Maternal multi-generational high fat diet (HFD) exposure increases the offspring HCC incidence
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ABSTRACT:
PROVIDER: PRJNA482414 | ENA |
REPOSITORIES: ENA
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Project description:Purpose: To investiagte why maternal obesity induces the susceptibility of offspring to diethylnitrosamine (DEN)-induced hepatocellular carcinoma (HCC) over generations upon over nutrition.The goals of this study are to find over-generationally altered genes and miRNAs which may contribute the accumulative progeny susceptibility to HCC under over nutrition. Methods: C57BL/6 female mice (F0 generation) were fed with either normal chow (NC) or HFD (60% kcal fat) from 1-month to 3-month old, and mated with NC-fed male mice to produce F1 generation. The F2 generation was similarly created. Male offspring of the F0, F1 and F2 generations were intraperitoneally injected with DEN at 2-weeks-old, and kept inmaintained on HFD and named as H1D, H2D and H3D groups, respectively. Male offspring of the F0 generation injected with PBS (Nor group) or DEN (NCD group) at the same age and kept inmaintained on NC. All groups were sacrificed at 40-weeks-old. Liver mRNA profiles and miRNA profiles from the different offspring groups were generated by LncRNA sequencing and small RNA sequencing. Results: We identified many over-generationally changed genes and miRNAs in the offspring by RNA-sequencing. Conclusions: The study revealed an important role of miRNA and targeting genes in regulating the incidence of HCC in the offspring of maternal-lineage under multi-generational HFD exposure, which has a profound effect on exploring the link between maternal obesity and the development of diseases in offspring.
2021-07-01 | GSE117539 | GEO
Project description:We perform scRNA-seq in the livers of C57BL/6 mice fed a CD-HFD or control diet for 3 months (NAFLD), 6 months (NASH) or 15 months (HCC)
2024-02-17 | GSE232182 | GEO
Project description:HNF4A intestinal epithelial conditional loss incidence on jejunum expression from mice fed a HFD.
| PRJNA613038 | ENA
Project description:We perform scRNA-seq in the livers of C57BL/6 mice fed a CD-HFD for 15 months. Starting from the 13M, mice were treated with FABP5 inhibitor to ameliorate HCC.
2024-02-17 | GSE231818 | GEO
Project description:To investigate the mechanism by which paternal exposure to high-fat diet (HFD) exacerbates environmental stress-impaired testicular germ cell development in offspring, testicular RNA sequencing was performed in H+Cd (the offspring were treated with Cd after paternal exposure to one-generational HFD) and H+H+Cd (the offspring were treated with Cd after paternal exposure to bi-generational HFD) groups. Compared with HFD1D group and HFD2D group, 229 mRNAs were upregulated and 268 mRNAs were downregulated, screened for a 1.2-fold change and adjusted with P < 0.05. GO analysis revealed that downregulated mRNAs were related to multiple biological processes, including the "retinol metabolic process," the "reproductive process," and the "spermatogenesis".
2023-12-22 | GSE241413 | GEO
Project description:Obesity is an established risk factor for cancer in many tissues such as the gastrointestinal tract. In the mammalian intestine, a pro-obesity high fat diet (HFD) promotes tumorigenesis in part by enhancing intestinal stem cell (ISC) numbers, proliferation and function. Although Ppar (Peroxisome proliferator-activated receptor) nuclear receptor activity has been proposed to mediate some of these effects in HFD ISCs, the exact role that different Ppar family members play in this process is unclear. Here, we find that in loss-of-function in vivo models, both Ppar family members alpha and delta contribute to the HFD response in ISCs. Mechanistically, both PPARs do so by robustly inducing a downstream fatty acid oxidation (FAO) metabolic program. Notably, pharmacologic and genetic disruption of CPT1a (the rate limiting enzyme of FAO) blunts the HFD phenotype in ISCs. Furthermore, just as HFD ISCs depend on CPT1a-mediated FAO, inhibition of CPT1a dampens the pro-tumorigenic consequences of a HFD on early tumor incidence and progression in the intestine. These findings demonstrate that inhibition of a HFD activated FAO program creates a therapeutic opportunity to counter the effects of a HFD on ISCs and intestinal tumorigenesis.
2021-06-01 | GSE151046 | GEO
Project description:Obesity is an established risk factor for cancer in many tissues such as the gastrointestinal tract. In the mammalian intestine, a pro-obesity high fat diet (HFD) promotes tumorigenesis in part by enhancing intestinal stem cell (ISC) numbers, proliferation and function. Although Ppar (Peroxisome proliferator-activated receptor) nuclear receptor activity has been proposed to mediate some of these effects in HFD ISCs, the exact role that different Ppar family members play in this process is unclear. Here, we find that in loss-of-function in vivo models, both Ppar family members alpha and delta contribute to the HFD response in ISCs. Mechanistically, both PPARs do so by robustly inducing a downstream fatty acid oxidation (FAO) metabolic program. Notably, pharmacologic and genetic disruption of CPT1a (the rate limiting enzyme of FAO) blunts the HFD phenotype in ISCs. Furthermore, just as HFD ISCs depend on CPT1a-mediated FAO, inhibition of CPT1a dampens the pro-tumorigenic consequences of a HFD on early tumor incidence and progression in the intestine. These findings demonstrate that inhibition of a HFD activated FAO program creates a therapeutic opportunity to counter the effects of a HFD on ISCs and intestinal tumorigenesis.
2021-06-01 | GSE151045 | GEO
Project description:HNF4A encodes a nuclear receptor required for the development of the intestine and involved in the homeostasis maintenance of intestinal epithelial cells during the adulthood. Also strongly related to the hepatic lipid metabolism, little was known about its metabolic relevance from the intestine when challenged by a high fat diet. We used microarrays to detail the global programme of jejunal gene expression depending on HNF4α and influenced by HFD.
2020-03-18 | GSE147105 | GEO
Project description:The prognosis of hepatocellular carcinoma (HCC) is poor due to the high incidence of intrahepatic metastasis. The aim of this study is to investigate the mechanism of intrahepatic metastasis in HCC via extracellular vesicles (EVs).
2021-03-23 | GSE151169 | GEO
Project description:Maternal overnutrition affects offspring susceptibility to nonalcoholic steatohepatitis (NASH). Male offspring from high-fat diet (HFD)-fed dams developed a severe form of NASH, leading to highly vascular tumor formation. The cancer/testis antigen HORMA domain containing protein 1 (HORMAD1), one of 146 upregulated differentially expressed genes in fetal livers from HFD-fed dams, was overexpressed with hypoxia-inducible factor 1 alpha (HIF-1alpha) in hepatoblasts and in NASH-based hepatocellular carcinoma (HCC) in offspring from HFD-fed dams at 15 weeks old. Hypoxia substantially increased Hormad1 expression in primary mouse hepatocytes. Despite the presence of three putative hypoxia response elements within the mouse Hormad1 gene, the Hif-1alpha siRNA only slightly decreased hypoxia-induced Hormad1 mRNA expression. In contrast, N-acetylcysteine, but not rotenone, inhibited hypoxia-induced Hormad1 expression, indicating its dependency on nonmitochondrial reactive oxygen species production. Synchrotron-based phase-contrast micro-CT of the fetuses from HFD-fed dams showed significant enlargement of the liver accompanied by a consistent size of the umbilical vein, which may cause hypoxia in the fetal liver. Based on these findings, a maternal HFD induces fetal origins of NASH/HCC via hypoxia, and HORMAD1 is a potential therapeutic target for NASH/HCC.
2022-07-29 | GSE183360 | GEO