Excessive manganese (Mn) exposure is toxic, and induces lipid deposition, but the underlying mechanisms remain elusive. Herein, we explored how dietary Mn supplementation affects lipid deposition and metabolism in the intestine of vertebrates using the yellow catfish Pelteobagrus fulvidraco as the model.
Results:
High-Mn (H-Mn) diet increased intestinal Mn content, promoted lipid accumulation and lipogenesis, and inhibited lipolysis. In addition, it induced oxidative stress, upregulated metal-response element-binding transcription factor-1 (MTF-1), and peroxisome proliferator-activated receptor gamma (PPARγ) protein expression in the nucleus, induced PPARγ acetylation, and the interaction between PPARγ and retinoid X receptor alpha (RXRα), while it downregulated sirtuin 1 (SIRT1) expression and activity. Mechanistically, Mn activated the MTF-1/divalent metal transporter 1 (DMT1) pathway, increased Mn accumulation in the mitochondria, and induced oxidative stress. This in turn promoted lipid deposition via deacetylation of PPARγ at K339 by SIRT1. Subsequently, PPARγ mediated Mn-induced lipid accumulation through transcriptionally activating fatty acid translocase, stearoyl-CoA desaturase 1, and perilipin 2 promoters.
Innovation:
These studies uncover a previously unknown mechanism by which Mn induces lipid deposition in the intestine via the oxidative stress–SIRT1–PPARγ pathway.
Conclusion:
High dietary Mn intake activates MTF-1/DMT1 and oxidative stress pathways. Oxidative stress-mediated PPARγ deacetylation at K339 site contributes to increased lipid accumulation. Our results provided a direct link between Mn and lipid metabolism via the oxidative stress–SIRT1–PPARγ axis. Antioxid. Redox Signal. 37, 417–436.
Get full access to this article
View all access options for this article.
References
1.
AngelovaPR, EsterasN, and AbramovAY. Mitochondria and lipid peroxidation in the mechanism of neurodegeneration: finding ways for prevention. Med Res Rev, 41: 770–784, 2021.
2.
AschnerJL and AschnerM. Nutritional aspects of manganese homeostasis. Mol Aspects Med, 26: 353–362, 2005.
3.
BornhorstJ, EbertF, LohrenH, HumpfHU, KarstU, and SchwerdtleT. Effects of manganese and arsenic species on the level of energy related nucleotides in human cells. Metallomics, 4: 297–306, 2012.
4.
BraidyN, GuilleminG, and GrantR. Promotion of cellular NAD (+) anabolism: therapeutic potential for oxidative stress in ageing and Alzheimer's disease. Neurotox Res, 13: 173–184, 2008.
5.
CantoC and AuwerxJ. Targeting sirtuin 1 to improve metabolism: all you need is NAD (+)?. Pharmacol Rev, 64: 166–187, 2012.
6.
ChenGH, LvWH, XuYH, WeiXL, XuYC, and LuoZ. Functional analysis of MTF-1 and MT promoters and their transcriptional response to zinc (Zn) and copper (Cu) in yellow catfish Pelteobagrus fulvidraco. Chemosphere, 246: 125792, 2020.
7.
CsiszarA, LabinskyyN, PintoJT, BallabhP, ZhangH, LosonczyG, PearsonK, de CaboR, PacherP, ZhangC, and UngvariZ. Resveratrol induces mitochondrial biogenesis in endothelial cells. Am J Physiol Heart Circ Physiol, 297: H13–H20, 2009.
8.
DingRB, BaoJ, and DengCX. Emerging roles of SIRT1 in fatty liver diseases. Int J Biol Sci, 13: 852–867, 2017.
9.
ElliottWH and ElliottDC. Biochemistry and Molecular Biology, 4th ed. Oxford, UK: Oxford University Press, 2009.
10.
EvansRM, BarishGD, and WangYX. PPARs and the complex journey to obesity. Nat Med, 10: 355–361, 2004.
11.
FangW, ChenQ, CuiK, ChenQ, LiX, XuN, MaiK, and AiQ. Lipid overload impairs hepatic VLDL secretion via oxidative stress-mediated PKCδ-HNF4α-MTP pathway in large yellow croaker (Larimichthys crocea). Free Radic Biol Med, 172: 213–225, 2021.
12.
GawlikM, GawlikMB, SmagaI, and FilipM. Manganese neurotoxicity and protective effects of resveratrol and quercetin in preclinical research. Pharmacol Rep, 69: 322–330, 2017.
13.
GongG, DanC, XiaoS, GuoW, HuangP, XiongY, WuJ, HeY, ZhangJ, LiX, ChenN, GuiJF, and MeiJ. Chromosomal-level assembly of yellow catfish genome using third-generation DNA sequencing and Hi-C analysis. GigaScience, 7: 1–9, 2018.
14.
GunterTE, GavinCE, and GunterKK. The role of mitochondrial oxidative stress and ATP depletion in the pathology of manganese toxicity. In: Metal Ion in Stroke, Springer Series in Translational Stroke Research, Vol. 29, edited by Li YV and Zhang JH. Rochester, NY: Springer Science and Business Media, 2012, pp. 591–606.
15.
GuzyRD, SharmaB, BellE, ChandelNS, and SchumackerPT. Loss of the SdhB, but not the SdhA, subunit of complex II triggers reactive oxygen species-dependent hypoxia-inducible factor activation and tumorigenesis. Mol Cell Biol, 28: 718–731, 2008.
16.
JiangX, YeX, GuoW, LuH, and GaoZ. Inhibition of HDAC3 promotes ligand- independent PPAR gamma activation by protein acetylation. J Mol Endocrinol, 53: 191–200, 2014.
17.
KatzN and RaderDJ. Manganese homeostasis: from rare single-gene disorders to complex phenotypes and diseases. J Clin Invest, 129: 5082–5085, 2019.
KorgeP, CalmettesG, and WeissJN. Reactive oxygen species production in cardiac mitochondria after complex I inhibition: modulation by substrate-dependent regulation of the NADH/NAD (+) ratio. Free Radic Biol Med, 96: 22–33, 2016.
20.
LegleiterLR, SpearsJW, and LloydKE. Influence of dietary manganese on performance, lipid metabolism, and carcass composition of growing and finishing steers. J Anim Sci, 83: 2434–2439, 2005.
21.
LeiMY, CongL, LiuZQ, LiuZF, MaZ, LiuK, LiJ, DengY, LiuW, and XuB. Resveratrol reduces DRP1-mediated mitochondrial dysfunction via the SIRT1-PGC1α signaling pathway in manganese-induced nerve damage in mice. Environ Toxicol, 37: 282–298, 2022.
22.
LiH.Sirtuin 1 (sirt1) and oxidative stress. In: Systems Biology of Free Radicals and Antioxidants, Vol. 19, edited by Laher I. Mainz: Springer-Verlag Berlin Heidelberg, 2014, pp. 417–435.
23.
LinCH, LiNT, ChengHS, and YenML. Oxidative stress induces imbalance of adipogenic/osteoblastic lineage commitment in mesenchymal stem cells through decreasing SIRT1 functions. J Cell Mol Med, 22: 786–796, 2018.
24.
LivakKJ and SchmittgenTD. Analysis of relative gene expression data using realtime quantitative PCR and the 2-ΔΔCT method. Methods, 25: 402–408, 2001.
25.
LuoL, HeY, ZhaoY, XuQ, WuJ, MaH, GuoH, BaiL, ZuoJ, ZhouJM, YuH, and LiJ. Regulation of mitochondrial NAD pool via NAD+ transporter 2 is essential for matrix NADH homeostasis and ROS production in Arabidopsis. Sci China Life Sci, 62: 991–1002, 2019.
26.
Martinez-FinleyEJ, GavinCE, AschnerM, and GunterTE. Manganese neurotoxicity and the role of reactive oxygen species. Free Radic Biol Med, 62: 65–75, 2013.
27.
MayoralR, OsbornO, McNelisJ, JohnsonAM, OhDY, IzquierdoCL, ChungH, LiP, TravesPG, BandyopadhyayG, PessentheinerAR, OfrecioJM, CookJR, QiangL, AcciliD, and OlefskyJM. Adipocyte SIRT1 knockout promotes PPARγ activity, adipogenesis and insulin sensitivity in chronic-HFD and obesity. Mol Metab, 4: 378–391, 2015.
28.
MilatovicD, YinZ, GuptaRC, SidorykM, AlbrechtJ, AschnerJL, and AschnerM. Manganese induces oxidative impairment in cultured rat astrocytes. Toxicol Sci, 98: 198–205, 2007.
29.
MoC, WangL, ZhangJ, NumazawaS, TangH, TangX, HanX, LiJ, YangM, WangZ, WeiD, and XiaoH. The crosstalk between Nrf2 and AMPK signal pathways is important for the anti-inflammatory effect of berberine in LPS-stimulated macrophages and endotoxin-shocked mice. Antioxid Redox Signal, 20: 574–588, 2014.
30.
NebertDW, Galvez-PeraltaM, HayEB, LiH, JohanssonE, YinC, WangB, HeL, SoleimaniM, and ThieleDJ. Zip14 and zip8 zinc/bicarbonate symporters in Xenopus oocytes: characterization of metal uptake and inhibition. Metallomics, 4: 1218–1225, 2012.
31.
PajarilloEAB, LeeE, and KangDK. Trace metals and animal health: interplay of the gut microbiota with iron, manganese, zinc, and copper. Anim Nutr, 7: 750–761, 2021.
32.
PanYX, LuoZ, ZhuoMQ, WeiCC, ChenGH, and SongYF. Oxidative stress and mitochondrial dysfunction mediated Cd-induced hepatic lipid accumulation in zebrafish Danio rerio. Aquat Toxicol, 199: 12–20, 2018.
33.
PanieriE and SantoroMM. ROS homeostasis and metabolism: a dangerous liason in cancer cells. Cell Death Dis, 7: e2253, 2016.
34.
ParkMW, ChaHW, KimJ, KimJH, YangH, YoonS, BoonpramanN, YiSS, YooID, and MoonJS. NOX4 promotes ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via the impairment of mitochondrial metabolism in Alzheimer's diseases. Redox Biol, 41: 101947, 2021.
35.
PicardF, KurtevM, ChungN, Topark-NgarmA, SenawongT, Machado De OliveiraR, LeidM, McBurneyMW, and GuarenteL. Sirt1 promotes fat mobilization in white adipocytes by repressing PPAR-gamma. Nature, 429: 771–776, 2004.
36.
PillaiVB, SundaresanNR, KimG, GuptaM, RajamohanSB, PillaiJB, SamantS, RavindraPV, IsbatanA, and GuptaMP. Exogenous NAD blocks cardiac hypertrophic response via activation of the SIRT3-LKB1-AMP-activated kinase pathway. J Biol Chem, 285: 3133–3144, 2010.
37.
QiangL, WangL, KonN, ZhaoW, LeeS, ZhangY, RosenbaumM, ZhaoY, GuW, FarmerSR, and AcciliD. Brown remodeling of white adipose tissue by SirT1-dependent deacetylation of Pparγ. Cell, 150: 620–632, 2012.
38.
QiaoL, GuoZ, BoscoC, GuidottiS, WangY, WangM, ParastM, SchaackJ, HayWWJr., MooreTR, and ShaoJ.Maternal high-fat feeding increases placental lipoprotein lipase activity by reducing SIRT1 expression in mice. Diabetes, 64: 3111–3120, 2021.
39.
QuadriM, FedericoA, ZhaoT, BreedveldGJ, BattistiC, DelnoozC, SeverijnenLA, Di Toro MammarellaL, MignarriA, MontiL, SannaA, LuP, PunzoF, CossuG, WillemsenR, RasiF, OostraBA, van de WarrenburgBP, and BonifatiV. Mutations in SLC30A10 cause parkinsonism and dystonia with hypermanganesemia, polycythemia, and chronic liver disease. Am J Hum Genet, 90: 467–477, 2012.
40.
RahmanI, KodeA, and BiswasSK. Assay for quantitative determination of glutathione and glutathione disulfide levels using enzymatic recycling method. Nat Protoc, 1: 3159–3165, 2006.
41.
RogerAJ, Munoz-GomezSA, and KamikawaR. The origin and diversification of mitochondria. Curr Biol, 27: 1177–1192, 2017.
42.
SatoY, HashiguchiY, and NishidaM. Temporal pattern of loss/persistence of duplicate genes involved in signal transduction and metabolic pathways after teleost-specific genome duplication. BMC Evol Biol, 9: 127, 2009.
43.
SeoE, KangH, ChoiH, ChoiW, and JunHS. Reactive oxygen species-induced changes in glucose and lipid metabolism contribute to the accumulation of cholesterol in the liver during aging. Aging Cell, 18: e12895, 2019.
44.
ShawkiA, AnthonySR, NoseY, EngevikMA, NiespodzanyEJ, BarrientosT, OhrvikH, WorrellRT, and MackenzieB. Intestinal DMT1 is critical for iron absorption in the mouse but is not required for the absorption of copper or manganese. Am J Physiol Gastrointest Liver Physiol, 8: 635–647, 2015.
45.
SmithMR, FernandesJ, GoYM, and JonesDP. Redox dynamics of manganese as a mitochondrial life-death switch. Biochem Biophys Res Commun, 482: 388–398, 2017.
46.
SongYF, HogstrandC, LingSC, ChenGH, and LuoZ. Creb-Pgc1α pathway modulates the interaction between lipid droplets and mitochondria and influences high fat diet-induced changes of lipid metabolism in the liver and isolated hepatocytes of yellow catfish. J Nutr Biochem, 80: 108364, 2020.
47.
SunX, BergerRS, HeinrichP, MarchiqI, PouyssegurJ, RennerK, OefnerPJ, and DettmerK. Optimized protocol for the in situ derivatization of glutathione with N-ethylmaleimide in cultured cells and the simultaneous determination of glutathione/glutathione disulfide ratio by HPLC-UV-QTOF-MS. Metabolites, 10: 292, 2020.
48.
TanXY, XieP, LuoZ, LinHZ, ZhaoYH, and XiWQ. Dietary manganese requirement of juvenile yellow catfish Pelteobagrus fulvidraco, and effects on whole body mineral composition and hepatic intermediary metabolism. Aquaculture, 326: 68–73, 2012.
49.
TianL, WangC, HagenFK, GormleyM, AddyaS, SoccioR, CasimiroMC, ZhouJ, PowellMJ, XuP, DengH, SauveAA, and PestellRG. Acetylation-defective mutant of Ppargamma is associated with decreased lipid synthesis in breast cancer cells. Oncotarget, 5: 7303–7315, 2014.
50.
TuschlK, ClaytonPT, GospeSM, GulabS, IbrahimS, SinghiP, AulakhR, RibeiroRT, BarsottiniOG, ZakiMS, Del RosarioML, DyackS, PriceV, RideoutA, GordonK, WeversRA, ChongWK, and MillsPB. Syndrome of hepatic cirrhosis, dystonia, polycythemia, and hypermanganesemia caused by mutations in SLC30A10, a manganese transporter in man. Am J Hum Genet, 90: 457–466, 2012.
51.
VandesompeleJ, De PreterK, PattynF, PoppeB, Van RoyN, and De PaepeA. Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes. Genome Biol, 3: 532–538, 2002.
52.
WangH.Proteomics and metabolomic analysis on the toxic mechanism of manganese. PhD dissertation, Northwest Agriculture and Forestry University, Yangling, China, 2018.
53.
WinslowJWW, LimesandKH, and ZhaoN. The functions of zip8, zip14, and znt10 in the regulation of systemic manganese homeostasis. Int J Mol Sci, 21: 3304, 2020.
54.
WolffNA, GarrickLM, ZhaoL, GarrickMD, and ThevenodF. Mitochondria represent another locale for the divalent metal transporter1 (DMT1). Channels, 8: 458–466, 2014.
55.
WolffNA, GarrickMD, ZhaoL, GarrickLM, GhioAJ, and ThévenodF. A role for divalent metal transporter (DMT1) in mitochondrial uptake of iron and manganese. Sci Rep, 8: 211, 2018.
56.
WuK, LuoZ, HogstrandC, ChenGH, WeiCC, and LiDD. Zn stimulates the phospholipids biosynthesis via the pathways of oxidative and endoplasmic reticulum stress in the intestine of freshwater teleost yellow catfish. Environ Sci Technol, 52: 9206–9214, 2018.
57.
WuK, ZhaoT, HogstrandC, XuYC, LingSC, ChenGH, and LuoZ. FXR-mediated inhibition of autophagy contributes to FA-induced TG accumulation and accordingly reduces FA-induced lipotoxicity. Cell Commun Signal, 18: 47, 2020.
58.
XinH, LiL, WangJ, MinJ, and WangF. Functional discoveries and mechanistic studies of manganese transporters. Chin Bull Life Sci, 30: 603–614, 2018.
59.
XuYC, XuYH, ZhaoT, WuLX, YangSB, and LuoZ. Waterborne Cu exposure increased lipid deposition and lipogenesis by affecting Wnt/beta-catenin pathway and the beta-catenin acetylation levels of grass carp Ctenopharyngodon idella. Environ Pollut, 263: 114420, 2020.
60.
XuYH, TanXY, XuYC, ZhaoT, ZhangLH, and LuoZ. Novel insights for SREBP-1 as a key transcription factor in regulating lipogenesis in a freshwater teleost, grass carp Ctenopharyngodon idella. Br J Nutr, 122: 1201–1211, 2019.
61.
YaoH, QiaoFQ, HaoJH, LiHQ, and WangJD. Interactive effects of organic manganese and organic chromium on lipid metabolism and their depositions in tissues of broilers. Chin J Vet Sci, 30: 1346–1351, 2010.
62.
ZhangMJ.H2S donors modulate post-ischemic neuron-inflammation via SQR. MA dissertation, Soochow University, Suzhou, China, 2017.
63.
ZhangXJ, WangBW, GeWH, ZhangMI, YueB, and ZhangYY. Effects of manganese on serum lipid metabolism, antioxidant indices and organ tissue manganese deposition of Wulong geese aged from 1 to 4 weeks. Chin J Anim Nutr, 29: 3792–3798, 2017.
64.
ZhaoT, WuK, HogstrandC, XuYH, ChenGH, WeiCC, and LuoZ. Lipophagy mediated carbohydrate-induced changes of lipid metabolism via oxidative stress, endoplasmic reticulum (ER) stress and ChREBP/PPARγ pathways. Cell Mol Life Sci, 77: 1987–2003, 2020.
65.
ZhongCC, ZhaoT, HogstrandC, ChenF, SongCC, and LuoZ. Copper (Cu) induced changes of lipid metabolism through oxidative stress-mediated autophagy and Nrf2/PPARγ pathways. J Nutr Biochem, 100: 108883, 2022.
66.
ZhongWX, WangYB, PengL, GeXZ, ZhangJ, LiuSS, ZhangXN, XuZH, ChenZ, and LuoJH. Lanthionine synthetase C-like protein 1 interacts with and inhibits cystathionine β-synthase: a target for neuronal antioxidant defense. J Biol Chem, 287: 34189–34201, 2012.
67.
ZhuoMQ, LuoZ, PanYX, WuK, FanYF, ZhangLH, and SongYF. Effects of insulin and its related signaling pathways on lipid metabolism in the yellow catfish Pelteobagrus fulvidraco. J Exp Biol, 218: 3083–3090, 2015.
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
