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MAFLD as part of systemic metabolic dysregulation

  • Special supplement : MAFLD
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Abstract

Nonalcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases worldwide. In recent years, a new terminology and definition of metabolic dysfunction-associated fatty liver disease (MAFLD) has been proposed. Compared to the NAFLD definition, MAFLD better emphasizes the pathogenic role of metabolic dysfunction in the development and progression of this highly prevalent condition. Metabolic disorders, including overweight/obesity, type 2 diabetes mellitus (T2DM), atherogenic dyslipidemia and hypertension, are often associated with systemic organ dysfunctions, thereby suggesting that multiple organ damage can occur in MAFLD. Substantial epidemiological evidence indicates that MAFLD is not only associated with an increased risk of liver-related complications, but also increases the risk of developing several extra-hepatic diseases, including new-onset T2DM, adverse cardiovascular and renal outcomes, and some common endocrine diseases. We have summarized the current literature on the adverse effect of MAFLD on the development of multiple extrahepatic (cardiometabolic and endocrine) complications and examined the role of different metabolic pathways and organ systems in the progression of MAFLD, thus providing new insights into the role of MAFLD as a multisystem metabolic disorder. Our narrative review aimed to provide insights into potential mechanisms underlying the known associations between MAFLD and extrahepatic diseases, as part of MAFLD as a multisystem disease, in order to help focus areas for future drug development targeting not only liver disease but also the risk of extrahepatic complications.

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Abbreviations

NAFLD:

Non-alcoholic fatty liver disease

MAFLD:

Metabolic dysfunctions associated fatty liver disease

T2DM:

Type 2 diabetes mellitus

HOMA:

Homeostasis model assessment

NHANES:

National Health and Nutrition Examination Survey

PPAR-α:

Peroxisome proliferator activated receptor-alpha

SREBP-1:

Sterol regulatory element-binding protein-1

MDM2:

Murine double minute 2

TG-VLDL:

Triglyceride-very low-density lipoprotein

apoB:

Apolipoprotein B

CREBH:

CAMP response element-binding protein H

SIRT3:

Sirtuin 3

AdipoR2:

Adiponectin receptor 2

FGF1-IGFBP2:

Fibroblast growth factor-insulin-like growth factor binding protein 2

SGLT2:

Sodium-glucose cotransporter 2

GLP-1:

Glucagon-like peptide-1

GLUT4:

Glucose transporter-4

PI3K/AKT:

Phosphatidylinositol 3-kinase/protein kinase B

AMPK:

AMP-activated protein kinase

GPX4:

Glutathione peroxidase 4

GCDCA:

Glycochenodeoxycholate

TFR/ACSL4:

Transferrin receptor/acyl-CoA synthetase long-chain family 4

TGR5:

Takeda G protein-coupled receptor 5

FXR:

Farnesoid X receptor

mtDNA:

Mitochondrial genome

IRX3:

Iroquois homeobox 3

Grx2a:

Glutaredoxin 2a

NLRP3:

NOD-, LRR- and pyrin domain-containing 3

NKG2D:

Monokine induced by interferon-gamma natural killer cell group 2D

CKD:

Chronic kidney disease

CVD:

Cardiovascular disease

PSVT:

Paroxysmal supraventricular tachycardia

GGT:

Gamma-glutamyl transferase

OSA:

Obstructive sleep apnea

COPD:

Chronic obstructive pulmonary disease

FIB-4:

Fibrosis-4

FVC:

Forced vital capacity

FEV1:

Forced expiratory volume in 1 s

BM:

Breast masses

HDL:

High-density lipoprotein

LDL:

Low-density lipoprotein

PCOS:

Polycystic ovary syndrome

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Funding

This work is supported by grants from the National Natural Science Foundation of China (82370577, 82070588, 82000690), National Key R&D Program of China (2023YFA1800801) and supported by China Postdoctoral Science Foundation (2023M732681). Jing Zhao is supported in part by grants from Youth Research Project Fund from Wuxi Municipal Health Commission (Q202212). Dan-Qin Sun is supported in part by grants from Top Talent Support Program for young and middle-aged people of Wuxi Health Committee and scientific technological innovation and venture capital fund in Wuxi (BJ2023023), scientific technological innovation and venture capital fund in Wuxi (Y20232011). GT is supported in part by grants from the School of Medicine, University of Verona, Italy. CDB is supported in part by the Southampton NIHR Biomedical Research Centre (NIHR 203319), UK.

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Authors and Affiliations

  1. Urologic Nephrology Center, Jiangnan University Medical Center, Wuxi, China

    Jing Zhao, Lu Liu & Dan-Qin Sun

  2. Affiliated Wuxi Clinical College of Nantong University, Wuxi, China

    Jing Zhao, Lu Liu & Dan-Qin Sun

  3. Wuxi No. 2 People’s Hospital, Wuxi, China

    Jing Zhao, Lu Liu & Dan-Qin Sun

  4. MAFLD Research Center, Department of Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China

    Ying-Ying Cao & Ming-Hua Zheng

  5. Key Laboratory of Diagnosis and Treatment for the Development of Chronic Liver Disease in Zhejiang Province, Wenzhou, Zhejiang, China

    Ying-Ying Cao & Ming-Hua Zheng

  6. Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, China

    Xin Gao

  7. Department of Medicine, University of Verona, Verona, Italy

    Giovanni Targher

  8. Metabolic Diseases Research Unit, IRCCS Sacro Cuore-Don Calabria Hospital, Negrar di Valpolicella, Italy

    Giovanni Targher

  9. Southampton National Institute for Health and Care Research Biomedical Research Centre, University Hospital Southampton, and University of Southampton, Southampton General Hospital, Southampton, UK

    Christopher D. Byrne

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  1. Jing Zhao
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  4. Xin Gao
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Contributions

MHZ, DQS and JZ researched data for the article. JZ wrote the manuscript. LL and YYC drew the schematic map for the manuscript. XG, GT and CDB conducted critical revision and writing of the manuscript. All authors reviewed and commented on the manuscript and approved the final version.

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Correspondence to Dan-Qin Sun or Ming-Hua Zheng.

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All authors (Jing Zhao, Lu Liu, Ying-Ying Cao, Xin Gao, Giovanni Targher, Christopher D. Byrne, Dan-Qin Sun, Ming-Hua Zheng) have confirmed that there are no conflicts of interest.

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Zhao, J., Liu, L., Cao, YY. et al. MAFLD as part of systemic metabolic dysregulation. Hepatol Int (2024). https://doi.org/10.1007/s12072-024-10660-y

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