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HFD-induced TRAF6 upregulation promotes liver cholesterol accumulation and fatty liver development via EZH2-mediated miR-429/PPARα axis.

ABSTRACT: Despite the increasing prevalence of fatty liver diseases worldwide, the molecular mechanism underlying their pathogenesis remains poorly defined. This study examines the expression and significance of tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6) in the high-fat diet (HFD)-induced mouse obesity model and the oleic acid/palmitic acid (OA/PA)-induced cell model. After developing these models, we measured the expressions of TRAF6, enhancer of the zeste homolog 2 (EZH2), and peroxisome proliferator activated receptor alpha (PPARα). The expression of TRAF6, EZH2, and PPARα was manipulated to investigate their roles in cholesterol accumulation through evaluating the plasma levels of total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C). Co-immunoprecipitation (coIP) assay was used to determine the interaction between TRAF6 and EZH2 and chromatin immunoprecipitation (ChIP) assay to detect the enrichment of EZH2 and H3K27me3 in microRNA-429 (miR-429) promoter. We found that HFD resulted in elevated TRAF6 and miR-429 in fatty liver and reduced EZH2 and PPARα. TRAF6 mediated the ubiquitination of EZH2 and increased miR-429 expression, and miR-429 targeted PPARα. TRAF6 increased cholesterol accumulation in liver cells in vitro via the EZH2/miR-429/PPARα axis. Collectively, HFD upregulates TRAF6 and ubiquitinates EZH2 to promote the miR-429-dependent inhibition of PPARα, leading to cholesterol accumulation in liver and the occurrence of fatty liver.

SUBMITTER: Zhang Z

PROVIDER: S-EPMC8099485 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundPancreatic cancer is a highly lethal malignancy with poor prognosis. Anillin (ANLN), an actin binding protein, is upregulated and plays an important role in many malignant tumors. However, the precise role of ANLN in pancreatic cancer remains unclear.MethodsThe expression of ANLN and its association with pancreatic cancer patient survival were analyzed using an online database and confirmed by immunohistochemistry. The ANLN protein expression in pancreatic cancer cell lines was detected by Western blot. Cell proliferation, colony formation and transwell assays in vitro and in vivo tumor growth were used to determine the role of ANLN in pancreatic cancer. Gene expression microarray analysis and a series of in vitro assays were used to elucidate the mechanisms of ANLN regulating pancreatic cancer progression.ResultsWe found that the ANLN expression was significantly upregulated in pancreatic cancer tissues and cell lines. The high expression of ANLN was associated with tumor size, tumor differentiation, TNM stage, lymph node metastasis, distant metastasis and poor prognosis in pancreatic cancer. ANLN downregulation significantly inhibited cell proliferation, colony formation, migration, invasion and tumorigenicity in nude mice. Meanwhile, we found that ANLN knockdown inhibited several cell-cell adhesion related genes, including the gene encoding LIM and SH3 protein 1 (LASP1). LASP1 upregulation partially reversed the tumor-suppressive effect of ANLN downregulation on pancreatic cancer cell progression. Moreover, we found that ANLN downregulation induced the expression of miR-218-5p which inhibited LASP1 expression through binding to its 3'UTR. We also found that ANLN-induced enhancer of zeste homolog 2 (EZH2) upregulation was involved in regulating miR-218-5p/LASP1 signaling axis. EZH2 upregulation or miR-218-5p downregulation partially reversed the tumor-suppressive effect of ANLN downregulation on pancreatic cancer cell progression.ConclusionANLN contributed to pancreatic cancer progression by regulating EZH2/miR-218-5p/LASP1 signaling axis. These findings suggest that ANLN may be a candidate therapeutic target in pancreatic cancer.

Project description:Background & aimsThe prevalence of nonalcoholic fatty liver disease (NAFLD) has reached epidemic proportions globally as a result of the rapid increase in obesity. However, there is no Food and Drug Administration-approved pharmacotherapy available for NAFLD. This study investigated the role of autotaxin, a secreted enzyme that hydrolyzes lysophosphatidylcholine to produce lysophosphatidic acid (LPA), in the pathogenesis of NAFLD and to explore whether genetic or pharmacologic interventions targeting autotaxin ameliorate NAFLD.MethodsThe clinical association of autotaxin with the severity of NAFLD was analyzed in 125 liver biopsy-proven NAFLD patients. C57BL/6N mice or fibroblast growth factor 21 (FGF21)-null mice were fed a high-fat diet or a choline-deficient diet to investigate the role of the autotaxin-FGF21 axis in NAFLD development by hepatic knockdown and antibody neutralization. Huh7 cells were used to investigate the autocrine effects of autotaxin.ResultsSerum autotaxin levels were associated positively with histologic scores and NAFLD severity. Hepatocytes, but not adipocytes, were the major contributor to increased circulating autotaxin in both patients and mouse models with NAFLD. In mice, knocking-down hepatic autotaxin or treatment with a neutralizing antibody against autotaxin significantly reduced high-fat diet-induced NAFLD and high fat- and choline-deficient diet-induced nonalcoholic steatohepatitis and fibrosis, accompanied by a marked increase of serum FGF21. Mechanistically, autotaxin inhibited the transcriptional activity of peroxisome proliferator-activated receptor α through LPA-induced activation of extracellular signal-regulated kinas, thereby leading to suppression of hepatic FGF21 production. The therapeutic benefit of anti-autotaxin neutralizing antibody against NAFLD was abrogated in FGF21-null mice.ConclusionsLiver-secreted autotaxin acts in an autocrine manner to exacerbate NAFLD through LPA-induced suppression of the peroxisome proliferator-activated receptor α-FGF21 axis and is a promising therapeutic target for NAFLD.

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HFD-induced TRAF6 upregulation promotes liver cholesterol accumulation and fatty liver development via EZH2-mediated miR-429/PPARα axis.

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