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The regulation effect of GLUT9/SLC2A9 on intrahepatic uric acid level and metabolic associated fatty liver disease

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Abstract

Background

Metabolic associated fatty liver disease (MAFLD) is the most common chronic liver disease worldwide. The important role of urid acid (UA) in MAFLD has been widely investigated. Our previous studies unveiled the elevation of serum UA levels independently predicts an increased risk of incident MAFLD. However, the role of intrahepatic UA in MAFLD has not been investigated yet. Glucose transporter 9 (GLUT9) is a key transporter that mediates the uptake of UA in hepatocytes.

Methods

In this study, we first explored the clinical association between GLUT9 polymorphism and MAFLD. Blood samples of 247 male Chinese (127 were MAFLD patients) were collected and tested for the blood UA levels and genotype of the single nucleotide polymorphism (SNP) of GLUT9 (rs1014290). Next, Glut9 hepatic-specific knockout mice (Glut9Hep−ko) were generated to investigate the role of hepatic GLUT9 in MAFLD in male mice.

Results

We found that the GA/AA genotypes (rs1014290) were associated with elevated serum UA levels in MAFLD patients. Meanwhile, we found that Glut9Hep−ko mice displayed lower intrahepatic UA levels, down-regulated lipogenesis genes expressions, and attenuated MAFLD symptoms after 12 weeks of high-fat diet feeding, compared with Glut9Fl/Fl littermates. However, Glut9Hep−ko mice and wild-type littermates showed no significant difference on hepatic fatty acid oxidation or inflammation.

Conclusions

Our results suggested that GLUT9 polymorphism was significantly associated with MAFLD, and hepatic-specific knockout of Glut9 significantly decreased intrahepatic contents and ameliorated diet-induced MAFLD in mice.

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Data availability

All data generated or analysed during this study are included in this article.

Abbreviations

MAFLD:

Metabolic-associated fatty liver disease

GLUT9:

Glucose transporter 9

SNP:

Single nucleotide polymorphism

UA:

Uric acid

BMI:

Body mass index

WBC:

White blood cell

HB:

Hemoglobin

PLT:

Platelet

GGT:

Gamma-glutamyl transferase

TG:

Triglyceride

TC:

Total cholesterol

HDL:

High-density lipoprotein

LDL:

Low-density lipoprotein

GLU:

Glucose

PA:

Palmitate

OA:

Oleic acid

FFA:

Free fatty acid

MSU:

Monosodium urate

SCD:

Standard chow diet

HFD:

High-fat diet

MCD:

Methionine- and choline-deficient diet

H&E:

Hematoxylin and eosin

GTT:

Glucose tolerance test

ITT:

Insulin tolerance test

DEME:

Dulbecco’s modified eagle medium

FBS:

Fetal bovine serum

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Funding

This work was supported by the National Natural Science Foundation of China [Grants 82030019].

Author information

Authors and Affiliations

  1. Department of Gastroenterology, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003, China

    Hang Zeng, Chenxi Tang, Bingru Lin, Mengli Yu, Xinyu Wang, Jinghua Wang & Chaohui Yu

  2. Department of Gastroenterology, School of Medicine, Affiliated Hangzhou First People’s Hospital, Zhejiang University, Hangzhou, 310003, China

    Shenghui Chen

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  1. Hang Zeng
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  2. Chenxi Tang
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  4. Mengli Yu
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Contributions

HZ and CY contributed to the study conception and design. Material preparation, data collection and analysis were performed by HZ, CT, BL. The first draft of the manuscript was written by HZ and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Hang Zeng.

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Conflict of interest

All the authors declare that they have no conflict of interest.

Animal research (ethics)

All procedures performed in studies involving animals were in accordance with the ethical standards of the Animal Care and Use Committee of the First Affiliated Hospital, Zhejiang University School of Medicine (reference number: 2021–133).

Consent to participate (ethics)

The experimental protocol was established, according to the ethical guidelines of the Helsinki Declaration and was approved by the Ethic Committee of the First Affiliated Hospital, Zhejiang University School of Medicine (reference number: 2021-190). Informed consent was obtained from individual or guardian participants.

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Zeng, H., Tang, C., Lin, B. et al. The regulation effect of GLUT9/SLC2A9 on intrahepatic uric acid level and metabolic associated fatty liver disease. Hepatol Int 16, 1064–1074 (2022). https://doi.org/10.1007/s12072-022-10371-2

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  • DOI: https://doi.org/10.1007/s12072-022-10371-2

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