LECT2: A pleiotropic and promising hepatokine, from bench to bedside

Abstract LECT2 (leucocyte cell‐derived chemotaxin 2) is a 16‐kDa protein mainly produced by hepatocytes. It was first isolated in PHA‐activated human T‐cell leukaemia SKW‐3 cells and originally identified as a novel neutrophil chemotactic factor. However, many lines of studies suggested that LECT2 was a pleiotropic protein, it not only functioned as a cytokine to exhibit chemotactic property, but also played multifunctional roles in some physiological conditions and pathological abnormalities, involving liver regeneration, neuronal development, HSC(haematopoietic stem cells) homeostasis, liver injury, liver fibrosis, hepatocellular carcinoma, metabolic disorders, inflammatory arthritides, systemic sepsis and systemic amyloidosis. Among the above studies, it was discovered that LECT2 could be a promising molecular biomarker and therapeutic target. This review summarizes LECT2‐related receptors and pathways, basic and clinical researches, primarily in mice and human, for a better comprehension and management of these diseases in the future.

cofactor and a preference for peptides containing polyglycine residues, noteworthily, it is the only vertebrate protein in the M23 family. [3][4][5] Although LECT2 is mainly synthesized and secreted to bloodstream by hepatocytes, 6 it is also found in presence of other cells, such as vascular endothelial cells, smooth muscle cells, cerebral nerve cells and adipocytes. 7 Accumulating evidence demonstrated that the mammalian LECT2 was a pleiotropic protein, it not only acted as a cytokine to exhibit chemotactic property, but also played multifunctional roles in several physiological conditions and pathological abnormalities, involving liver regeneration, neuronal development, HSC (haematopoietic stem cells) homeostasis, liver injury, liver fibrosis, hepatocellular carcinoma, metabolic disorders, inflammatory arthritides, systemic sepsis and systemic amyloidosis. In this review, we summarize LECT2related receptors and pathways (Table 1), basic and clinical researches (Table 2), primarily in mice and human, for a better comprehension and management of these diseases in the future.

| Liver regeneration
LECT2 may be involved in the early period of liver regeneration. In concanavalin A (ConA)-induced hepatic injury model, both LECT2 mRNA and protein levels decreased temporarily in the liver and serum from 8 to 24 h after intravenous injection of Con A (13 mg/kg), and they could be detected again at 48 h after recovery from hepatic injury. 8 Likewise, in hepatectomy-induced hepatic injury model, the expression of either LECT2 mRNA or LECT2 protein could not be detected in the liver tissue at 0.5 h after partial hepatectomy. A significant magnitude of hepatocytes expressing LECT2 mRNA and protein could be seen across the liver at 6 h. 9 It was observed in patients with acute liver failure that the level of serum LECT2 was lower in the expired group, compared with the alive group (0.96 ± 0.8 ng/ml vs 12.9 ± 4.3 ng/ml p < 0.05). Serum LECT2 level increased with the improvement of liver function. Besides, it was negatively correlated with serum AST(aspartate transaminase) and ALT (alanine transaminase) level, the nadir of LECT2 was concomitant with the peak of ALT. 10 All these studies suggest that LECT2 may participate in hepatic regeneration in the early phase. Koshimizu et al 11 uncovered that the length of axons and dendrites was shorter in neurons from LECT2-knockout mice after 4 days of culture in vitro. Moreover, the neurons from LECT2-knockout mice had several neurotrophin expressions that differed from that of wildtype mice, including NGF (nerve growth factor), BDNF (brain-derived neurotrophic factor) and NT-3 (neurotrophin-3). A subsequent investigation 12 elucidated that there were more fragmentations and shorter microtubules in cultured neurons from LECT2-knockout mice.

| Neuronal development
Furthermore, an increased expression of katanin-P60, a microtubulesevering enzyme, was present in these cultured neurons at the first and the fourth day, when compared to the wild-type ones.
The results show that LECT2 may affect the extension and neurotrophin expressions of the brain neurons during neuronal development. Yet, the function of LECT2 in the brain remains to be deeply explored and more studies are expected to spring up.

| HSC homeostasis
Lu et al 13 illustrated that TNF(tumour necrosis factor) was the specific downstream target of LECT2 signal in the macrophages and osteolineage cells. Recombinant LECT2 administration were capable of enhancing HSC (haematopoietic stem cells) expansion in the marrow and promoting HSC mobilization to the blood, on account of reduced TNF expressions from these macrophages and osteolineage cells through LECT2/CD209a axis. The effect of LECT2 on HSC fell into a decline, after a specific depletion of macrophages and osteolineage cells, or in the TNF-knockout mice.
The study may bring a promising future for the treatment of patients who are in need of HSC transplantation due to a wide variety of haematological diseases.

| Liver fibrosis
Xu et al 16  Yet, AAV9-LECT2 small hairpin RNA combining with bevacizumab showed better therapeutic outcomes and less side effects than with rVEGF in mice.
The expressions of serum LECT2 may vary in different pathogenesis, with the advancement of liver fibrosis. Xu et al 18  In brief, the referred researches illustrate that LECT2 may play a crucial role in liver fibrogenesis, and it may represent a potential biomarker and therapeutic target for liver fibrosis. The mentioned results reveal that LECT2 may take part in hepatocarcinogenesis and this may open a potential avenue, in terms of diagnosis and treatment, for HCC.

| Metabolic disorders
Serum LECT2 levels were positively correlated with liver triglyceride contents in mice, 27 and plasma LECT2 levels exhibited a strong relationship with visceral fat area in human. 28 Higher levels of LECT2 expression were present in participants with dyslipidemia and plasma LECT2 levels could be used as potential biomarker to differentiate the participants with dyslipidemia from those without dyslipidemia, accompanied by a sensitivity of 60.3%, specificity of 66.7%, based on the plasma cut-off value at 16.5 ng/ml. 28 In parallel with the above studies, the increase in serum LECT2 levels was also found in population with obesity and fatty liver, which was positively correlated with all the four major anthropometric measures in both males and females, including BMI (body mass index), WC (waist circumference), WHR (waist-to-hip ratio) and W/Ht (waist-to-height ratio). 29 Serum LECT2 levels presented a close correlation with the sever-  Together, these data uncover that LECT2 may be utilized as a novel therapeutic option regarding inflammatory arthritides such as RA. These studies highlight the potential value of LECT2 as a diagnostic indicator and immunal modulation target for acute severe inflammation.

| Systemic amyloidosis
Amyloidosis is the abnormal deposition and aggregation of insoluble protein fibrils in tissues, leading to progressive organ dysfunction. In addition to the liver, 43 the kidney is the site most frequently affected by systemic amyloidosis. Currently, more than 30 proteins have been found to cause amyloidosis in human. 44 First described in 2008, LECT2 is a newly discovered amyloidogenic protein in a renal biopsy. 45 LECT2 amyloidosis (ALECT2) accounted for 2.5% (7/285) and 2.7% (13/474) cases in two large series of renal amyloidosis, respectively. 46,47 ALECT2 has a strong racial bias and it is highly prevalent in the Hispanic population. Among the patients with ALECT2, Hispanics made up a considerable percentage of 88% (35/40) and 92% (66/72) cases respectively in two studies focusing on renal amyloidosis. 48,49 Genomic analysis indicated that no pathogenic mutations were detected in the LECT2-encoding gene, although each of the patient was homozygous for the G allele (SNP rs31517 in exon 3), which was present in about 60% of the European population. 43,48,50,51 An observational study (NCT03774784) has been launched to investigate the natural history of ALECT2. As yet, there is no better therapy except transplantation for ALECT2. Recently, it has been suggested that I40V mutation may destabilize the structure of LECT2 and increase the aggregation tendency, when in a deficiency or removal of zinc icon. 52 Whereas, LECT2 amyloidosis remains unclear and elusive, more thorough studies are in need to explore the disease.

| D ISCUSS I ON AND PER S PEC TIVE S
LECT2 is mainly produced and released to blood by hepatocytes, like albumin, it is able to reflect the condition of liver function at cer- The balance between pro-inflammatory and anti-inflammatory cytokines has a direct impact on the severity of inflammation. IFNγ, as a pro-inflammatory cytokine, is primarily produced by activated lymphocytes, including CD4 and CD8 T cells, gamma delta T cells and NK and NKT cells. 58 The production of IFNγ from these cells could also stimulate macrophages to produce several pro-inflammatory cytokines, such as TNFα. 59 G-CSF(granulocyte colony stimulating factor), as a bone marrow (BW)-derived cytokine, is a HSC-mobilizing agent widely used in clinical settings. For some cancer patients undergoing chemotherapy or radiotherapy, it may fail to mobilize HSC due to a severe alteration of the BM microenvironment induced by G-CSF. 64

CO N FLI C T O F I NTE R E S T
We declare no conflict of interest in this work, and all authors approve the manuscript.

DATA AVA I L A B I L I T Y S TAT E M E N T
Data sharing is not applicable as no new data were generated for the review article.