Dataset Information

Non-alcoholic fatty liver disease promotes breast cancer progression through upregulated hepatic fibroblast growth factor 21.

ABSTRACT: Non-alcoholic fatty liver disease (NAFLD) has been shown to influence breast cancer progression, but the underlying mechanisms remain unclear. In this study, we investigated the impact of NAFLD on breast cancer tumor growth and cell viability through the potential mediator, hepatic fibroblast growth factor 21 (FGF21). Both peritumoral and systemic administration of FGF21 promoted breast cancer tumor growth, while FGF21 knockout attenuated the tumor-promoting effects of the high-fat diet. Mechanistically, exogenous FGF21 treatment enhanced the anti-apoptotic ability of breast cancer cells through STAT3 and Akt/FoXO1 signaling pathways, and mitigated doxorubicin-induced cell death. Furthermore, we observed overexpression of FGF21 in tumor tissues from breast cancer patients, which was associated with poor prognosis. These findings suggest a novel role for FGF21 as an upregulated mediator in the context of NAFLD, promoting breast cancer development and highlighting its potential as a therapeutic target for cancer treatment.

SUBMITTER: Sui Y

PROVIDER: S-EPMC10796330 | biostudies-literature | 2024 Jan

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Non-alcoholic fatty liver disease promotes breast cancer progression through upregulated hepatic fibroblast growth factor 21.

Sui Yue Y Liu Qingqing Q Xu Cong C Ganesan Kumar K Ye Zhen Z Li Yan Y Wu Jianmin J Du Bing B Gao Fei F Song Cailu C Chen Jianping J

Cell death & disease 20240118 1

Non-alcoholic fatty liver disease (NAFLD) has been shown to influence breast cancer progression, but the underlying mechanisms remain unclear. In this study, we investigated the impact of NAFLD on breast cancer tumor growth and cell viability through the potential mediator, hepatic fibroblast growth factor 21 (FGF21). Both peritumoral and systemic administration of FGF21 promoted breast cancer tumor growth, while FGF21 knockout attenuated the tumor-promoting effects of the high-fat diet. Mechani ...[more]

PMID: 38238320

Similar Datasets

Project description:Aims/hypothesisSystemic fibroblast growth factor (FGF)21 levels and hepatic FGF21 production are increased in non-alcoholic fatty liver disease patients, suggesting FGF21 resistance. We examined the effects of exenatide on FGF21 in patients with type 2 diabetes and in a diet-induced mouse model of obesity (DIO).MethodsType 2 diabetes mellitus patients (n = 24) on diet and/or metformin were randomised (using a table of random numbers) to receive additional treatment consisting of pioglitazone 45 mg/day or combined therapy with pioglitazone (45 mg/day) and exenatide (10 μg twice daily) for 12 months in an open label parallel study at the Baylor Clinic.ResultsTwenty-one patients completed the entire study and were included in the analysis. Pioglitazone treatment (n = 10) reduced hepatic fat as assessed by magnetic resonance spectroscopy, despite a significant increase in body weight (Δ = 3.7 kg); plasma FGF21 levels did not change (1.9 ± 0.6 to 2.2 ± 0.6 ng/ml [mean ± SEM]). However, combined pioglitazone and exenatide therapy (n = 11) was associated with a significant reduction of FGF21 levels (2.3 ± 0.5 to 1.1 ± 0.3 ng/ml) and a greater decrease in hepatic fat. Besides weight gain observed in the pioglitazone-treated patients, lower extremity oedema was observed as a side effect in two of the ten patients. Three patients who received pioglitazone and exenatide combination therapy complained of significant nausea that was self-limiting and did not require them to leave the study. In DIO mice, exendin-4 for 4 weeks significantly reduced hepatic triacylglycerol content, decreased hepatic FGF21 protein and mRNA, and enhanced phosphorylation of hepatic AMP-activated protein kinase (AMPK) and acetyl-CoA carboxylase, although no significant difference in weight and body fat was observed. Hepatic FGF21 correlated inversely with hepatic AMPK phosphorylationConclusions/interpretationIn type 2 diabetes mellitus, combined pioglitazone and exenatide therapy is associated with a reduction in plasma FGF21 levels, as well as a greater decrease in hepatic fat than that achieved with pioglitazone therapy. In DIO mice, exendin-4 treatment reduces hepatic triacylglycerol and FGF21 protein, and enhances hepatic AMPK phosphorylation, suggesting an improvement of hepatic FGF21 resistance.Trial registration numberClinicalTrials.gov NCT 01432405.

Project description:Background & aimsNon-alcoholic fatty liver disease (NAFLD) contributes to the global epidemic of metabolic syndrome and is considered a prelude to end-stage liver diseases such as cirrhosis and hepatocellular carcinoma. During NAFLD pathogenesis, hepatic parenchymal cells (hepatocytes) undergo both morphological and functional changes owing to a rewired transcriptome. The underlying mechanism is not entirely clear. In the present study, we investigated the involvement of early growth response 1 (Egr1) in NAFLD.MethodsQuantitative PCR, Western blotting, and histochemical staining were used to assess gene expression levels. Chromatin immunoprecipitation was used to evaluate protein binding to DNA. NAFLD was evaluated in leptin receptor-deficient (db/db) mice.ResultsWe report here that Egr1 was upregulated by pro-NAFLD stimuli in vitro and in vivo. Further analysis revealed that serum response factor (SRF) was recruited to the Egr1 promoter and mediated Egr1 transactivation. Importantly, Egr1 depletion markedly mitigated NAFLD in db/db mice. RNA sequencing revealed that Egr1 knockdown in hepatocytes, on the one hand, boosted fatty acid oxidation (FAO) and, on the other hand, suppressed the synthesis of chemoattractants. Mechanistically, Egr1 interacted with peroxisome proliferator-activated receptor α (PPARα) to repress PPARα-dependent transcription of FAO genes by recruiting its co-repressor NGFI-A binding protein 1 (Nab1), which potentially led to promoter deacetylation of FAO genes.ConclusionsOur data identify Egr1 as a novel modulator of NAFLD and a potential target for NAFLD intervention.Impact and implicationsNon-alcoholic fatty liver disease (NAFLD) precedes cirrhosis and hepatocellular carcinoma. In this paper, we describe a novel mechanism whereby early growth response 1 (Egr1), a transcription factor, contributes to NAFLD pathogenesis by regulating fatty acid oxidation. Our data provide novel insights and translational potential for NAFLD intervention.

Dataset Information

Non-alcoholic fatty liver disease promotes breast cancer progression through upregulated hepatic fibroblast growth factor 21.

Publications

Non-alcoholic fatty liver disease promotes breast cancer progression through upregulated hepatic fibroblast growth factor 21.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets