Abstract
Background
Long non-coding RNAs (lncRNAs) have emerged as a rapidly expanding area of interest in chronic diseases. They are mostly unknown for roles in metabolic regulation. Sirtuins, an epigenetic modulator class, regulate metabolic pathways. However, how sirtuins are regulated via lncRNA is unknown. We hypothesized that a high-fat high-fructose diet (HFD-HF) during pregnancy would increase the risk for obesity via lncRNA-Sirtuin pathways.
Methods
Female C57Bl/6 mice (F0) were fed either chow diet (CD) or HFD-HF for 6 weeks till birth. The pups (F1) were fed either CD or HFD-HF for 20 weeks. Expression of Dleu2, sirtuins, mitochondrial respiratory complexes, and oxidative stress were investigated in the F1 livers. Fasting blood glucose, insulin sensitivity, glucose tolerance, body and tissues weight were measured. A mechanistic interaction was then carried out using a DLEU2 knockdown experiment in the HepG2 cell.
Results
Dleu2 and sirtuins were both significantly decreased in the livers of HFD-HF fed male F1 whose mothers were either fed CD or HFD-HF during reproductive and pregnancy windows. Confirming this connection, upon silencing DLEU2, transcription levels of SIRT1 through 6 and translational levels of SIRT1, 3, 5, and 6 were significantly downregulated. Knockdown of DLEU2 significantly decreased the protein level of cytochrome-c oxidase (complex IV, MTCO1) without altering other mitochondrial complexes, decreased mitochondrial membrane potential, decreased ATP, and increased reactive oxygen species. Interestingly, in F1 livers, the protein level of MTCO1 was also significantly decreased under an HFD-HF diet or even under chow diet if the mother was exposed to HFD-HF.
Conclusion
Our findings reveal for the first time that one lncRNA can regulate sirtuins and a specific mitochondrial complex. Furthermore, diet or maternal diet can modulate Dleu2 and its downstream regulators in offspring, suggesting a potential role of DLEU2 in metabolic disorders over one or more generations.
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References
Ng M, Fleming T, Robinson M, Thomson B, Graetz N, Margono C, et al. Global, regional, and national prevalence of overweight and obesity in children and adults during 1980-2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet. 2014;384:766-81. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4624264/.
Soro-Arnaiz I, Li QOY, Torres-Capelli M, Melendez-Rodriguez F, Veiga S, Veys K, et al. Role of mitochondrial complex IV in age-dependent obesity. Cell Rep. 2016;16:2991–3002.
Taylor PD, Poston L. Developmental programming of obesity in mammals. Exp Physiol. 2007;92:287–98.
Yajnik CS, Deshmukh US. Maternal nutrition, intrauterine programming and consequential risks in the offspring. Rev Endocr Metab Disord. 2008;9:203–11.
King SE, Skinner MK. Epigenetic transgenerational inheritance of obesity susceptibility. Trends Endocrinol Metab. 2020;31:478–94.
Li Y. Epigenetic mechanisms link maternal diets and gut microbiome to obesity in the offspring. Front Genet. 2018;9:342.
Dupont C, Armant DR, Brenner CA. Epigenetics: definition, mechanisms and clinical perspective. Semin Reprod Med. 2009;27:351–7.
Ma L, Bajic VB, Zhang Z. On the classification of long non-coding RNAs. RNA Biol. 2013;10:925–33.
Rinn JL, Kertesz M, Wang JK, Squazzo SL, Xu X, Brugmann SA, et al. Functional demarcation of active and silent chromatin domains in human HOX loci by noncoding RNAs. Cell. 2007;129:1311–23.
Mazo A, Hodgson JW, Petruk S, Sedkov Y, Brock HW. Transcriptional interference: an unexpected layer of complexity in gene regulation. J Cell Sci. 2007;120:2755–61. Pt 16
Klein U, Lia M, Crespo M, Siegel R, Shen Q, Mo T, et al. The DLEU2/miR-15a/16-1 cluster controls B cell proliferation and its deletion leads to chronic lymphocytic leukemia. Cancer Cell. 2010;17:28–40.
Lv M, Zhong Z, Huang M, Tian Q, Jiang R, Chen J. lncRNA H19 regulates epithelial-mesenchymal transition and metastasis of bladder cancer by miR-29b-3p as competing endogenous RNA. Biochim Biophys Acta. 2017;1864:1887–99.
Xu B, Gong X, Zi L, Li G, Dong S, Chen X, et al. Silencing of DLEU2 suppresses pancreatic cancer cell proliferation and invasion by upregulating microRNA-455. Cancer Sci. 2019;110:1676–85.
Lerner M, Harada M, Loven J, Castro J, Davis Z, Oscier D, et al. DLEU2, frequently deleted in malignancy, functions as a critical host gene of the cell cycle inhibitory microRNAs miR-15a and miR-16-1. Exp Cell Res. 2009;315:2941–52.
Kwon DN, Chang BS, Kim JH. MicroRNA dysregulation in liver and pancreas of CMP-Neu5Ac hydroxylase null mice disrupts insulin/PI3K-AKT signaling. Biomed Res Int. 2014;2014:236385.
Milazzo G, Mercatelli D, Di Muzio G, Triboli L, De Rosa P, Perini G, et al. Histone deacetylases (HDACs): evolution, specificity, role in transcriptional complexes, and pharmacological actionability. Genes (Basel). 2020;11:556.
Choudhary C, Kumar C, Gnad F, Nielsen ML, Rehman M, Walther TC, et al. Lysine acetylation targets protein complexes and co-regulates major cellular functions. Science. 2009;325:834–40.
Hirschey MD, Shimazu T, Jing E, Grueter CA, Collins AM, Aouizerat B, et al. SIRT3 deficiency and mitochondrial protein hyperacetylation accelerate the development of the metabolic syndrome. Mol Cell. 2011;44:177–90.
Kendrick AA, Choudhury M, Rahman SM, McCurdy CE, Friederich M, Van Hove JL, et al. Fatty liver is associated with reduced SIRT3 activity and mitochondrial protein hyperacetylation. Biochem J. 2011;433:505–14.
Feldman JL, Dittenhafer-Reed KE, Denu JM. Sirtuin catalysis and regulation. J Biol Chem. 2012;287:42419–27.
Borengasser SJ, Lau F, Kang P, Blackburn ML, Ronis MJ, Badger TM, et al. Maternal obesity during gestation impairs fatty acid oxidation and mitochondrial SIRT3 expression in rat offspring at weaning. PLoS One. 2011;6:e24068.
Chang TC, Yu D, Lee YS, Wentzel EA, Arking DE, West KM, et al. Widespread microRNA repression by Myc contributes to tumorigenesis. Nat Genet. 2008;40:43–50.
Zwaans BM, Lombard DB. Interplay between sirtuins, MYC and hypoxia-inducible factor in cancer-associated metabolic reprogramming. Dis Model Mech. 2014;7:1023–32.
Chen CQ, Chen CS, Chen JJ, Zhou LP, Xu HL, Jin WW, et al. Histone deacetylases inhibitor trichostatin A increases the expression of Dleu2/miR-15a/16-1 via HDAC3 in non-small cell lung cancer. Mol Cell Biochem. 2013;383:137–48.
Lombard DB, Tishkoff DX, Bao J. Mitochondrial sirtuins in the regulation of mitochondrial activity and metabolic adaptation. Handb Exp Pharmacol. 2011;206:163–88.
Ngo DTM, Sverdlov AL, Karki S, Macartney-Coxson D, Stubbs RS, Farb MG, et al. Oxidative modifications of mitochondrial complex II are associated with insulin resistance of visceral fat in obesity. Am J Physiol Endocrinol Metab. 2019;316:E168–E177.
Sverdlov AL, Elezaby A, Behring JB, Bachschmid MM, Luptak I, Tu VH, et al. High fat, high sucrose diet causes cardiac mitochondrial dysfunction due in part to oxidative post-translational modification of mitochondrial complex II. J Mol Cell Cardiol. 2015;78:165–73.
Qiu X, Brown K, Hirschey MD, Verdin E, Chen D. Calorie restriction reduces oxidative stress by SIRT3-mediated SOD2 activation. Cell Metab. 2010;12:662–7.
Tseng AH, Shieh SS, Wang DL. SIRT3 deacetylates FOXO3 to protect mitochondria against oxidative damage. Free Radic Biol Med. 2013;63:222–34.
Kong X, Wang R, Xue Y, Liu X, Zhang H, Chen Y, et al. Sirtuin 3, a new target of PGC-1alpha, plays an important role in the suppression of ROS and mitochondrial biogenesis. PLoS One. 2010;5:e11707.
Potthast AB, Heuer T, Warneke SJ, Das AM. Alterations of sirtuins in mitochondrial cytochrome c-oxidase deficiency. PLoS One. 2017;12:e0186517.
Powell CA, Choudhury M. Advancing metabolism research to overcome low litter survival in metabolically stressed mice. Am J Physiol Endocrinol Metab. 2019;317:E261–E268.
Zhang J, Powell CA, Kay MK, Sonkar R, Meruvu S, Choudhury M. Effect of chronic western diets on non-alcoholic fatty liver of male mice modifying the PPAR-gamma pathway via miR-27b-5p regulation. Int J Mol Sci. 2021; 22.
Zhang J, Powell CA, Kay MK, Park MH, Meruvu S, Sonkar R, et al. A moderate physiological dose of benzyl butyl phthalate exacerbates the high fat diet-induced diabesity in male mice. Toxicol Res. 2020;9:353–70.
An T, Zhang T, Teng F, Zuo JC, Pan YY, Liu YF, et al. Long non-coding RNAs could act as vectors for paternal heredity of high fat diet-induced obesity. Oncotarget. 2017;8:47876–89.
Verdin E, Hirschey MD, Finley LW, Haigis MC. Sirtuin regulation of mitochondria: energy production, apoptosis, and signaling. Trends Biochem Sci. 2010;35:669–75.
Nita M, Grzybowski A. The role of the reactive oxygen species and oxidative stress in the pathomechanism of the age-related ocular diseases and other pathologies of the anterior and posterior eye segments in adults. Oxid Med Cell Longev. 2016;2016:3164734.
Lustig RH, Mulligan K, Noworolski SM, Tai VW, Wen MJ, Erkin-Cakmak A, et al. Isocaloric fructose restriction and metabolic improvement in children with obesity and metabolic syndrome. Obesity. 2016;24:453–60.
Abdelmalek MF, Suzuki A, Guy C, Unalp-Arida A, Colvin R, Johnson RJ, et al. Increased fructose consumption is associated with fibrosis severity in patients with nonalcoholic fatty liver disease. Hepatology. 2010;51:1961–71.
Gotto AM Jr, Blackburn GL, Dailey GE III, Garber AJ, Grundy SM, Sobel BE, et al. The metabolic syndrome: a call to action. Coron Artery Dis. 2006;17:77–80.
Goran MI, Ulijaszek SJ, Ventura EE. High fructose corn syrup and diabetes prevalence: a global perspective. Globe Public Health. 2013;8:55–64.
Chukijrungroat N, Khamphaya T, Weerachayaphorn J, Songserm T, Saengsirisuwan V. Hepatic FGF21 mediates sex differences in high-fat high-fructose diet-induced fatty liver. Am J Physiol Endocrinol Metab. 2017;313:E203–E212.
Luo Y, Burrington CM, Graff EC, Zhang J, Judd RL, Suksaranjit P, et al. Metabolic phenotype and adipose and liver features in a high-fat Western diet-induced mouse model of obesity-linked NAFLD. Am J Physiol Endocrinol Metab. 2016;310:E418–39.
Wadhwa PD, Buss C, Entringer S, Swanson JM. Developmental origins of health and disease: brief history of the approach and current focus on epigenetic mechanisms. Semin Reprod Med. 2009;27:358–68.
Lacal I, Ventura R. Epigenetic inheritance: concepts, mechanisms and perspectives. Front Mol Neurosci. 2018;11:292.
Horsthemke B. A critical view on transgenerational epigenetic inheritance in humans. Nat Commun. 2018;9:2973.
Gonzalez-Rodriguez P, Cantu J, O’Neil D, Seferovic MD, Goodspeed DM, Suter MA, et al. Alterations in expression of imprinted genes from the H19/IGF2 loci in a multigenerational model of intrauterine growth restriction (IUGR). Am J Obstet Gynecol. 2016;214:625 e1–625 e11.
Suter MA, Chen A, Burdine MS, Choudhury M, Harris RA, Lane RH, et al. A maternal high-fat diet modulates fetal SIRT1 histone and protein deacetylase activity in nonhuman primates. FASEB J. 2012;26:5106–14.
Fang J, Ianni A, Smolka C, Vakhrusheva O, Nolte H, Kruger M, et al. Sirt7 promotes adipogenesis in the mouse by inhibiting autocatalytic activation of Sirt1. Proc Natl Acad Sci USA. 2017;114:E8352–E8361.
Bober E, Fang J, Smolka C, Ianni A, Vakhrusheva O, Krüger M, et al. Sirt7 promotes adipogenesis by binding to and inhibiting Sirt1. BMC Proc. 2012;6:P57.
Michishita E, Park JY, Burneskis JM, Barrett JC, Horikawa I. Evolutionarily conserved and nonconserved cellular localizations and functions of human SIRT proteins. Mol Biol Cell. 2005;16:4623–35.
Salminen A, Kaarniranta K, Kauppinen A. Crosstalk between oxidative stress and SIRT1: impact on the aging process. Int J Mol Sci. 2013;14:3834–59.
Bause AS, Haigis MC. SIRT3 regulation of mitochondrial oxidative stress. Exp Gerontol. 2013;48:634–9.
Liu B, Che W, Zheng C, Liu W, Wen J, Fu H, et al. SIRT5: a safeguard against oxidative stress-induced apoptosis in cardiomyocytes. Cell Physiol Biochem. 2013;32:1050–9.
Cheng MY, Cheng YW, Yan J, Hu XQ, Zhang H, Wang ZR, et al. SIRT6 suppresses mitochondrial defects and cell death via the NF-kappaB pathway in myocardial hypoxia/reoxygenation induced injury. Am J Transl Res. 2016;8:5005–15.
Singh CK, Chhabra G, Ndiaye MA, Garcia-Peterson LM, Mack NJ, Ahmad N. The role of sirtuins in antioxidant and redox signaling. Antioxid Redox Signal. 2018;28:643–61.
Hirschey MD, Shimazu T, Goetzman E, Jing E, Schwer B, Lombard DB, et al. SIRT3 regulates mitochondrial fatty-acid oxidation by reversible enzyme deacetylation. Nature. 2010;464:121–5.
Jeninga EH, Schoonjans K, Auwerx J. Reversible acetylation of PGC-1: connecting energy sensors and effectors to guarantee metabolic flexibility. Oncogene. 2010;29:4617–24.
Nakagawa T, Lomb DJ, Haigis MC, Guarente L. SIRT5 Deacetylates carbamoyl phosphate synthetase 1 and regulates the urea cycle. Cell. 2009;137:560–70.
Kim HS, Patel K, Muldoon-Jacobs K, Bisht KS, Aykin-Burns N, Pennington JD, et al. SIRT3 is a mitochondria-localized tumor suppressor required for maintenance of mitochondrial integrity and metabolism during stress. Cancer Cell. 2010;17:41–52.
Sundaresan NR, Gupta M, Kim G, Rajamohan SB, Isbatan A, Gupta MP. Sirt3 blocks the cardiac hypertrophic response by augmenting Foxo3a-dependent antioxidant defense mechanisms in mice. J Clin Invest. 2009;119:2758–71.
Wikstrom M, Springett R. Thermodynamic efficiency, reversibility, and degree of coupling in energy conservation by the mitochondrial respiratory chain. Commun Biol. 2020;3:451.
Haschler TN, Horsley H, Balys M, Anderson G, Taanman JW, Unwin RJ, et al. Sirtuin 5 depletion impairs mitochondrial function in human proximal tubular epithelial cells. Scientific reports. 2021;11:15510.
Vassilopoulos A, Pennington JD, Andresson T, Rees DM, Bosley AD, Fearnley IM, et al. SIRT3 deacetylates ATP synthase F1 complex proteins in response to nutrient- and exercise-induced stress. Antioxid Redox Signal. 2014;21:551–64.
Acknowledgements
The work was supported by the Morris L Lichtenstein Jr. Medical Research Foundation. We would like to acknowledge Dr. Raktima Bhattacharya for running some qPCR plates. We also thank Faith Upton for helping with the model drawing and Nidhi Wunnava, Basel Kesbeh, Sarah Garcia, Martin Donjuan, Jazmin Diaz, Kayla Riley, Sumiya Wahab, Grace Chen, Jay Mendenhall, Crustal Chacko, Shroq Kesbeh, and Dr. Luis F Schutz for other activities (e.g., labeling, sac help etc).
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MC conceptualized the project and others carry out the experiments and data analysis. MC, MK, and JZ wrote the manuscript.
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Zhang, J., Kay, M.K., Park, M.H. et al. LncRNA DLEU2 regulates sirtuins and mitochondrial respiratory chain complex IV: a novel pathway in obesity and offspring’s health. Int J Obes 46, 969–976 (2022). https://doi.org/10.1038/s41366-022-01075-6
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DOI: https://doi.org/10.1038/s41366-022-01075-6
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