PON1 rs662, rs854560 and TRIB1 rs17321515, rs2954029 Gene Polymorphisms Are Associated with Lipid Parameters in Patients with Unstable Angina.

Acute coronary heart disease (CHD) is mainly caused by the rupture of an unstable atherosclerotic plaque. Many different factors can cause stenosis or even occlusion of the coronary artery lumen, such as vasculitis and platelet aggregation. Our study was performed to assess the association between PON1 rs662, rs854560 and TRIB1 rs17321515, rs2954029 polymorphisms and the risk of CHD, as well as the association between studied polymorphisms and selected clinical parameters affecting the risk of developing ischemic heart disease. A total of 232 patients with unstable angina were enrolled in this study. There were no statistically significant differences in the PON1 rs662, rs854560 and TRIB1 rs17321515, rs2954029 polymorphism distributions between the total study and control groups. Total cholesterol plasma levels were significantly higher in patients with the PON1 rs662 TT genotype compared to those with the CC+TC genotypes, as well as in patients with the PON1 rs854560 TT genotype compared to those with the AA+AT genotypes. LDL plasma levels were significantly increased in patients with the PON1 rs854560 TT genotype compared to those with the AA+AT genotypes. Plasma levels of HDL were significantly decreased in patients with the TRIB1 rs17321515 AA+AG genotypes compared to those with the GG genotype, as well as in patients with the TRIB1 rs2954029 AA+AT genotypes compared to those with the TT genotype. Our results suggest that the analysed polymorphisms are not risk factors for unstable angina in the Polish population. However, the results of this study indicate an association between the PON1 rs662, rs854560 and TRIB1 rs17321515, rs2954029 polymorphisms with lipid parameters in patients with coronary artery disease.

PNPLA3 Genotype and Diabetes Identify Patients With Nonalcoholic Fatty Liver Disease at High Risk of Incident Cirrhosis.

BACKGROUND & AIMS: Non-alcoholic fatty liver disease (NAFLD) can progress to cirrhosis and hepatic decompensation, but whether genetic variants influence the rate of progression to cirrhosis or are useful in risk stratification among patients with NAFLD is uncertain. METHODS: We included participants from 2 independent cohorts, they Michigan Genomics Initiative (MGI) and UK Biobank (UKBB), who had NAFLD defined by elevated alanine aminotransferase (ALT) levels in the absence of alternative chronic liver disease. The primary predictors were genetic variants and metabolic comorbidities associated with cirrhosis. We conducted time-to-event analyses using Fine-Gray competing risk models. RESULTS: We included 7893 and 46,880 participants from MGI and UKBB, respectively. In univariable analysis, PNPLA3-rs738409-GG genotype, diabetes, obesity, and ALT of ≥2× upper limit of normal were associated with higher incidence rate of cirrhosis in both MGI and UKBB. PNPLA3-rs738409-GG had additive effects with clinical risk factors including diabetes, obesity, and ALT elevations. Among patients with indeterminate fibrosis-4 (FIB4) scores (1.3-2.67), those with diabetes and PNPLA3-rs738409-GG genotype had an incidence rate of cirrhosis comparable to that of patients with high-risk FIB4 scores (>2.67) and 2.9-4.8 times that of patients with diabetes but CC/CG genotypes. In contrast, FIB4 <1.3 was associated with an incidence rate of cirrhosis significantly lower than that of FIB4 of >2.67, even in the presence of clinical risk factors and high-risk PNPLA3 genotype. CONCLUSIONS: PNPLA3-rs738409 genotype and diabetes identified patients with NAFLD currently considered indeterminate risk (FIB4 1.3-2.67) who had a similar risk of cirrhosis as those considered high-risk (FIB4 >2.67). PNPLA3 genotyping may improve prognostication and allow for prioritization of intensive intervention.

Molecular characterization of TRIB1 gene and its role in regulation of steroidogenesis in bos grunniens granulosa cells.

To explore the expression pattern of the TRIB1 gene in yak follicles and its effect on the steroidogenesis of granulosa cells (GCs). Here, 4-5 years old female yaks were treated as the subjects. Immunohistochemically assay found that TRIB1 protein was expressed in different developmental follicles. Among different cell types of follicles, including cumulus cells (CCs), granulosa cells (GCs) and theca cells (TCs), the TRIB1 protein was most abundant in GCs (P < 0.0001). In addition, we cloned the coding sequence (CDS) of the yak TRIB1 gene, which is 1119 bp, encoding 372 amino acids (AA). The amino acid sequence homology of TRIB1 is >80% to those of other species, except for zebrafish. To further explore the function of TRIB1 in steroidogenesis, the pcDNA3.1(+)-TRIB1 eukaryotic expression vector was constructed and then transfected into GCs. The data showed that overexpression of TRIB1 significantly reduced the progesterone (P4) secretion of granulosa cells measured by ELISA assay (P < 0.05), but not Estradiol (E2) secretion. Consistently, TRIB1 gain-of-function downregulated the mRNA levels of steroidogenesis related genes steroidogenic acute regulatory protein (StAR), cytochrome P450 family 11 subfamily A member 1 (CYP11A1) and 3ß-hydroxysteroid dehydrogenase (3ß-HSD) (P < 0.01), while cytochrome P450 family 17 subfamily A member 1 (CYP17A1) and cytochrome P450 family 19 subfamily A member 1 (CYP19A1) had no significant difference (P > 0.05). Interestingly, mito-tracker staining showed that mitochondrial number significantly decreased in TRIB1 overexpressed GCs (P < 0.01). Further, overexpression of TRIB1 inhibited mRNA levels of mitochondrial biogenesis related genes, including Mitochondrial transcription factor (TFAM) and Peroxisome proliferator-activated receptor alpha co-activator (PPARGC1A) (P < 0.05). Conclusively, this work indicates that TRIB1 inhibited progesterone synthesis of GCs might be involved in the reduction of the mitochondria number.

Icariin represses the inflammatory responses and survival of rheumatoid arthritis fibroblast-like synoviocytes by regulating the TRIB1/TLR2/NF-kB pathway.

BACKGROUND: Effective treatment methods for rheumatoid arthritis (RA) are still lacking. Previous studies have shown that icariin exerts a significant therapeutic effect on RA; however, the molecular mechanism requires further analysis. METHODS: qRT-PCR and western blot were performed to examine the gene or protein levels, respecctively. The proinflammatory cytokine levels were determined utilizing ELISA and western blot assays. Cell proliferation and apoptosis were quantified using CCK-8, EdU and flow cytometry assays, respectively. A RA mouse model was established to observe histopathological changes. RESULTS: Both icariin treatment and TRIB1 overexpression inhibited proliferation and inflammatory responses but promoted the apoptosis of TNF-α-treated RA-FLSs. Icariin treatment increased TRIB1 expression by promoting Nrf2 expression, thus blocking TLR2/NF-κB signalling. In addition, functional rescue experiments suggested that TRIB1 knockdown strikingly restrained the biological effects of icariin on TNF-α-treated RA-FLSs. Moreover, in vivo experimental results revealed that icariin restored inflammation and deterioration in RA mice by upregulating TRIB1. CONCLUSIONS: Based on these results, icariin repressed TNF-α-induced inflammatory responses and survival in RA-FLSs by regulating the TRIB1/TLR2/NF-kB pathway, implying that icariin may be a promising candidate drug for RA treatment.

TRIB1 regulates tumor growth via controlling tumor-associated macrophage phenotypes and is associated with breast cancer survival and treatment response.

Molecular mechanisms that regulate tumor-associated macrophage (TAM) phenotype and function are incompletely understood. The pseudokinase TRIB1 has been reported as a regulator of macrophage phenotypes, both in mouse and human systems. Methods: Bioinformatic analysis was used to investigate the link between TRIB1 expression in breast cancer and therapeutic response to chemotherapy. In vivo models of breast cancer included immune-competent mice to characterize the consequences of altered (reduced or elevated) myeloid Trib1 expression on tumor growth and composition of stromal immune cell populations. Results: TRIB1 was highly expressed by TAMs in breast cancer and high TRIB1 expression correlated with response to chemotherapy and patient survival. Both overexpression and knockout of myeloid Trib1 promote mouse breast tumor growth, albeit through different molecular mechanisms. Myeloid Trib1 deficiency led to an early acceleration of tumor growth, paired with a selective reduction in perivascular macrophage numbers in vivo and enhanced oncogenic cytokine expression in vitro. In contrast, elevated levels of Trib1 in myeloid cells led to an increased late-stage mammary tumor volume, coupled with a reduction of NOS2 expressing macrophages and an overall reduction of macrophages in hypoxic tumor regions. In addition, we show that myeloid Trib1 is a previously unknown, negative regulator of the anti-tumor cytokine IL-15, and that increased myeloid Trib1 expression leads to reduced IL-15 levels in mammary tumors, with a consequent reduction in the number of T-cells that are key to anti-tumor immune responses. Conclusions: Together, these results define a key role for TRIB1 in chemotherapy responses for human breast cancer and provide a mechanistic understanding for the importance of the control of myeloid TRIB1 expression in the development of this disease.

Structural and biophysical characterization of Tribbles homolog 1.

Tribbles proteins are pervasive pseudokinases in cellular signaling. They play a major role in the differentiation of myeloid cells, hepatocytes and adipocytes, and more widely in immune function, metabolism and cancer. Like many other pseudokinases, an inherent lack of catalytic activity has meant that a specialized cadre of techniques has been required to investigate Tribbles function. A prerequisite to most in vitro biochemistry has been robust methods for purifying useful quantities of Tribbles protein, which can sometimes exhibit non-optimal behavior upon recombinant expression. For instance, structural studies of the Tribbles family have largely focused on TRIB1, in part because of more readily available protein. Here we describe methods we have developed to routinely produce milligram quantities of TRIB1, and specific considerations when employing TRIB1 protein for various downstream analyses. Namely, we describe preparation and crystallization of TRIB1 for structural studies, and using fluorescence polarization and isothermal titration calorimetry to analyze interactions with TRIB1. We hope that applying these considerations can facilitate further understanding of TRIB1 function, specifically, and can be selectively applied to improve studies of other Tribbles proteins and pseudokinases more generally.

The Pseudokinase TRIB1 in Immune Cells and Associated Disorders.

Research advances in Tribbles homolog (TRIB) genes have established the consensus that this protein family plays roles in diverse biological conditions and regulates intracellular signaling networks and several human diseases. In this review, we focus on one member of the family, TRIB1, and its role at the crossroads of immune signaling. TRIB1 directly interacts with transcription factors such as FOXP3 and C/EBPα, with several signaling molecules such as MEK1 and MALT1 and directly acts on key cell signaling pathways such as the MAPK and NF-κB pathways. Altogether, these interactions emphasize that TRIB1 is at the center of major cell signaling pathways while TRIB1 has cell-specific roles, potentially depending on the expressing cells and binding partners. In this review, we describe its roles in immune cells and highlight the interacting partners explaining these functions which suggests TRIB1 as a precise mediator of cellular homeostasis as well as in different cancers and immune-related disorders.

Aging deteriorated liver Ischemia and reperfusion injury by suppressing Tribble's proteins 1 mediated macrophage polarization.

Aggravated liver injury has been reported in aged ischemia/reperfusion-stressed livers; however, the mechanism of aged macrophage inflammatory regulation is not well understood. Here, we found that the adaptor protein TRIB1 plays a critical role in the differentiation of macrophages and the inflammatory response in the liver after ischemia/reperfusion injury. In the present study, we determined that aging promoted macrophage-mediated liver injury and that inflammation was mainly responsible for lower M2 polarization in liver transplantation-exposed humans post I/R. Young and aged mice were subjected to hepatic I/R modeling and showed that aging aggravated liver injury and suppressed macrophage TRIB1 protein expression and anti-inflammatory function in I/R-stressed livers. Restoration of TRIB1 is mediated by lentiviral infection-induced macrophage anti-inflammatory M2 polarization and alleviated hepatic I/R injury. Moreover, TRIB1 overexpression in macrophages facilitates M2 polarization and anti-inflammation by activating MEK1-ERK1/2 signaling under IL-4 stimulation. Taken together, our results demonstrated that aging promoted hepatic I/R injury by suppressing TRIB1-mediated MEK1-induced macrophage M2 polarization and anti-inflammatory function.

Molecular dynamics and structural analysis of the binding of COP1 E3 ubiquitin ligase to ß-catenin and TRIB pseudokinases.

Tribbles pseudokinases, Tribbles homolog 1 (TRIB1), Tribbles homolog 2 (TRIB2), and Tribbles homolog 3 (TRIB3), bind to constitutive photomorphogenesis protein 1 (COP1) E3 ligase to mediate the regulation of ß-catenin expression. The interaction mechanism between COP1 E3 ligase and ß-catenin has not been addressed to date. Based on the functional presence of TRIBs in wingless-related integration site (WNT) signaling, we analyzed their interaction patterns with ß-catenin and COP1. Here, through in silico approaches, we ascribe the COP1 binding pattern against TRIBs and ß-catenin. TRIB1 (355-DQIVPEY-361), TRIB2 (326-DQLVPDV-332), and TRIB3 (333-AQVVPDG-339) peptides revealed a shallow binding pocket at the COP1 interface to accommodate the V-P sequence motif. Reinvigoration of the comparative binding pattern and subtle structural analysis via docking, molecular dynamics simulations, molecular mechanics Poisson-Boltzmann surface area, topological, and tunnel analysis revealed that both ß-catenin phosphodegron (DSGXXS) and TRIB (D/E/AQXVPD/E) motifs occupied a common COP1 binding site. Current study suggests a structural paradigm of TRIB homologs bearing a conserved motif that may compete with ß-catenin phosphodegron signature for binding to WD40 domain of COP1. Thorough understanding of the structural basis for TRIB-mediated regulation of WNT/ß-catenin signaling may help in devising more promising therapeutic strategy for liver and colorectal cancers.

Berberine Improves the Protective Effects of Metformin on Diabetic Nephropathy in db/db Mice through Trib1-dependent Inhibiting Inflammation.

PURPOSE: Diabetic nephropathy (DN), one of severe diabetic complications in the diabetes, is the main cause of end stage renal disease (ESRD). Notably, the currently available medications used to treat DN remain limited. Here, we determined whether berberine (BBR) could enhance the anti-diabetic nephropathy activities of metformin (Met) and explored its possible mechanisms. METHOD: The anti-diabetic nephropathy properties were systematically analyzed in the diabetic db/db mice treated with Met, BBR or with combination of Met and BBR. RESULTS: We found that both single Met and BBR treatments, and combination therapy could lower blood glucose, and ameliorate insulin resistance. The improvement of lipids metabolism by co-administration was more evident, as indicated by reduced serum cholesterol and less fat accumulation in the liver. Further, it was found that Met and BBR treatments, and co-administration could attenuate the progression of DN. However, anti-diabetic nephropathy activities of Met were enhanced when combined with BBR, as evidenced by improved renal function and histological abnormalities of diabetic kidney. Mechanistically, BBR enhanced renal-protective effects of Met primarily through potently promoting expression of Trib1, which subsequently downregulated the increased protein levels of CCAAT/enhancer binding protein α (C/EBPα), and eventually inhibited fatty synthesis proteins and nuclear factor kappa-B (NF-κB) signaling. CONCLUSION: Our data provide novel insight that co-administration of BBR and Met exerts a preferable activity of anti-diabetic nephropathy via collectively enhancing lipolysis and inhibiting inflammation. Combination therapy with these two drugs may provide an effective therapeutic strategy for the medical treatment of diabetic nephropathy.

Current Progress in Delineating the Roles of Pseudokinase TRIB1 in Controlling Human Diseases.

Tribbles homolog 1 (TRIB1) is a member of the tribbles family of pseudoprotein kinases and is widely expressed in numerous tissues, such as bone marrow, skeletal muscle, liver, heart, and adipose tissue. It is closely associated with acute myeloid leukemia, prostate cancer, and tumor drug resistance, and can interfere with the hematopoietic stem cell cycle, promote tumor cell proliferation, and inhibit apoptosis. Recent studies have shown that TRIB1 can regulate acute and chronic inflammation by affecting the secretion of inflammatory factors, which is closely related to the occurrence of hyperlipidemia and cardiovascular diseases. Given the important biological functions of TRIB1, the reviews published till now are not sufficiently comprehensive. Therefore, this paper reviews the progress in TRIB1 research aimed at exploring its roles in cancer, hyperlipidemia, and cardiovascular disease, and providing a theoretical basis for further studies on the biological roles of TRIB1.

miR-513b-5p inhibits the proliferation and promotes apoptosis of retinoblastoma cells by targeting TRIB1.

MicroRNAs are involved in the pathogenesis of various human malignant tumors. This study aims to explore the role of miR-513b-5p in the malignant proliferation of retinoblastoma (RB) cells and its potential molecular mechanisms. The function-gain and function-loss experiments were performed in Weri-RB1 cells using miR-513b-5 mimics and inhibitors. miR-513b-5p mimics inhibited the proliferation and clone formation and promoted apoptosis of Weri-RB1 cells. In contrast, the miR-513b-5p inhibitor promoted the proliferation and clone formation of Weri-RB1 cells and inhibited cell apoptosis. miR-513b-5p can directly bind to the 3'UTR region of TRIB1 mRNA, and inhibit its protein expression. Overexpression of TRIB1 promoted the proliferation and cloning of Weri-RB1 cells but inhibited their apoptosis. The knockdown of TRIB1 inhibited the proliferation and clone formation of Weri-RB1 cells and promoted cell apoptosis. In addition, miR-513b-5p mimics neutralized the effects of TRIB1 overexpression on the proliferation and apoptosis of Weri-RB1 cells. Finally, miR-513b-5p can inhibit the phosphorylation level of AKT, mTOR, and p70, while TRIB1 played the opposite role. miR-513b-5p inhibits the malignant proliferation of Weri-RB1 cells by repressing the expression of TRIB1. miR-513b-5p and TRIB1 may be the biomarkers and/or key targets for clinical diagnosis and treatment of RB.

Structure vs. Function of TRIB1-Myeloid Neoplasms and Beyond.

The Tribbles family of proteins-comprising TRIB1, TRIB2, TRIB3 and more distantly related STK40-play important, but distinct, roles in differentiation, development and oncogenesis. Of the four Tribbles proteins, TRIB1 has been most well characterised structurally and plays roles in diverse cancer types. The most well-understood role of TRIB1 is in acute myeloid leukaemia, where it can regulate C/EBP transcription factors and kinase pathways. Structure-function studies have uncovered conformational switching of TRIB1 from an inactive to an active state when it binds to C/EBPα. This conformational switching is centred on the active site of TRIB1, which appears to be accessible to small-molecule inhibitors in spite of its inability to bind ATP. Beyond myeloid neoplasms, TRIB1 plays diverse roles in signalling pathways with well-established roles in tumour progression. Thus, TRIB1 can affect both development and chemoresistance in leukaemia; glioma; and breast, lung and prostate cancers. The pervasive roles of TRIB1 and other Tribbles proteins across breast, prostate, lung and other cancer types, combined with small-molecule susceptibility shown by mechanistic studies, suggests an exciting potential for Tribbles as direct targets of small molecules or biomarkers to predict treatment response.

Genomic and Functional Regulation of TRIB1 Contributes to Prostate Cancer Pathogenesis.

Prostate cancer is the most frequent malignancy in European men and the second worldwide. One of the major oncogenic events in this disease includes amplification of the transcription factor cMYC. Amplification of this oncogene in chromosome 8q24 occurs concomitantly with the copy number increase in a subset of neighboring genes and regulatory elements, but their contribution to disease pathogenesis is poorly understood. Here we show that TRIB1 is among the most robustly upregulated coding genes within the 8q24 amplicon in prostate cancer. Moreover, we demonstrate that TRIB1 amplification and overexpression are frequent in this tumor type. Importantly, we find that, parallel to its amplification, TRIB1 transcription is controlled by cMYC. Mouse modeling and functional analysis revealed that aberrant TRIB1 expression is causal to prostate cancer pathogenesis. In sum, we provide unprecedented evidence for the regulation and function of TRIB1 in prostate cancer.

Do TRIB1 and IL-9 Gene Polymorphisms Impact the Development and Manifestation of Pituitary Adenoma?

BACKGROUND/AIM: To evaluate the association between TRIB1(rs6987702) and IL-9(rs1859430, rs2069870) genotypes with the development and manifestation of pituitary adenoma (PA). MATERIALS AND METHODS: The study group included 141 patients with PA and the control group consisted of 287 healthy people. The genotyping of rs6987702, rs1859430 and rs2069870 was carried out using a real-time polymerase chain reaction. RESULTS: Statistically significant results were obtained regarding the rs1859430, but there were no significant results regarding rs6987702. We found that the rs1859430 A/A genotype increased the odds of having recurrent PA six times (p=0.006) under the co-dominant model and four times (p=0.021) under the recessive model. Furthermore, the analysis showed that the G/A genotype increased the odds of having recurrent PA 2.3 times (p=0.003) under the co-dominant model, while G/A and A/A genotypes increased the odds 2.7 times (p=0.011) under the over-dominant model. CONCLUSION: Certain genotypes of rs1859430 can be associated with PA recurrence.

Interaction between Coffee Drinking and TRIB1 rs17321515 Single Nucleotide Polymorphism on Coronary Heart Disease in a Taiwanese Population.

A complex interplay of several genetic and lifestyle factors influence coronary heart disease (CHD). We determined the interaction between coffee consumption and the tribbles pseudokinase 1 (TRIB1) rs17321515 variant on coronary heart disease (CHD). Data on CHD were obtained from the National Health Insurance Research Database (NHIRD) while genotype data were collected from the Taiwan Biobank (TWB) Database. From the linked electronic health record data, 1116 individuals were identified with CHD while 7853 were control individuals. Coffee consumption was associated with a lower risk of CHD. The multivariate-adjusted odds ratio (OR) and 95% confidence interval (CI) was 0.84 (0.72-0.99). Association of CHD with the TRIB1 rs17321515 variant was not significant. The OR (95% CI) was 1.01 (0.72-0.99). There was an interaction between TRIB1 rs17321515 and coffee consumption on CHD risk (p for interaction = 0.0330). After stratification by rs17321515 genotypes, coffee drinking remained significantly associated with a lower risk of CHD only among participants with GG genotype (OR, 0.62; 95% CI, 0.45-0.85). In conclusion, consumption of coffee was significantly associated with a decreased risk of CHD among Taiwanese adults with the TRIB1 GG genotype.

Trib1 Contributes to Recovery From Ischemia/Reperfusion-Induced Acute Kidney Injury by Regulating the Polarization of Renal Macrophages.

Increasing evidence suggests that macrophage polarization is involved in the recovery from ischemia-reperfusion (I/R)-induced acute kidney injury (AKI), implying that the regulation of macrophage polarization homeostasis might mediate AKI recovery. Trib1 is a key regulator of macrophage differentiation, but its role in AKI remains unclear. Here, we aimed to investigate the role of Trib1 and its link with the macrophage phenotype in the process of adaptive recovery from I/R-induced renal injury. Lentiviral vector-mediated RNA interference (RNAi) was used to knock down Trib1 expression in vitro and in vivo, and a mouse model of moderate AKI was established by the induction of I/R injury. Renal function measurements and inflammatory factors were determined by the corresponding kits. Histomorphology was assessed by hematoxylin-eosin, Masson and PAS staining. Western blot and flow cytometry were employed for the analysis of signal transduction, cell apoptosis and macrophage phenotypes. Trib1 knockdown inhibited cell viability of tubular epithelial cells (TECs) by inhibiting proliferation and enhancing apoptosis in vitro. I/R-induced AKI significantly impaired renal function in mice via increasing the levels of BUN, Scr, NGAL and renal tubular damage, leading to renal fibrosis from days 1 to 3. Through the adaptive self-repair mechanism, renal dysfunction recovered over time and returned to almost normal levels on day 28 after I/R intervention. However, Trib1 depletion worsened renal damage on day 3 and blunted the adaptive repair process of the renal tissue. Mechanistically, Trib1 inhibition suppressed renal tubular cell proliferation under adaptive self-repair conditions by affecting the expression of the proliferation-related proteins cyclin D1, cyclin B, p21, and p27, the apoptosis-related proteins Bcl-2 and Bax, and the fibrosis-related proteins collagen I and III. Furthermore, the M1/M2 macrophage ratio increased in the first 3 days and decreased from day 7 to day 28, consistent with changes in the expression of inflammatory factors, including TNFα, IL-6, IL-12, IL-10, and IL-13. Trib1 inhibition blocked macrophage polarization during adaptive recovery from I/R-induced moderate AKI. Our results show that Trib1 plays a role in kidney recovery and regeneration via the regulation of renal tubular cell proliferation by affecting macrophage polarization. Thus, Trib1 might be a viable therapeutic target to improve renal adaptive repair following I/R injury.

TRIB1 rs17321515 gene polymorphism increases the risk of coronary heart disease in general population and non-alcoholic fatty liver disease patients in Chinese Han population.

BACKGROUND: Present evidences suggested that TRIB1 rs17321515 polymorphism was tightly associated with the increased risk of NAFLD and CHD. CHD is one of the main complications of NAFLD, whether TRIB1 rs17321515 polymorphism could affect the risk of CHD in general population and NAFLD patients in Chinese Han population was remain unknown. The present study was designed to investigate the association between TRIB1 rs17321515 polymorphism and the risk of CHD in general population and NAFLD patients in Chinese Han population, and investigate the effect of TRIB1 rs17321515 polymorphism on serum lipid levels. PATIENTS AND METHODS: TRIB1 rs17321515 gene polymorphism was genotyped using the polymerase chain reaction (PCR) in healthy controls (n = 175), CHD patients (n = 155), NAFLD patients (n = 146), and NAFLD+CHD patients (n = 156). Serum lipid profiles were determined using biochemical methods. Statistical analyses were performed using SPSS 24.0 statistical software. RESULTS: The TRIB1 rs17321515 AA+GA genotypes were the significant risk factors for the CHD in general population (OR = 1.788; 95% CI: 1.104-2.897; P = 0.018) and in the NAFLD patients (OR = 1.760; 95% CI: 1.071-2.891; P = 0.026). After adjusted for age, gender, and body mass index, the risk for CHD in general population (OR = 1.857; 95% CI: 1.116-3.089; P = 0.017) and NAFLD patients was still significant (OR = 1.723; 95% CI: 1.033-2.873; P = 0.037). In addition, TRIB1 rs17321515 A carriers possess the higher lipid profiles in the included subjects. CONCLUSIONS: TRIB1 rs17321515 AA+GA genotypes were significant associated with the risk of CHD in general population and in NAFLD patients in Chinese Han population. The rs17321515 A allele increases the serum lipid profiles in included subjects.

TRIB1 induces macrophages to M2 phenotype by inhibiting IKB-zeta in prostate cancer.

Immunotherapy has made great breakthroughs in the field of cancer. However, the immunotherapeutic effect of prostate cancer is unsatisfactory. We found that the expression of TRIB1 was significantly correlated with the infiltration of CD163+ macrophages in prostate cancer. This study focused on the effects of TRIB1 on macrophage polarization in the immune microenvironment of prostate cancer. RNA sequencing analysis demonstrated that TRIB1 has significant effects on the regulation of the nuclear factor (NF)-κB signaling pathway and downstream cytokines. Flow cytometry and enzyme-linked immunosorbent assay were used to examine THP-1 cells cultured in conditioned medium from prostate cancer cells overexpressing TRIB1 and showed that overexpression of TRIB1 promoted the secretion of CXCL2 and interleukin (IL)8 by PC3 cells, which increased the secretion of IL12 by THP-1 cells as well as the expression of CD163 on THP-1 cells. IKB-zeta, regulated by TRIB1, was expressed in PC3 cells but was barely detectable in DU145 cells. The reductions in CXCL2 and IL8 by the inhibition of TRIB1 were rescued by the deletion of IKB-zeta. Here we showed that TRIB1 promoted the secretion of cytokines from prostate cancer cells and induced the differentiation of monocytes/macrophages into M2 macrophages.

TRIB1 rs17321515 and rs2954029 gene polymorphisms increase the risk of non-alcoholic fatty liver disease in Chinese Han population.

BACKGROUND: Dysregulation of the lipid homeostasis is an independent risk factor for non-alcoholic fatty liver disease (NAFLD). Some studies had demonstrated that TRIB1 gene polymorphisms affect the plasma lipids metabolism, but no related data was available for TRIB1 gene polymorphisms in the lipids metabolism in Chinses Han population. The present study was conducted to investigate the association between TRIB1 gene polymorphisms (rs17321515 and rs2954029) and the risk of NAFLD in Chinese Han population and their effects on serum lipid profiles. PATIENTS AND METHODS: TRIB1 rs17321515 and rs2954029 gene polymorphisms were genotyped using the polymerase chain reaction (PCR) in B-type ultrasonography-proven NAFLD patients (n = 146) and healthy controls (n = 175). Serum lipid profiles were determined using biochemical methods. Statistical analyses were performed using SPSS 22.0 statistical software. RESULTS: The allele distributions of TRIB1 rs17321515 A and rs2954029 A were significant different between the NAFLD patients and healthy controls (P = 0.026, P = 0.045, respectively). The genotype distribution of TRIB1 rs17321515 was significant different between NAFLD patients and healthy controls (P = 0.038). The TRIB1 rs17321515 GA + AA genotype and TRIB1 rs2954029 TA + AA genotype markedly increase the NAFLD risk (OR = 1.885; 95%CI: 1.157-3.070; OR = 1.627; 95%CI: 1.011-2.619, respectively), after adjusted for age, gender, and body mass index, the NAFLD risk still significant (OR = 2.240; 95%CI: 1.196-4.197; OR = 2.050; 95%CI: 1.110-3.786, respectively). In addition, TRIB1 rs17321515 A and rs2954029 A carriers possess the higher lipid profiles in the included subjects. CONCLUSIONS: TRIB1 rs17321515 and rs2954029 were significant associated with the risk of NAFLD in Chinese Han population. The rs17321515 A and rs2954029 A allele increases the serum lipid profiles in Chinese Han population.