Leukocyte Cell-derived Chemotaxin Research Articles

LECT2 deletion exacerbates liver steatosis and macrophage infiltration in a male mouse model of LPS-mediated NASH.

Leukocyte cell-derived chemotaxin 2 (LECT2) is a protein initially isolated as a neutrophil chemotactic factor. We previously found that LECT2 is an obesity-associated hepatokine that senses liver fat and induces skeletal muscle insulin resistance. In addition, hepatocyte-derived LECT2 activates macrophage pro-inflammatory activity by reinforcing the LPS-induced c-Jun N-terminal kinase (JNK) signaling. Based on these findings, we examined the impact of LECT2 deletion on NAFLD/NASH caused by bacterial translocation. We created the bacterial translocation-mediated NAFLD/NASH model using LECT2 knockout mice (LECT2 KO) with 28 times a low-dose LPS injection under high-fat diet feeding conditions. LECT2 deletion exacerbated steatosis and significantly reduced p38 phosphorylation in the liver. In addition, LECT2 deletion increased macrophage infiltration with decreased M1/M2 ratios. LECT2 might contribute to protecting against lipid accumulation and macrophage activation in the liver under pathological conditions, which might be accomplished via p38 phosphorylation. This study provides novel aspects of LECT2 in the bacterial translocation-mediated NAFLD/NASH model.

Mimicking kidney flow shear efficiently induces aggregation of LECT2, a protein involved in renal amyloidosis

Aggregation of leukocyte cell-derived chemotaxin 2 (LECT2) causes ALECT2, a systemic amyloidosis that affects the kidney and liver. Previous studies established that LECT2 fibrillogenesis is accelerated by loss of its bound zinc ion and stirring/shaking. These forms of agitation create heterogeneous shear conditions, including air-liquid interfaces that denature proteins, that are not present in the body. Here, we determined the extent to which a more physiological form of mechanical stress—shear generated by fluid flow through a network of narrow channels—drives LECT2 fibrillogenesis. To mimic blood flow through the kidney, where LECT2 and other proteins form amyloid deposits, we developed a microfluidic device consisting of progressively branched channels narrowing from 5 mm to 20 μm in width. Shear was particularly pronounced at the branch points and in the smallest capillaries. Aggregation was induced within 24 h by shear levels that were in the physiological range and well below those required to unfold globular proteins such as LECT2. EM images suggested the resulting fibril ultrastructures were different when generated by laminar flow shear vs. shaking/stirring. Importantly, results from the microfluidic device showed the first evidence that the I40V mutation accelerated fibril formation and increased both size and density of the aggregates. These findings suggest that kidney-like flow shear, in combination with zinc loss, acts in combination with the I40V mutation to trigger LECT2 amyloidogenesis. These microfluidic devices may be of general use for uncovering mechanisms by which blood flow induces misfolding and amyloidosis of circulating proteins.

Elevated serum levels of leukocyte cell-derived chemotaxin 2 are associated with the prevalence of metabolic syndrome.

Inflammation is central to the pathogenesis of metabolic syndrome (MetS). Leukocyte cell-derived chemotaxin 2 (LECT2) is constitutively secreted in response to inflammatory stimuli and oxidative stress contributing to tissue or systemic inflammation. We explored the relationship between LECT2 levels and MetS severity in humans and mice. Serum LECT2 levels were measured in 210 participants with MetS and 114 without MetS (non-MetS). LECT2 expression in the liver and adipose tissue was also examined in mice fed a high-fat diet (HFD) and genetically obese (ob/ob) mice. Serum LECT2 levels were significantly higher in MetS participants than in non-MetS participants (7.47[3.36-17.14] vs. 3.74[2.61-5.82], P < 0.001). Particularly, serum LECT2 levels were significantly elevated in participants with hypertension, central obesity, diabetes mellitus (DM), hyperglycaemia, elevated triglyceride (TG) levels, and reduced high-density lipoprotein cholesterol (HDL-C) levels compared to those in participants without these conditions. Pearson's correlation analysisshowed that serum LECT2 levels were positively associated with conventional risk factors in all patients. Moreover, LECT2 was positively associated with the number of MetS components (r = 0.355, P < 0.001), indicating that higher serum LECT2 levels reflected MetS severity. Multivariate regression analysis revealed that a one standard deviation increase in LECT2 was associated with an odds ratio of 1.52 (1.01-2.29, P = 0.044) for MetS prevalence after adjusting for age, sex, body mass index, waist circumference, smoking status, white blood cell count, fasting blood glucose, TG, total cholesterol, HDL-C, blood urea nitrogen, and alanine aminotransferase. Receiver operating characteristic curve analysis confirmed the strong predictive ability of serum LECT2 levels for MetS. The optimum serum LECT2 cut-off value was 9.05. The area under the curve was 0.73 (95% confidence interval 0.68-0.78, P < 0.001), with a sensitivity and specificity of 45.71% and 95.61%, respectively. Additionally, LECT2 expression levels were higher at baseline and dramatically enhanced in metabolic organs (e.g. the liver) and adipose tissue in HFD-induced obese mice and ob/ob mice. Increased LECT2 levels were significantly and independently associated with the presence and severity of MetS, indicating that LECT2 could be used as a novel biomarker and clinical predictor of MetS.

Elucidation of pericholangitis and periductal fibrosis in cholestatic liver diseases via extracellular vesicles released by polarized biliary epithelial cells.

Cholestatic liver diseases causes inflammation and fibrosis around bile ducts. However, the pathological mechanism has not been elucidated. Extracellular vesicles (EVs) are released from both the basolateral and apical sides of polarized biliary epithelial cells. We aimed to investigate the possibility that EVs released from the basolateral sides of biliary epithelial cells by bile acid stimulation induce inflammatory cells and fibrosis around bile ducts, and they may be involved in the pathogenesis of cholestatic liver disease. Human biliary epithelial cells (H69) were grown on cell culture inserts and stimulated with chenodeoxycholic acid + IFN-γ. Human THP-1-derived M1-macrophages, LX-2 cells, and KMST-6 cells were treated with the extracted basolateral EVs, and inflammatory cytokines and fibrosis markers were detected by RT-PCR. Highly expressed proteins from stimulated EVs were identified, and M1-macrophages, LX-2, KMST-6 were treated with these recombinant proteins. Stimulated EVs increased the expression of TNF, IL-1β, and IL-6 in M1-macrophages, TGF-β in LX-2 and KMST-6 compared with the corresponding expression levels in unstimulated EVs. Nucleophosmin, nucleolin, and midkine levels were increased in EVs from stimulated cells compared with protein expression in EVs from unstimulated cells. Leukocyte cell-derived chemotaxin-2 (LECT2) is highly expressed only in EVs from stimulated cells. Stimulation of M1-macrophages with recombinant nucleophosmin, nucleolin, and midkine significantly increased the expression of inflammatory cytokines. Stimulation of LX-2 and KMST-6 with recombinant LECT2 significantly increased the expression of fibrotic markers. These results suggest that basolateral EVs are related to the development of pericholangitis and periductal fibrosis in cholestatic liver diseases.NEW & NOTEWORTHY Our research elucidated that the composition of basolateral EVs from the biliary epithelial cells changed under bile acid exposure and the basolateral EVs contained the novel inflammation-inducing proteins NPM, NCL, and MK and the fibrosis-inducing protein LECT2. We report that these new results are possible to lead to the potential therapeutic target of cholestatic liver diseases in the future.

The Hepatokine Leukocyte Cell-Derived Chemotaxin-2 Is Elevated in People with Impaired Glycaemic Regulation and Augmented by Acute Exercise

The hepatokine leukocyte cell-derived chemotaxin-2 (LECT2) promotes insulin resistance and hepatic fibrogenesis. In rodents, acute exercise suppresses circulating LECT2; however, human data are lacking. This study compared circulating LECT2 across populations and explored whether acute exercise impacts circulating LECT2. In Part A (n = 43), data were pooled from three experimental studies, regarding the following groups: healthy individuals, individuals with impaired glycaemic regulation (IGR), and individuals with type 2 diabetes and metabolic dysfunction-associated steatotic liver disease (T2DM-MASLD). Generalised linear models assessed differences in circulating LECT2 among groups. Part B (n = 20) involved exercise (30 min, 65% peak oxygen uptake) and control (resting) trials in the healthy and IGR groups. Circulating LECT2 was measured before and at 0, 1, 2 and 3 h post-exercise. Generalised estimating equations assessed differences in LECT2 responses to the trials among groups. In Part A, circulating LECT2 levels were 28.7% and 37.3% higher in the IGR and T2DM-MASLD groups, vs. healthy individuals (p ≤ 0.038), with BMI identified as the main predictor (p = 0.008). In Part B, average circulating LECT2 levels were 6.3% higher after exercise vs. in the control (p &lt; 0.001), with similar responses between groups (p = 0.829). In the combined cohort, circulating LECT2 levels were elevated 1–3 h after exercise vs. control (p ≤ 0.009). LECT2 is elevated in people with dysglycaemia, with BMI as a leading predictor. Contrary to previous rodent work, acute exercise augments, rather than suppresses, circulating LECT2 in humans.

Loss of LECT2 promotes ovarian cancer progression by inducing cancer invasiveness and facilitating an immunosuppressive environment

Leukocyte cell-derived chemotaxin 2 (LECT2) is a multifunctional cytokine that can bind to several receptors and mediate distinct molecular pathways in various cell settings. Changing levels of LECT2 have been implicated in multiple human disease states, including cancers. Here, we have demonstrated reduced serum levels of LECT2 in patients with epithelial ovarian cancer (EOC) and down-regulated circulating Lect2 as the disease progresses in a syngeneic mouse ID8 EOC model. Using the murine EOC model, we discovered that loss of Lect2 promotes EOC progression by modulating both tumor cells and the tumor microenvironment. Lect2 inhibited EOC cells’ invasive phenotype and suppressed EOC’s transcoelomic metastasis by targeting c-Met signaling. In addition, Lect2 downregulation induced the accumulation and activation of myeloid-derived suppressor cells (MDSCs). This fostered an immunosuppressive microenvironment in EOC by inhibiting T-cell activation and skewing macrophages toward an M2 phenotype. The therapeutic efficacy of programmed cell death-1 (PD-1)/PD-L1 pathway blockade for the ID8 model was significantly hindered. Overall, our data highlight multiple functions of Lect2 during EOC progression and reveal a rationale for synergistic immunotherapeutic strategies by targeting Lect2.

Association between Leukocyte Cell-Derived Chemotaxin 2 and Metabolic and Renal Diseases in a Geriatric Population: A Pilot Study.

LECT2 is not a routine diagnostic marker for any disease, but it has been associated with many pathologies, including systemic amyloidosis, rheumatoid arthritis, diabetes, atherosclerosis, and metabolic syndrome. With human aortic sections (n = 22) and sera from geriatric subjects (n = 79), we analyzed the relationships that could be observed between this protein and other parameters related to metabolic diseases. As a result, we observed a relatively high (r~0.8, p < 0.05) positive correlation between SRA and LECT2 and a negative correlation between EGFR and LECT2 (r~-0.4, p < 0.05). We observed LECT2 expression in macrophages, myocytes, and other aortic cells, with a tendency to be overexpressed in developed atherosclerotic plaques. We conclude that LECT2 exerts its chemotactic effects not only as a protein synthesized in the liver and secreted and circulating in the blood but also as a locally expressed protein within atherosclerotic plaque development. The LECT2-EGFR correlation suggests an association of this protein with loss of normal renal function. This fact can be associated with LECT2 amyloidosis, although it should be verified whether in the geriatric population there is indeed a widespread accumulation of LECT2 with the progression of aging or whether it is rather a marker of general deterioration of renal function.

Relationship between the changes in hepatokine levels and metabolic effects after laparoscopic sleeve gastrectomy in severely obese patients

PurposeTo clarify the relationships between the changes in hepatokines and weight loss, and between these changes and the metabolic effects, and the roles played by these changes, after laparoscopic sleeve gastrectomy (LSG).MethodsWe recruited 25 Japanese patients with severe obesity, who underwent LSG. We measured two hepatokines: selenoprotein P (SeP) and leukocyte cell-derived chemotaxin 2 (LECT2), at the baseline, and then 6 months and 1 year after LSG. Finally, we compared the changes in the hepatokines with the parameters of type 2 diabetes (T2D) and non-alcoholic steatohepatitis (NASH).ResultsChanges in LECT2 were correlated with the percentage of total weight loss (ρ = − 0.499, P = 0.024) and the decrease in total fat area (ρ = 0.559, P = 0.003). The changes in SeP were correlated with those in hemoglobin A1c (ρ = 0.526, P = 0.043) and the insulinogenic index (ρ = 0.638, P = 0.010) in T2D patients. In patients with NASH, the LECT2 levels were correlated with liver steatosis (ρ = 0.601).ConclusionsSeP levels decrease in association with HbA1c reduction, whereas LECT2 levels are associated with reductions in fat mass and NASH scores after LSG. Hepatokines may be involved in the pathology of obesity and its complications.

Leukocyte cell-derived chemotaxin 2 correlates with pediatric non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD), newly renamed metabolic dysfunction-associated liver disease (MASLD), is a leading cause of liver disease in children and adults. There is a paucity of data surrounding potential biomarkers and therapeutic targets, especially in pediatric NAFLD. Leukocyte cell-derived chemotaxin 2 (LECT2) is a chemokine associated with both liver disease and skeletal muscle insulin resistance. Our aim was to determine associations between LECT2 and common clinical findings of NAFLD in pediatric patients. Enzyme-linked immunosorbent assay (ELISA) was used to measure serum LECT2 concentrations in children (aged 2-17 years) with and without NAFLD. LECT2 concentrations were then correlated to clinical parameters in NAFLD. Mean LECT2 was significantly elevated in children with NAFLD versus healthy controls (n = 63 vs. 42, 5.83 ± 1.98 vs. 4.02 ± 2.02 ng/mL, p < 0.005). Additionally, LECT2 had strong correlations with body mass index (BMI) (Pearson r = 0.301, p = 0.002). A LECT2 concentration of 3.76 mg/mL predicts NAFLD with a sensitivity of 90.5% and specificity of 54.8%. Principal component analysis and logistic regression models further confirmed associations between LECT2 and NAFLD status. This study demonstrates increased serum LECT2 concentrations in pediatric NAFLD, which correlates with BMI and shows strong predictive value within these patients. Our data indicate that LECT2 is a potential diagnostic biomarker of disease and should be further investigated in pediatric as well as adult NAFLD.

Hepatokines as Biomarkers of Obesity-Associated Liver Pathophysiology: Deciphering Advances in Basic and Clinical Aspects

Hepatokines are specialized secretory proteins of the liver that play pivotal role in regulation of metabolic homeostasis as well as ensure crosstalk of liver to other organs. In recent years, the correlation of hepatokines and hepatic diseases has been exhibited, positively. Several stimuli, particularly hepatic steatosis provoke dysregulation in metabolic homeostasis and subsequently, pathogenesis of liver diseases that influence expression and release of hepatokines. In this review, we have interlinked the association of hepatic steatosis, a hallmark of obesity, to liver and liver-derived hepatokines. Furthermore, we summarized briefly the impact of several etiologically and epidemiologically important hepatokines, including Fetuin-A, fibroblast growth factor-21 (FGF-21), selenoprotein P, sexual hormone binding globulin (SHBG), angiopoietin like 4 (ANGPTL4) and leukocyte cell-derived chemotaxin (LECT2), in health and disease. Such hepatokines could serve as non-invasive biomarkers of early stages of liver pathogenesis and might contribute in improving patient safety profile for screening purposes and expediting drug development.

Cryo-EM structure of a human LECT2 amyloid fibril reveals a network of polar ladders at its core

ALECT2 systemic amyloidosis is associated with deposition of the leukocyte cell-derived chemotaxin-2 (LECT2) protein in the form of fibrils. In ALECT2 amyloidosis, ALECT2 fibrils deposit in the glomerulus, resulting in renal failure. Patients lack effective treatment options outside of renal transplant or dialysis. The structure of globular LECT2 has been determined but structures of ALECT2 amyloid fibrils remain unknown. Using single-particle cryo-EM, we find that recombinant human LECT2 forms robust twisting fibrils with canonical amyloid features. ALECT2 fibrils contain two mating protofilaments spanning residues 55-75 of the LECT2 sequence. The geometry of the ALECT2 fibril displays features in line with other pathogenic amyloids. Its core is tightly packed and stabilized by both hydrophobic contacts and hydrogen-bonded uncharged polar residues. The robustness of ALECT2 fibril cores is illustrated by their resistance to denaturants and proteases. This ALECT2 fibril structure presents a potential new target for treatments against ALECT2 systemic amyloidosis.

Urinary Proteomics for Discovery of Gastric Cancer Biomarkers to Enable Precision Clinical Oncology.

For precision in clinical oncology practice, detection of tumor-derived peptides and proteins in urine offers an attractive and noninvasive alternative for diagnostic or screening purposes. In this study, we report comparative quantitative proteomic profiling of urine samples from patients with gastric cancer and healthy controls using tandem mass tags-based multiplexed mass spectrometry approach. We identified 1504 proteins, of which 246 were differentially expressed in gastric cancer cases. Notably, ephrin A1 (EFNA1), pepsinogen A3 (PGA3), sortilin 1 (SORT1), and vitronectin (VTN) were among the upregulated proteins, which are known to play crucial roles in the progression of gastric cancer. We also found other overexpressed proteins, including shisa family member 5 (SHISA5), mucin like 1 (MUCL1), and leukocyte cell derived chemotaxin 2 (LECT2), which had not previously been linked to gastric cancer. Using a novel approach for targeted proteomics, SureQuant, we validated changes in abundance of a subset of proteins discovered in this study. We confirmed the overexpression of vitronectin and sortilin 1 in an independent set of urine samples. Altogether, this study provides molecular candidates for biomarker development in gastric cancer, and the findings also support the promise of urinary proteomics for noninvasive diagnostics and personalized/precision medicine in the oncology clinic.

Inflammation-related mRNA expression in patients with multiple myeloma undergoing hematopoietic stem cell mobilization

Mobilization of CD34+ cells is a key element in the therapy of patients with multiple myeloma undergoing autologous stem cell transplantation. The use of chemotherapy and the granulocyte colony-stimulating factor can significantly affect the expression of inflammation-related proteins and the migration of hematopoietic stem cells. We assessed the mRNA expression of selected proteins involved in the inflammatory landscape in MM patients (n=71). The aim of the study was to evaluate C-C motif chemokine ligand 3, 4, 5 (CCL3, CCL4, CCL5), leukocyte cell-derived chemotaxin 2 (LECT2), tumor necrosis factor (TNF), and formyl peptide receptor 2 (FPR2) levels in the course of mobilization and their role in the CD34+ collection efficacy. mRNA expression from peripheral blood plasma was evaluated by RT-PCR. We observed a deep decline in CCL3, CCL4, LECT2, and TNF mRNA expression on the day of the first apheresis (day A) as compared to baseline. A negative correlation was observed between CCL3, FPR2, LECT2, TNF level, and the CD34+ cells count in peripheral blood on day A, and the number of CD34+ cells obtained at first apheresis . Our results indicate that the investigated mRNAs significantly alter and may regulate the migration of CD34+ cells during mobilization. Moreover, in case of FPR2 and LECT2, the results obtained in patients differ from the murine models.

The emerging roles of leukocyte cell-derived chemotaxin-2 in immune diseases: From mechanisms to therapeutic potential.

Leukocyte cell-derived chemotaxin-2 (LECT2, also named ChM-II), initially identified as a chemokine mediating neutrophil migration, is a multifunctional secreted factor involved in diverse physiological and pathological processes. The high sequence similarity of LECT2 among different vertebrates makes it possible to explore its functions by using comparative biology. LECT2 is associated with many immune processes and immune-related diseases via its binding to cell surface receptors such as CD209a, Tie1, and Met in various cell types. In addition, the misfolding LECT2 leads to the amyloidosis of several crucial tissues (kidney, liver, and lung, etc.) by inducing the formation of insoluble fibrils. However, the mechanisms of LECT2-mediated diverse immune pathogenic conditions in various tissues remain to be fully elucidated due to the functional and signaling heterogeneity. Here, we provide a comprehensive summary of the structure, the "double-edged sword" function, and the extensive signaling pathways of LECT2 in immune diseases, as well as the potential applications of LECT2 in therapeutic interventions in preclinical or clinical trials. This review provides an integrated perspective on the current understanding of how LECT2 is associated with immune diseases, with the aim of facilitating the development of drugs or probes against LECT2 for the theranostics of immune-related diseases.

Circulating leukocyte cell-derived chemotaxin 2 and fibroblast growth factor 21 are negatively associated with cardiorespiratory fitness in healthy volunteers

Leukocyte cell-derived chemotaxin-2 (LECT2) and fibroblast growth factor 21 (FGF21) are hepatokines that are regulated by energy balance and mediate insulin sensitivity and glycaemic control. This cross-sectional study examined the independent associations of cardiorespiratory fitness (CRF), moderate-to-vigorous intensity physical activity (MVPA), and sedentary time with circulating LECT2 and FGF21. Data were combined from two previous experimental studies in healthy volunteers (n = 141, male = 60%, mean ± SD age = 37 ± 19 years, body mass index (BMI) = 26.1 ± 6.3 kg·m-2). Sedentary time and MVPA were measured via an ActiGraph GT3X + accelerometer, while magnetic resonance imaging quantified liver fat. CRF was assessed using incremental treadmill tests. Generalized-linear models examined the association of CRF, sedentary time, and MVPA with LECT2 and FGF21 while controlling for key demographic and anthropometric variables. Interaction terms explored the moderating influence of age, sex, BMI, and CRF. In the fully adjusted models, each SD increase in CRF was independently associated with a 24% (95% CI: -37% to-9%, P = 0.003) lower plasma LECT2 concentration and 53% lower FGF21 concentration (95% CI: -73% to -22%, P = 0.004). Each SD increase in MVPA was independently associated with 55% higher FGF21 (95% CI: 12% to 114%, P = 0.006), and this relationship was stronger in those with lower BMI and higher levels of CRF. These findings demonstrate that CRF and wider activity behaviours may independently modulate the circulating concentrations of hepatokines and thereby influence inter-organ cross-talk.

Tandem mass tag-based quantitative proteomic profiling identifies candidate serum biomarkers of drug-induced liver injury in humans

Diagnosis of drug-induced liver injury (DILI) and its distinction from other liver diseases are significant challenges in drug development and clinical practice. Here, we identify, confirm, and replicate the biomarker performance characteristics of candidate proteins in patients with DILI at onset (DO; n = 133) and follow-up (n = 120), acute non-DILI at onset (NDO; n = 63) and follow-up (n = 42), and healthy volunteers (HV; n = 104). Area under the receiver operating characteristic curve (AUC) for cytoplasmic aconitate hydratase, argininosuccinate synthase, carbamoylphosphate synthase, fumarylacetoacetase, fructose-1,6-bisphosphatase 1 (FBP1) across cohorts achieved near complete separation (range: 0.94–0.99) of DO and HV. In addition, we show that FBP1, alone or in combination with glutathione S-transferase A1 and leukocyte cell-derived chemotaxin 2, could potentially assist in clinical diagnosis by distinguishing NDO from DO (AUC range: 0.65–0.78), but further technical and clinical validation of these candidate biomarkers is needed.

LECT2 modulates dendritic cell function after Helicobacter pylori infection via the CD209a receptor.

Helicobacter pylori, a gram-negative bacterium persisting on the gastric mucosa, is involved in the pathogenesis of a variety of gastric diseases. Leukocyte cell-derived chemotaxin 2 (LECT2) treatment increased the phagocytic capacity of lymphocytes and improved immune function in bacterial infection. Whether the immune cells infected with H. pylori are affected by LECT2 is unclear. Bone marrow-derived dendritic cells (BMDCs) from wild-type C57BL/6 mice, CD209a knockout mice, or LECT2 knockout mice were exposed to H. pylori at a multiplicity of infection of 10 for 24h. The maturity of DCs and the cytokines secreted by DCs were analyzed by flow cytometry, western blot, and real-time PCR. The signaling pathway underlying CD209a activation after LECT2 treatment were also detected. LECT2 treatment promoted H. pylori-induced BMDC maturation and produced a high level of anti-inflammatory cytokine (IL-10) but a low level of pro-inflammatory cytokine (IL-23p40). Moreover, LECT2-pretreated DCs shifted the development of pro-inflammatory Th1/Th17 cells to Treg cells. CD209a mediated LECT2-induced maturation and secretion of DC in H. pylori-primed BMDCs. LECT2 was further confirmed to induce the secretion of certain cytokines via CD209a-JNK/P38 MAPK pathway. This study reveals that LECT2 modulated the functions of H. pylori-primed DCs in a CD209a-dependent manner, which might hinder the clearance of H. pylori and contribute to its colonization.

β-catenin/TCF4 inhibitors ICG-001 and LF3 alleviate BDL-induced liver fibrosis by suppressing LECT2 signaling

Liver fibrosis can be characterized by the over-deposition of extracellular matrix (ECM). It has been reported that β-catenin/TCF4 interaction was enhanced in bile duct ligation (BDL) model, which implicated the critical role of β-catenin/TCF4 interaction during the progression of fibrosis. However, whether inhibiting β-catenin/TCF4 signaling attenuates liver fibrosis remains unknown. In the current study, we used ICG-001, an inhibitor that disrupts the interaction between CREB binding protein (CBP) and β-catenin, to inhibit β-catenin/TCF4 transcriptional activity. We also used LF3, a small molecule antagonist, to inhibit β-catenin/TCF4 interaction. The antifibrotic effect of ICG-001 and LF3 was assessed on BDL-induced liver fibrosis model. The results indicated both ICG-001 and LF3 significantly reduced the positive staining area of Sirius Red and α-SMA. The protein expression levels of α-SMA, Collagen Ⅰ and CD31 were also significantly downregulated in BDL + ICG-001 and BDL + LF3 groups. Besides, ICG-001 and LF3 promoted portal angiogenesis and inhibited sinusoids capillarization in fibrotic livers. For mechanistic study, we measured the level of leukocyte cell-derived chemotaxin 2 (LECT2), a direct target of β-catenin/TCF4, which was recently reported to participate in hepatic fibrosis by regulating angiogenesis. The results showed that both ICG-001 and LF3 reduced LECT2 expression in BDL mice. LF3 also downregulated pSer 675 β-catenin and nuclear β-catenin. In conclusion, this study demonstrated that inhibiting β-catenin/TCF4 signaling by ICG-001 or LF3 mitigated liver fibrosis by downregulating LECT2, promoting portal angiogenesis and inhibiting sinusoids capillarization, which provided new evidence that β-catenin/TCF4 signaling might be a target for the treatment of liver fibrosis.

PFOS-elicited metabolic perturbation in liver and fatty acid metabolites in testis of adult mice.

Multiple factors can contribute to sub-fecundity, including genetics, lifestyle, and environmental contaminants. PFASs are characterized as "forever chemicals" due to their ubiquitous contamination and their persistence in the environment, wildlife, and humans. Numerous studies have demonstrated that PFAS exposure adversely affects multiple bodily functions, including liver metabolism and gonadal function. It is unclear, however, how the disruption of hepatic fatty acid metabolism affects testicular function. In this study, male mice were administered 0.3 and 3 μg/g body weight of PFOS for 21 days. Our data showed that PFOS exposure caused hepatic steatosis, as evidenced by significant increases in triglyceride levels, expression of ATP-citrate lyase, and fatty acid synthase, as well as fasting insulin levels. PFOS perturbed the expression levels of hepatokines, of which fibroblast growth factor-21 (Fgf-21), leukocyte cell-derived chemotaxin-2 (Lect-2), and retinol-binding protein-4 (Rbp-4) were significantly reduced, whereas angiopoietin-like 4 (Angptl4) was noticeably increased. While Rbp-4 and Fgf-21 are known to contribute to spermatogenesis and testosterone synthesis. In PFOS-exposed groups, testicular ATP, and testosterone decreased significantly with a significant increase in the expression of peroxisome proliferator-activated receptor-coactivator 1α. Mass spectrophotometry imaging revealed the localization of PFOS in testes, along with significant increases in fatty acid metabolites. These included arachidonic acid, dihomo-α-linolenic acid, dihomo-γ-linolenic acid, oxidized ceramide, diacylglycerol, phosphatidylcholine, and phosphatidylethanolamine, which are associated with inflammation and post-testicular causes of infertility. This study revealed potential links between PFOS-elicited changes in hepatic metabolism and their impacts on testicular biology. This study provides insights into alternative targets elicited by PFOS that can be used to develop diagnostic and therapeutic strategies for improving testicular dysfunction.

Hepatokines and Adipokines in Metabolic Syndrome

AbstractHepatokines and adipokines are secretory proteins derived from hepatocytes and adipocytes, respectively. These proteins play a main role in the pathogenesis of metabolic syndrome (MetS), characterized by obesity, dysglycemia, insulin resistance, dyslipidemia, and hypertension. Adipose tissue and liver are important endocrine organs because they regulate metabolic homeostasis as well as inflammation because they secrete adipokines and hepatokines, respectively. These adipokines and hepatokines communicate their action through different autocrine, paracrine and endocrine pathways. Liver regulates systemic homeostasis and also glucose and lipid metabolism through hepatokines. Dysregulation of hepatokines can lead to progression toward MetS, type 2 diabetes (T2D), inflammation, hypertension, and other diseases. Obesity is now a worldwide epidemic. Increasing cases of obesity and obesity-associated metabolic syndrome has brought the focus on understanding the biology of adipocytes and the mechanisms occurring in adipose tissue of obese individuals. A lot of facts are now available on adipose tissue as well. Adipose tissue is now given the status of an endocrine organ. Recent evidence indicates that obesity contributes to systemic metabolic dysfunction. Adipose tissue plays a significant role in systemic metabolism by communicating with other central and peripheral organs via the production and secretion of a group of proteins known as adipokines. Adipokine levels regulate metabolic state of our body and are potent enough to have a direct impact upon energy homeostasis and systemic metabolism. Dysregulation of adipokines contribute to obesity, T2D, hypertension and several other pathological changes in various organs. This makes characterization of hepatokines and adipokines extremely important to understand the pathogenesis of MetS. Hepatokines such as fetuin-A and leukocyte cell-derived chemotaxin 2, and adipokines such as resistin, leptin, TNF-α, and adiponectin are some of the most studied proteins and they can modulate the manifestations of MetS. Detailed insight into the function and mechanism of these adipokines and hepatokines in the pathogenesis of MetS can show the path for devising better preventative and therapeutic strategies against this present-day pandemic.