HNF4α

Hepatocyte nuclear factor 4α (HNF4α) is a ligand-sensing transcription factor and presents as a potential drug target in metabolic diseases and cancer. In humans, mutations in the HNF4α gene cause maturity-onset diabetes of the young (MODY), and the elevated activity of this protein has been associated with gastrointestinal cancers. Despite the high therapeutic potential, available ligands and structure-activity relationship knowledge for this nuclear receptor are scarce. Here, we disclose a chemically diverse collection of orthogonally validated fragment-like activators as well as inverse agonists, which modulate HNF4α activity in a low micromolar range...

Hepatocyte nuclear factor 4α (HNF4α) is highly enriched in the liver, but its role in the progression of liver steatosis (NAFL) to non-alcoholic steatohepatitis (NASH) has not been elucidated. In this study, we investigated the effect of gain or loss of hepatocyte HNF4α function on the development and progression of non-alcoholic fatty liver disease (NAFLD) in mice. Over-expression of human HNF4α protected against high fat/cholesterol/fructose (HFCF) diet-induced steatohepatitis whereas loss of hepatocyte Hnf4α had opposite effects...

BACKGROUND: Acute liver failure (ALF) is a complicated condition that is characterized by global hepatocyte death and often requires immediate liver transplantation. However, this therapy is limited by shortage of donor organs. Mesenchymal stem cells (MSCs) and hepatocytes are two attractive sources of cell-based therapies to treat ALF. The combined transplantation of hepatocytes and MSCs is considered to be more effective for the treatment of ALF than single-cell transplantation. We have previously demonstrated that HNF4α-overexpressing human umbilical cord MSCs (HNF4α-UMSCs) promoted the expression of hepatic-specific genes...

INTRODUCTION: Congenital hyperinsulinism (CH) is a severe disorder characterised by the appearance of severe hypoglycaemia. Pathogenic mutations in the ABCC8 and KCNJ11 genes are the most frequent cause, although its appearance also been associated to mutations in other genes (GCK, GLUD1, HADH, HNF1A, HNF4A, SLC16A1, UCP2, HK1), and with different syndromes. MATERIALS AND METHODS: Retrospective review of patients diagnosed with CH in this unit during the last 18years (2001-2018)...

Increasing populations are found to bear mild hepatic iron overload (HIO) due to unhealthy lifestyles, metabolic diseases, etc., whether this mild but chronic HIO induces hepatic inflammation is unknown. In the present study, mice receiving a 12-months 0.3% dextran-iron diet show mild HIO with no detectable oxidative damages in the liver but have infiltrated macrophages and increased IL-6, TNFα, AST and ALT since 6-months. The HNF4α/miR-122/CCL2 pathway, identified by our previous studies to induce macrophages infiltration, is initiated by chronic mild HIO...

Macroautophagy/autophagy, a self-degradative process, regulates metabolic homeostasis in response to various stress conditions and is a therapeutic target for nonalcoholic fatty liver disease. We found that autophagic activity was inhibited as a result of a significant reduction in the expression of autophagy-related genes such as Ulk1 in a mouse model and patients with fatty liver. This downregulation was caused by increased Mir214-3p levels and decreased Hnf4a/Hnf4α mRNA levels in hepatocytes. Mir214-3p suppressed Ulk1 expression through direct binding at a 3' untranslated region sequence...

ETHNOPHARMACOLOGICAL RELEVANCE: Vinegar-baked Radix Bupleuri (VBRB) is a processed form of Bupleurum chinense DC. As a well-known meridian-guiding drug, it is traditionally used as a component of traditional Chinese medicine formulations indicated for the treatment of liver diseases. However, the liver targeting component in VBRB remains unclear. Therefore, this study aims to explore the efficacy and mechanism of PSS (polysaccharides in Vinegar-baked Radix Bupleuri) in enhancing liver targeting...

Low plasma levels of sex hormone-binding globulin (SHBG) are a marker for obesity, insulin resistance, non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes. The transcription factor HNF4α is a major determinant of hepatic SHBG expression and thereby serum SHBG levels, and mediates in part the association of low SHBG with hyperinsulinemia and hepatic steatosis. We analyzed the lipidome in human liver specimens from a cohort of patients who underwent hepatic resection as a treatment for cancer, providing insight into hepatic lipids in those without extreme obesity or the clinical diagnosis of NAFLD or non-alcoholic steatohepatitis...

Hepatocyte nuclear factor 4 α (HNF4α) is an important transcription factor that acts as a pro-proliferative mediator during tumorigenesis, yet its function in colorectal cancer (CRC) remain unclear. Hence, this study aims to explore roles that HNF4α plays in the CRC development. RNA quantification analysis was conducted to characterize the expression pattern of long intergenic non-coding RNA 00511 (LINC00511)/HNF4α/IL24 in CRC tissues and cell lines. Using gain- and loss-of-function approaches, effects of HNF4α/LINC00511/IL24 axis on biological processes such as proliferative, migrating, invading, apoptotic, and tumorigenic functions of CRC cells were evaluated...

BACKGROUND & AIMS: Tristetraprolin (TTP) is a key post-transcriptional regulator of inflammatory and oncogenic transcripts. Accordingly, TTP was reported to act as a tumor suppressor in specific cancers. Herein, we investigated how TTP contributes to the development of liver inflammation and fibrosis, which are key drivers of hepatocarcinogenesis, as well as to the onset and progression of hepatocellular carcinoma (HCC). METHODS: TTP expression was investigated in mouse/human models of hepatic metabolic diseases and cancer...

Vincristine sulfate (VCR), a commonly used chemotherapeutic agent, kills cancer cells as well as the normal cells for its cytotoxicity. But it is still unclear whether it can exert therapeutic effect on untreated cancer cells by changing the supernatant of cancer cells. Here, we explored the subsequent cascade effects of the supernatant of cancer cells that were transiently treated with VCR on untreated tumor cells and its responsible mechanisms. VCR and three different hepatocellular carcinoma (HCC) cell lines were used for an experiment...

Chimeric mice with humanized livers are considered a useful animal model for predicting human (h-) drug metabolism and toxicity. In this study, the characteristics of fresh h-hepatocytes (cFHHs, PXB-cells®) isolated from chimeric mice (PXB-mice®) were evaluated in vitro to confirm their utility for drug development. cFHHs cultured at high density (2.13 × 105 cells/cm2) displayed stable production of h-albumin and cytochrome P450 (CYP) 3A activities for at least 21 days. The mRNA expression levels of 10 of 13 CYP, UDP-glucuronosyltransferase (UGT), and transporters were maintained at >10% of the levels of freshly isolated cFHHs after 21 days...

Endoplasmic reticulum stress (ER stress) plays a main role in pancreatic [Formula: see text]-cell dysfunction and death because of intracellular Ca[Formula: see text] turbulence and inflammation activation. Although several drugs are targeting pancreatic [Formula: see text]-cell to improve [Formula: see text]-cell function, there still lacks agents to alleviate [Formula: see text]-cell ER stress conditions. Therefore we used thapsigargin (THAP) or high glucose (HG) to induce ER stress in [Formula: see text]-cell and aimed to screen natural molecules against ER stress-induced [Formula: see text]-cell dysfunction...

OBJECTIVE: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with a 5-year survival of less than 5%. Transcriptomic analysis has identified two clinically relevant molecular subtypes of PDAC: classical and basal-like. The classical subtype is characterised by a more favourable prognosis and better response to chemotherapy than the basal-like subtype. The classical subtype also expresses higher levels of lineage specifiers that regulate endodermal differentiation, including the nuclear receptor hepatocyte nuclear factor 4 α (HNF4α)...

The original version of this Article contained an error in the spelling of the author Chan FL, which was incorrectly given as leung Chan F. This has now been corrected in both the PDF and HTML versions of the Article.

Hepatic estrogen sulfotransferase (SULT1E1), the enzyme that inactivates estrogen, regulates metabolic estrogen homeostasis. Here, we have demonstrated how nuclear receptor PXR regulated the SULT1E1 gene in response to glucose in human hepatoma-derived cells and in response to fasting in mouse livers. The SULT1E1 gene was activated by a nuclear receptor HNF4α-RORα complex binding on an upstream enhancer of the SULT1E1 promoter in cells cultured in high glucose medium (Hu and Negishi, 2020). The SULT1E1 gene was repressed in cells cultured in low glucose medium, in which PXR was phosphorylated at Ser350 by vaccinia virus-related kinase 1...

Infection of Zika virus (ZIKV) has become a severe threaten to global health while no specific drug is available. In this study, we explored the relationship between ZIKV and a cellular protein, ankyrin repeat and sterile motif domain containing 4b (ANKS4B). Our data revealed that the expression of ANKS4B in cultured cells and in neonatal mice was downregulated by ZIKV infection. The reduction of ANKS4B upon ZIKV infection was caused by decrease of two hepatocyte nuclear factors HNF1α and HNF4α . Through CRISPR/Cas9 gene editing system, we generated two ANKS4B knockout (KO) cell clones in A549 and Huh7 cells respectively...

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Methionine restriction, a dietary regimen that protects against metabolic diseases and aging, represses cancer growth and improves cancer therapy. However, the response of different cancer cells to this nutritional manipulation is highly variable, and the molecular determinants of this heterogeneity remain poorly understood. Here we report that hepatocyte nuclear factor 4α (HNF4α) dictates the sensitivity of liver cancer to methionine restriction. We show that hepatic sulfur amino acid (SAA) metabolism is under transcriptional control of HNF4α...

Specific combinations of two transcription factors (Hnf4α plus Foxa1, Foxa2, or Foxa3) can induce direct conversion of mouse fibroblasts into hepatocyte-like cells. However, the molecular mechanisms underlying hepatic reprogramming are largely unknown. Here, we show that the Foxa protein family members and Hnf4α sequentially and cooperatively bind to chromatin to activate liver-specific gene expression. Although all Foxa proteins bind to and open regions of closed chromatin as pioneer factors, Foxa3 has the unique potential of transferring from the distal to proximal regions of the transcription start site of target genes, binding RNA polymerase II, and co-traversing target genes...