P.; Schulz, M.; Meierhofer, D.; et al. Regulation of the cytochrome P450 epoxyeicosanoid pathway is associated with distinct histologic features in pediatric non-alcoholic fatty liver disease. Prostaglandins Leukot. Essent. Fat. Acids 2021, 164, 102229. [Google Scholar] [CrossRef]
Characteristic | Intervention, N = 20 1 | Control, N = 20 1 | p-Value 2 |
---|---|---|---|
Age (y) | 12.75 (1.80) | 13.30 (1.81) | 0.3 |
BMI (kg/m2) | 33.70 (5.57) | 32.29 (6.28) | 0.4 |
BMI z-score | 2.38 (0.28) | 2.22 (0.48) | 0.3 |
ALT (U/L) | 132.30 (112.23) | 91.90 (47.12) | 0.4 |
AST (U/L) | 65.30 (52.15) | 49.85 (28.08) | 0.7 |
GGT (U/L) | 53.25 (34.17) | 52.30 (35.00) | >0.9 |
Glucose (mg/dL) | 91.05 (9.80) | 90.45 (13.85) | >0.9 |
Insulin (uIU/L) | 42.99 (22.99) | 53.62 (43.76) | 0.5 |
HOMA-IR | 9.94 (5.99) | 12.76 (12.67) | 0.6 |
TG (mg/dL) | 144.15 (83.01) | 148.00 (48.67) | 0.5 |
TC (mg/dL) | 162.10 (42.46) | 157.25 (31.30) | 0.9 |
LDL (mg/dL) | 100.50 (34.85) | 95.20 (24.06) | 0.7 |
HDL (mg/dL) | 40.10 (7.06) | 40.50 (7.16) | >0.9 |
Hepatic steatosis (%) | 24.93 (11.21) | 20.78 (8.16) | 0.2 |
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Huneault, H.E.; Chen, C.-Y.; Cohen, C.C.; Liu, X.; Jarrell, Z.R.; He, Z.; DeSantos, K.E.; Welsh, J.A.; Maner-Smith, K.M.; Ortlund, E.A.; et al. Lipidome Changes Associated with a Diet-Induced Reduction in Hepatic Fat among Adolescent Boys with Metabolic Dysfunction-Associated Steatotic Liver Disease. Metabolites 2024, 14, 191. https://doi.org/10.3390/metabo14040191
Huneault HE, Chen C-Y, Cohen CC, Liu X, Jarrell ZR, He Z, DeSantos KE, Welsh JA, Maner-Smith KM, Ortlund EA, et al. Lipidome Changes Associated with a Diet-Induced Reduction in Hepatic Fat among Adolescent Boys with Metabolic Dysfunction-Associated Steatotic Liver Disease. Metabolites. 2024; 14(4):191. https://doi.org/10.3390/metabo14040191
Chicago/Turabian StyleHuneault, Helaina E., Chih-Yu Chen, Catherine C. Cohen, Xueyun Liu, Zachery R. Jarrell, Zhulin He, Karla E. DeSantos, Jean A. Welsh, Kristal M. Maner-Smith, Eric A. Ortlund, and et al. 2024. "Lipidome Changes Associated with a Diet-Induced Reduction in Hepatic Fat among Adolescent Boys with Metabolic Dysfunction-Associated Steatotic Liver Disease" Metabolites 14, no. 4: 191. https://doi.org/10.3390/metabo14040191