ReviewNeutrophil: An emerging player in the occurrence and progression of metabolic associated fatty liver disease
Introduction
Recently, the nomenclature “metabolic-associated fatty liver disease (MAFLD)” was proposed to replace nonalcoholic fatty liver disease (NAFLD), which has aroused much concern. The new concept of MAFLD emphasizes that the disease should be considered a continuous process instead of a dichotomous classification as nonalcoholic steatohepatitis (NASH) and non-NASH. MAFLD is one of the most common chronic liver diseases, with a global prevalence of approximately 25%, and has brought a huge burden to people worldwide, especially in America, Europe and the Asian-Pacific region[1]. MAFLD is characterized by excessive lipid accumulation in hepatocytes (more than 5% of hepatocytes develop steatosis histologically) and is recognized as the hepatic manifestation of metabolic disease that affects nearly 70% of type 2 diabetes mellitus (T2DM) patients and almost 80% of individuals with metabolic syndrome[2], [3]. MAFLD includes a range of disease phenotypes, which start with simple hepatocyte steatosis and progresses to the advanced disease stage, which exhibits pathological features including hepatocellular injury (ballooning), lobular inflammation, and various degrees of fibrosis. Eventually, MAFLD may develop into liver fibrosis, cirrhosis and hepatocellular carcinoma (HCC)[4], [5]. The development of pathogenic characteristics such as insulin resistance, mitochondrial dysfunction, lipid peroxidation, oxidative stress, intestinal flora disturbance, endoplasmic reticulum stress and genetic factors have been shown to orchestrate a complicated network to initiate and develop MAFLD[6], [7]. Furthermore, MAFLD is a fatal risk factor associated with cardiovascular disease (CVD), which is the main cause of mortality among MAFLD patients, and MAFLD is also involved in chronic kidney disease (CKD) and various tumorigeneses[8], [9]. Additional, MAFLD is expected to become the main operation indication for liver transplantation surgery in the future[10].
To date, abnormal immune responses to most of these pathogenic factors are thought to be a major mechanism involved in MAFLD. Many innate immunocytes, such as macrophages, natural killer cells, natural killer T cells, dendritic cells, and neutrophils, have been reported to promote the occurrence and development of MAFLD[11], [12]. In recent years, many studies have examined the relationship between neutrophils and MAFLD. Liver biopsies have shown that excessive neutrophil infiltration in the liver is a prominent histological hallmark of MAFLD[13], [14]. In addition, neutrophil depletion significantly alleviated liver injuries in MAFLD mice, indicating the potential effects of neutrophils on the induction of MAFLD[15], [16], [17]. Further, neutrophils were also shown to release increased levels of granule proteins in MAFLD and significantly promoted disease progression.
Section snippets
Neutrophils
Neutrophils are a type of polymorphonuclear leukocyte derived from the bone marrow that account for approximately 55–70% of white blood cells in adults. As the major effectors and first‐line responders of the innate immune system, neutrophils participate in almost all kinds of acute inflammation and most chronic inflammatory processes, including phagocytosis, bactericidal activities, chemotaxis and immunoregulation, since these cells are rich in various granules and secretory vesicles, which
Hepatic steatosis
Hepatic steatosis, the most obvious pathological hallmark of MAFLD, is a heterogeneous condition that includes insulin resistance, mitochondrial dysfunction and excessive lipid accumulation. As an important pathogenic characteristic, insulin resistance was also described as a prime predictor of MAFLD. Insulin resistance could elevate blood glucose levels and suppress lipase-mediated lipolysis, resulting in the excessive production of free fatty acids (FFAs) and promoting lipid redistribution
Prospects in neutrophil-associated clinical diagnosis and treatment of MAFLD
To date, liver biopsy is still the gold standard for MAFLD diagnosis, although it is an invasive, expensive and high-risk diagnostic operation with potential serious complications. MAFLD treatment is usually limited to the regulation of diet and lifestyle. Therefore, noninvasive diagnostic methods and specific therapies for MAFLD are currently unmet clinical needs.
Currently, clinical evidence indicates that the neutrophil-to-lymphocyte ratio (NLR) might be a promising diagnostic and prognostic
Conclusion
In recent years, studies have brought new insights into our understanding of the nomenclatural change from “NAFLD” to “MAFLD”, as well as the role of neutrophils and their granule proteins in the pathogenesis of MAFLD. In this review, we summarized the roles of neutrophils in the different stages of MAFLD and their involvement in multiple mechanisms (Table 1). Neutrophils can secrete multiple factors to accelerate MAFLD progression via multiple signaling cascades, as illustrated in detail in
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgements
The study was supported by Grants from the National Nature Science Foundation of China, No. U20A20348; Grants from the States S&T Projects of the 13th Five Year, 2018ZX10302206; the Natural Science Foundation of China, 81871646; the Self-Topic Science Foundation of State Key Laboratory for Diagnosis and Treatment of Infectious Diseases.
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