Impact of high fat diet and hepatocyte nuclear factor four alpha loss on hepatic gene expression in mice.
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PROVIDER: PRJNA564330 | ENA |
REPOSITORIES: ENA
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Project description:The transcription factor hepatocyte nuclear factor four alpha (Hnf4a) has various isoforms, one of which (P1-Hnf4a) is expressed in adult liver, where it functions as a tumor suppressor by providing circadian restrains at genes promoting cell proliferation and epithelial to mesenchymal transition. High fat diet feeding promotes the loss of nuclear P1-Hnf4a activity and a gain in the pro-proliferative P2-Hnf4a isoform, which does not function as a tumor suppressor, nor provide similar circadian restraint at cell cycle-promoting genes. P2-Hnf4a is found in all Hnf4a-positive hepatocellular carcinoma. Purpose: To determine whether inducible loss of hepatic Hnf4a followed by high fat feeding predisposes a liver to hepatocellular carcinoma. Methods: Hepatic Hnf4a was inducibly knocked out in mice at six weeks of age ("H4LivKO") followed by vivarium chow ("H4LivKOVC") or high fat feeding ("H4LivKOHF")at 8 weeks of age. Control, littermate wild-type mice (WT) were also treated with tamoxifen at six weeks of age, but since they lacked the Cre transgene, Hnf4a expression remained intact. Control mice were divided into the same feeding groups as H4LivKO mice ("WTVC" and "WTHF"). Livers were harvested at 38 weeks of age and liver tissue was flash frozen in liquid nitrogen. RNA was extracted from frozen liver tissue using Trizol, and purified RNA was submitted to Novogene for quality control and RNA-seq analysis using a 250-300 bp insert cDNA library and Illumina Platform sequencing.
2019-09-07 | GSE137051 | GEO
Project description:The transcription factor Forkhead box protein O1 (FoxO1) is a well-established regulator of glucose and lipid metabolism, yet its role in metabolic dysfunction-associated steatohepatitis (MASH) pathogenesis remains debated. This study investigates hepatocyte-specific FoxO1 mechanisms driving hepatic inflammation in MASH. Using hepatocyte-specific FoxO1-knockout (KO) mice fed a methionine-choline-deficient diet and LPS-treated FoxO1-KO cells, we demonstrate FoxO1 depletion exacerbates hepatic inflammation, ballooning degeneration, and upregulates TNF-alpha, CXCL8, and CXCL2 in vivo and in vitro. Transcriptomics linked FoxO1 deficiency to enriched pro-inflammatory pathways and suppressed cysteine/methionine metabolism.
2025-07-30 | GSE293003 | GEO
Project description:In this study we sought to determine how hepatocyte-specific PPARgamma expression regulates hepatic gene expression in normal (healthy) mice fed a LFCF diet, or mice that were fed a HFCF diet for 24 weeks to induce non-alcoholic steatohepatitis (NASH). Specifically, we used chow-fed adult (10 week-old) PPARgamma floxed male mice and injected them with AAV8-TBG-Cre to knockout PPARgamma in hepatocytes (KO). A subset of PPARgamma floxed mice were injected with AAV8-TBG-Null to generate controls (C). Two weeks after AAV injections, half of the mice in each group were fed a low fat, cholesterol and fructose (LFCF) diet, or a high fat, cholesterol and fructose (HFCF) diet for 24 weeks. Livers were collected at the end of the study to assess hepatic gene expression with RNA-seq (performed by Novogen, Inc.)
2021-01-15 | GSE162249 | GEO
Project description:Genomic analysis of human hepatocellular carcinoma (HCC) is potentially confounded by the differentiation state of the hepatic cell-of-origin. Here we integrated genomic analysis of mouse HCC (with defined cell-of-origin) along with normal liver development. We found a major shift in expression of Wnt and RXR-α pathway genes (up and down, respectively) coincident with the transition from hepatoblasts to hepatocytes. A combined Wnt and RXR-α gene signature categorized HCCs into two subtypes (high Wnt, low RXR-α and low Wnt, high RXR-α), which matched cell-of-origin in mouse models and the differentiation state of human HCC. Suppression of RXR-α levels in hepatocytes increased Wnt signaling and enhanced tumorigenicity, whereas ligand activation of RXR-α achieved the opposite. These results corroborate that there are two main HCC subtypes that correspond to the degree of hepatocyte differentation and that RXR-α, in part via Wnt signaling, plays a key functional role in the hepatocyte-like subtype and potentially could serve as a selective therapeutic target.
2015-01-17 | GSE65063 | GEO
Project description:Liver fibrosis is a strong predictor of long-term mortality in patients with non-alcoholic fatty liver disease; yet the mechanisms underlying the progression from the comparatively benign fatty liver state to advanced non-alcoholic steatohepatitis (NASH) and liver fibrosis are incompletely under-stood. Using a cell type-resolved genomics approach, we show that comprehensive alterations in hepatocyte genomic and transcriptional settings during NASH progression, led to a partial loss of hepatocyte identity. The hepatocyte reprogramming was under tight cooperative control of a net-work of NASH-activated transcription factors (TFs), as exemplified by Elf3 and Glis2. Indeed, Elf3 and Glis2 controlled hepatocyte identity and fibrosis-dependent hepatokine genes targeting disease-associated hepatic stellate cell (HSC) gene programs. Thus, interconnected TF networks not only promoted hepatocyte dysfunction, but also directed the intra-hepatic crosstalk with HSCs necessary for NASH and fibrosis progression implying molecular “hub-centered” targeting strategies to be superior to existing mono-target approaches as currently used in NASH therapy.
2021-07-13 | PXD025691 | Pride
Project description:Most western diets or Amilyn-based diets induce MASLD and MASH in mice but do not fully reproduce metabolic dysfunction in male and female mice. In this study, a high fat diet containing cholesterol (D12120101, Research Diets, Inc) supplemented with 10% w/v fructose in the drinking water (HFC+Fr diet) was provided to control and hepatocyte specific Pparg knockout male and female mice for 24 weeks. Both HFC+Fr-fed male and female mice developed obesity and insulin resistance. Only male mice developed clear signs of MASH with fibrosis. Hepatocyte specific Pparg had a significant effect in the regulation of hepatic transcriptomics in HFC+Fr-fed male mice.
2026-04-06 | GSE315007 | GEO
Project description:In this study, we sought to thoroughly characterize the liver pathophysiology of a human transgenic mouse model for alpha-1 antitrypsin deficiency (AATD) with a strong manifestation of AATD-mediated liver disease. Male and female transgenic mice for normal variant human alpha-1 antitrypsin (Pi*M) and mutant human alpha-1 antitrypsin (Pi*Z) at 3 and 6 months of age with a C57BL/6J background were subjected to study. The progression of hepatic accumulation of mutant alpha-1 antitrypsin (ZAAT), hepatocyte injury, steatosis, liver inflammation and fibrotic features of this mouse model were monitored by performing an in vivo study.
2023-03-19 | GSE206619 | GEO
Project description:ObjectiveNonalcoholic hepatic steatosis, also known as fatty liver, is a uniform response of the liver to hyperlipidic-hypercaloric diet intake. However, the post-ingestive signals and mechanistic processes driving hepatic steatosis are not well understood. Emerging data demonstrate that protein kinase C beta (PKCβ), a lipid-sensitive kinase, plays a critical role in energy metabolism and adaptation to environmental and nutritional stimuli. Despite its powerful effect on glucose and lipid metabolism, knowledge of the physiological roles of hepatic PKCβ in energy homeostasis is limited.MethodsThe floxed-PKCβ and hepatocyte-specific PKCβ-deficient mouse models were generated to study the in vivo role of hepatocyte PKCβ on diet-induced hepatic steatosis, lipid metabolism, and mitochondrial function.ResultsWe report that hepatocyte-specific PKCβ deficiency protects mice from development of hepatic steatosis induced by high-fat diet, without affecting body weight gain. This protection is associated with attenuation of SREBP-1c transactivation and improved hepatic mitochondrial respiratory chain. Lipidomic analysis identified significant increases in the critical mitochondrial inner membrane lipid, cardiolipin, in PKCβ-deficient livers compared to control. Moreover, hepatocyte PKCβ deficiency had no significant effect on either hepatic or whole-body insulin sensitivity supporting dissociation between hepatic steatosis and insulin resistance.ConclusionsThe above data indicate that hepatocyte PKCβ is a key focus of dietary lipid perception and is essential for efficient storage of dietary lipids in liver largely through coordinating energy utilization and lipogenesis during post-prandial period. These results highlight the importance of hepatic PKCβ as a drug target for obesity-associated nonalcoholic hepatic steatosis.
| S-EPMC7785956 | biostudies-literature
Project description:Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease. Persistent NAFLD can progress to nonalcoholic steatohepatitis (NASH) with inflammation and fibrosis, which predisposes patients to cirrhosis and hepatocellular carcinoma. CCAAT/enhancer-binding protein alpha (CEBPA) is a transcription factor that modulates glycolipid homeostasis, cell differentiation and tumor progression. MTL-CEBPA, a first-in-human small activating RNA therapeutic, has been used to overexpress CEBPA and treat hepatocellular carcinoma by targeting myeloid cells in clinical trials. However, whether and how hepatocyte-specific CEBPA modulates NASH are unknown. Here we found that CEBPA expression was inhibited in the livers of high-fat, high-cholesterol, and high-fructose diet (HFCFD)-fed mice, NASH patients and palmitic/oleic acid-treated primary hepatocytes. Liver-specific Cebpa knockout mice (Cebpa-dLiv) and liver-specific tamoxifen-inducible ERT2-Cre mice (Cebpa-dLiv-ERT2) were then generated. Both Cebpa-dLiv and Cebpa-dLiv-ERT2 mice (treated with tamoxifen) developed enhanced NASH and fibrosis compared to control mice. Global transcriptome analyses demonstrated hepatic secreted phosphoprotein 1 (Spp1) encoding the fibrosis-promoting factor SPP1, was markedly induced by hepatocyte CEBPA knockout in HFCFD-fed mice. Consistently, hepatic SPP1 was upregulated by NASH and negatively correlated with CEBPA expression in humans. Hepatocyte loss of CEBPA enhanced hepatic SPP1 expression and serum SPP1 levels both at the early and late stage of NASH in mice. CEBPA-knockout primary hepatocytes released more SPP1 to the culture medium than wild-type mouse hepatocytes, resulting in enhanced fibrogenesis of hepatic stellate cells, a phenotype that was rescued by the Spp1 shRNA. Hepatocyte-directed AAV8-deliverey of Spp1 shRNA rescued the fibrosis in HFCFD-fed Cebpa-dLiv mice. Mechanistically, CEBPA overexpression reduced, while CEBPA knockout enhanced, SPP1 expression in primary hepatocytes in vitro. The Spp1 promoter had functional CEBPA response elements, while CEBPA modulated histone acetylation to restrict SPP1 expression in a novel feedback loop. Furthermore, overexpression of CEBPA in hepatocytes with AAV8-TBG-CEBPA, inhibited hepatic SPP1 expression and reduced fibrosis in HFCFD-fed wild-type mice. This study demonstrates a novel hepatocyte CEBPA-SPP1 axis involved in modulating NASH fibrosis that supports hepatocyte CEBPA as an anti-NASH target.
2024-03-08 | GSE248340 | GEO
Project description:Functionally relevant in vitro human hepatocyte models are critical for drug safety and efficacy screening, and liver research. However, currently available models, such as primary human hepatocytes and immortalized cell lines, often either rapidly de-differentiate or lack metabolic maturity. Human pluripotent stem cell (hPSC)-derived hepatocyte-like cells (HLCs) and hepatic organoids represent scalable and patient-representative alternatives to conventional models, particularly for long-term cell-based assays. STEMdiff™ Hepatic Organoid media are designed to support the establishment, expansion, and differentiation of proliferative and differentiated hepatic organoids, derived from HLCs generated using the STEMdiff™ Hepatocyte Kit. Here, we compare the composition of proliferative and differentiated HLC-derived hepatic organoids, cultured in STEMdiff™ Hepatic Organoid Growth Medium and STEMdiff™ Hepatic Organoid Differentiation Medium, respectively.
2026-02-26 | GSE320584 | GEO