Deletion of <i><scp>HNF</scp>1</i>α in hepatocytes results in fatty liver‐related hepatocellular carcinoma in mice

Ni, Qi; Ding, Kai; Wang, Keqi; He, Jia; Yin, Chuan; Shi, Jian; Zhang, Xin; Xie, Wei‐Fen; Shi, Yongquan

doi:10.1002/1873-3468.12689

Cited by 28 publications

(26 citation statements)

References 43 publications

(50 reference statements)

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“…It has been shown that the expression of HFN‐1α is associated with cancer risk in several tumors, including hepatocellular and pancreatic carcinoma, renal cancer, ovarian cancer, endometrial cancer, and prostate cancer . However, recent studies also reported the antitumor potentials of HFN‐1α . At this juncture, it is not clear whether the downregulation of HFN‐1α observed in this study is responsible for apoptosis induction and hence, further studies are warranted on these lines.…”

Section: Discussionmentioning

confidence: 65%

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Cytotoxic potentials of S. cumini methanolic seed kernel extract in human hepatoma HepG2 cells

Prakash

Ezhilarasan

2019

Environmental Toxicology

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Syzygium cumini (Myrtaceae) is commonly called as Jamun or Jambolan. It has antidiabetic, anti‐inflammatory, antipyretic, and antioxidant activities. Hepatocellular carcinoma is the most frequent and deadliest cancers worldwide. We investigated the cytotoxic potentials of S. cumini methanolic seed kernel extract against human hepatoma HepG2 cells. HepG2 cells were treated with 10, 20, and 40 μg/mL of seed kernel extract for 24 hours and cytotoxic analysis was performed by MTT assay. S. cumini induced apoptosis related morphological changes in HepG2 cells were analyzed by annexin V and propidium iodide double staining. Nuclear fragmentation and chromatin condensation were analyzed by Hoechst nuclear staining. Mitochondrial membrane potential (MMP) was investigated by 5,5′,6,6′‐tetrachloro‐1,1′,3,3′‐tetraethylbenzimidazolyl‐carbocyanine iodide (JC‐1) staining. Protein expressions of hepatocyte nuclear factor‐1α (HFN‐1α) was performed using western blotting. S. cumini treatments caused a significant and a concentration‐dependent increase in the cytotoxicity of HepG2 cells. S. cumini treatments increased the percentage of cells in an early and late apoptosis stage. This treatment also caused chromatin condensation and nuclear fragmentation. Further, S. cumini treatments decreased MMP and also caused a significant downregulation of HFN‐1α protein expression. The present study demonstrated that S. cumini seed extract induced apoptosis in HepG2 cells through decrease in MMP and downregulation of HFN‐1α.

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Section: Discussionmentioning

confidence: 65%

“…29,30 However, recent studies also reported the antitumor potentials of HFN-1α. 31,32 At this juncture, it is not clear whether the downregulation of HFN-1α observed in this study is responsible for apoptosis induction and hence, further studies are warranted on these lines.…”

Section: Discussionmentioning

confidence: 87%

Cytotoxic potentials of S. cumini methanolic seed kernel extract in human hepatoma HepG2 cells

Prakash

Ezhilarasan

2019

Environmental Toxicology

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“…We have previously reported that the enforced expression of HNF1α impedes the growth of HCC xenografts in mice by inducing the differentiation of hepatoma cells into hepatocytes [ 9 ]. Our recent study further demonstrated that hepatocyte-specific Hnf1α knockout mice spontaneously develop HCC from fatty liver without cirrhosis [ 10 ]. In addition, it has been reported that HNF1α inhibits Wnt and NF-κB signalling during hepatocarcinogenesis and HCC metastasis by transcriptionally regulating the expression of miR-194 [ 11 , 12 ].…”

Section: Introductionmentioning

confidence: 99%

The HNF1α-regulated lncRNA HNF1A-AS1 reverses the malignancy of hepatocellular carcinoma by enhancing the phosphatase activity of SHP-1

et al. 2018

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BackgroundOur previous study has demonstrated that hepatocyte nuclear factor 1α (HNF1α) exerts potent therapeutic effects on hepatocellular carcinoma (HCC). However, the molecular mechanisms by which HNF1α reverses HCC malignancy need to be further elucidated.MethodslncRNA microarray was performed to identify the long noncoding RNAs (lncRNAs) regulated by HNF1α. Chromatin immunoprecipitation and luciferase reporter assays were applied to clarify the mechanism of the transcriptional regulation of HNF1α to HNF1A antisense RNA 1 (HNF1A-AS1). The effect of HNF1A-AS1 on HCC malignancy was evaluated in vitro and in vivo. RNA pulldown, RNA-binding protein immunoprecipitation and the Bio-Layer Interferometry assay were used to validate the interaction of HNF1A-AS1 and Src homology region 2 domain-containing phosphatase 1 (SHP-1).ResultsHNF1α regulated the expression of a subset of lncRNAs in HCC cells. Among these lncRNAs, the expression levels of HNF1A-AS1 were notably correlated with HNF1α levels in HCC cells and human HCC tissues. HNF1α activated the transcription of HNF1A-AS1 by directly binding to its promoter region. HNF1A-AS1 inhibited the growth and the metastasis of HCC cells in vitro and in vivo. Moreover, knockdown of HNF1A-AS1 reversed the suppressive effects of HNF1α on the migration and invasion of HCC cells. Importantly, HNF1A-AS1 directly bound to the C-terminal of SHP-1 with a high binding affinity (KD = 59.57 ± 14.29 nM) and increased the phosphatase activity of SHP-1. Inhibition of SHP-1 enzymatic activity substantially reversed the HNF1α- or HNF1A-AS1-induced reduction on the metastatic property of HCC cells.ConclusionsOur data revealed that HNF1A-AS1 is a direct transactivation target of HNF1α in HCC cells and involved in the anti-HCC effect of HNF1α. HNF1A-AS1 functions as phosphatase activator through the direct interaction with SHP-1. These findings suggest that regulation of the HNF1α/HNF1A-AS1/SHP-1 axis may have beneficial effects in the treatment of HCC.Electronic supplementary materialThe online version of this article (10.1186/s12943-018-0813-1) contains supplementary material, which is available to authorized users.

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“…The probably mechanism of it on insulin level and lipometabolic disorder might be related to targeted tissues of insulin, i.e., liver and surrounding adipose. HNF1α and CTRP6 are supposed to be the substance metabolic indicators of these two targets during lowering lipid (32, 33). Deficiency of HNF1α in liver lipometabolism may lead to diabetes and hypercholesterolemia by increasing bile acid and cholesterol synthesis (34, 35).…”

Section: Discussionmentioning

confidence: 99%

Regulating AMPKα and insulin level by Vinegar, Swimming and Refeeding on High-Fat Diet Rats to Rebuild Lipid Homeostasis

Yang

Zhang

Xiao

et al. 2020

Preprint

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Our aims were to explore the effects of dietary and behavior interventions on lipometabolism caused by unhealthy high-fat diet and the best method to rebuild lipid homeostasis of this lifestyle. Apart from normal diet rats, 34 rats were fed with high-fat emulsion for 4 weeks before being divided into 4 groups and intervened for another 4 weeks. 8 of them were classified into high-fat control group and 9 were sorted into high-fat diet with rice vinegar group. Meanwhile, 10 were put into high-fat diet with swimming group and 7 were just for refeeding normal diet group. Then the data of body weight was recorded and analyzed. Serum, pancreas, liver, cardiac tissues and epididymis adipose were sampled as required. Indexes of serum were tested by kits. AMPKα, HNF1α, CTRP6 from tissues were detected by western blot.According to our experiments, Swimming and refeeding groups reflected a better regulation on lipid homeostasis mainly by up-regulating the expression of pancreas AMPKα. To be more specific, the refeeding rats showed lower T-CHO (P<0.001) and LDL-C (P<0.05), but higher weight gain (P<0.001), insulin level (P<0.01) and pancreas AMPKα (P<0.01) than high-fat control rats. Compared with rats experimented by swimming or rice vinegar, they showed higher weight gain (P<0.001), insulin level (P<0.01) and HNF1α, but lower of CTRP6. In summary, refeeding diet functioned better in regulating the lipometabolic level after high-fat diet. Whatever approach mentioned above we adopted to intervene, the best policy to keep the balance of lipid homeostasis is to maintain a healthy diet.

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Deletion of HNF1α in hepatocytes results in fatty liver‐related hepatocellular carcinoma in mice

Cited by 28 publications

References 43 publications

Cytotoxic potentials of S. cumini methanolic seed kernel extract in human hepatoma HepG2 cells

Cytotoxic potentials of S. cumini methanolic seed kernel extract in human hepatoma HepG2 cells

The HNF1α-regulated lncRNA HNF1A-AS1 reverses the malignancy of hepatocellular carcinoma by enhancing the phosphatase activity of SHP-1

Regulating AMPKα and insulin level by Vinegar, Swimming and Refeeding on High-Fat Diet Rats to Rebuild Lipid Homeostasis

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