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Iron increases lipid deposition via oxidative stress-mediated mitochondrial dysfunction and the HIF1α-PPARγ pathway

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Abstract

Iron is an essential micro-element, involved in multiple biological activities in vertebrates. Excess iron accumulation has been identified as an important mediator of lipid deposition. However, the underlying mechanisms remain unknown. In the present study, we found that a high-iron diet significantly increased intestinal iron content and upregulated the mRNA expression of two iron transporters (zip14 and fpn1). Intestinal iron overload increased lipogenesis, reduced lipolysis and promoted oxidative stress and mitochondrial dysfunction. Iron-induced lipid accumulation was mediated by hypoxia-inducible factor-1 α (HIF1α), which was induced in response to mitochondrial oxidative stress following inhibition of prolyl hydroxylase 2 (PHD2). Mechanistically, iron promoted lipid deposition by enhancing the DNA binding capacity of HIF1α to the pparγ and fas promoters. Our results provide experimental evidence that oxidative stress, mitochondrial dysfunction and the HIF1α-PPARγ pathway are critical mediators of iron-induced lipid deposition.

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Data availability

All materials and data supporting this study are available from the corresponding author (luozhi99@mail.hzau.edu.cn) upon reasonable request.

Abbreviations

6PGD:

6-Phosphogluconate dehydrogenase

ACCα:

Acetyl-CoA carboxylase α

ACSL4:

Acyl-CoA synthetase long-chain family member 4

ATP:

Adenosine triphosphate

B2M:

Beta-2 microglobulin

CAT:

Catalase

DFO:

Deferoxamine mesylate

DMEM:

Dulbecco's Modified Eagles Medium

DMT1:

Divalent metal transporter 1

ELFA:

Translation elongation factor

EMSA:

Electrophoretic mobility-shift assay

FAS:

Fatty acid synthase

Fe:

Iron

FBS:

Fetal bovine serum

FPN1:

Ferroportin

FerM:

Ferritin middle chain

FTH:

Ferritin heavy chain

FTL:

Ferritin light chain

G6PD:

Glucose 6-phosphate dehydrogenase

GAPDH:

Glyceraldehyde-3-phosphate dehydrogenase

GLUT1:

Solute carrier family 2 member 1

HK1:

Hexokinase 1

HK2:

Hexokinase 2

GK:

Glucokinase

GPx:

Glutathione peroxidase

GSH:

Glutathione

GSSG:

Glutathione disulfide

HIF1α:

Hypoxia-inducible factors-1α

HIF2α:

Hypoxia-inducible factor-2α

HPRT:

Hypoxanthine-guanine phosphoribosyltransferase

HRE:

Hypoxia response elements

HSL:

Hormone-sensitive lipase

LDH:

Lactate dehydrogenase

ICDH:

Isocitrate dehydrogenase

ICP-OES:

Inductively coupled plasma optical emission spectrometry

JC-1:

5,5ʹ,6,6ʹ-Tetrachloro-1,1ʹ,3,3ʹ-tetraethyl-imidacarbocyanine iodide

LOX:

Lipoxygenase

LPCAT3:

Lysophosphatidylcholine acyltransferase 3

MDA:

Malondialdehyde

ME:

Malic enzyme

MMP:

Mitochondrial membrane potential

MTT:

3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide

mtROS:

Mitochondrial ROS

NEFA:

Nonesterified fatty acid

NOX1:

NADPH oxidases 1

NRF2:

Nuclear factor E2-related factor 2

ORO:

Oil red O

PFK:

Phosphofructokinase

PGK1:

Phosphoglycerate kinase 1

PHD2:

Prolyl hydroxylases 2

PK:

Pyruvate kinase

PPARγ:

Peroxisome proliferator-activated receptor γ

PTGS2:

Prostaglandin endoperoxide synthase 2

ROS:

Reactive oxygen species

RPL7:

Ribosomal protein L7

SEM:

Standard error of means

SLC7A11:

Cystine-glutamate antiporter

SREBP1:

Sterol regulatory element-binding proteins 1

TEM:

Transmission electron microscopy

TF:

Transferrin

TFR1:

Transferrin receptor 1

TFR2:

Transferrin receptor 2

TG:

Triglyceride

T-SOD:

Total superoxide dismutase

TUBA:

Tubulin alpha chain

UBCE:

Ubiquitin-conjugating enzyme

UTR:

Untranslated region

ZIP14:

ZRT-IRE-like protein 14

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Acknowledgements

This work was supported by the National Key R&D Program of China (grant No. 2018YFD0900400).

Funding

This work was supported by the National Key R&D Program of China (grant No. 2018YFD0900400).

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Authors and Affiliations

  1. Laboratory of Molecular Nutrition for Aquatic Economic Animals, Fishery College, Huazhong Agricultural University, Wuhan, 430070, China

    Chang-Chun Song, Guang-Hui Chen, Chong-Chao Zhong, Tao Zhao, Dian-Guang Zhang & Zhi Luo

  2. Hubei Hongshan Laboratory, Fishery College, Huazhong Agriculture University, Wuhan, 430070, China

    Zhi Luo

  3. Lady Davis Institute for Medical Research and Department of Medicine, McGill University, Montreal, QC, H3T 1E2, Canada

    Kostas Pantopoulos

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  1. Chang-Chun Song
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  2. Kostas Pantopoulos
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  3. Guang-Hui Chen
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  4. Chong-Chao Zhong
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  5. Tao Zhao
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Contributions

The authors’ responsibilities were as follows: CCS and ZL designed the experiments; CCS conducted the experiments and sample analyses with the help of GHC, CCZ, TZ, and DGZ; KP provided many critical suggestions for the experimental designs and data analysis; CCS analyzed the data and drafted the manuscript; KP and ZL revised the manuscript; all authors read and approved the final manuscript.

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Correspondence to Zhi Luo.

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Song, CC., Pantopoulos, K., Chen, GH. et al. Iron increases lipid deposition via oxidative stress-mediated mitochondrial dysfunction and the HIF1α-PPARγ pathway. Cell. Mol. Life Sci. 79, 394 (2022). https://doi.org/10.1007/s00018-022-04423-x

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