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At least 19 recordsLinked to original sources
PubMed2026

Human umbilical cord-derived mesenchymal stem cell exosomes ameliorate hepatocyte ferroptosis and sepsis-associated liver injury by restoring iron homeostasis in hepatocytes.

Mesenchymal stem cells-derived exosomes (MSCs-Exo) constitute critical mediators of intercellular communication between stem cells and other cell types. Among these, exosomes derived from human umbilical cord mesenchymal stem cells (HUMSCs-Exo) have attracted considerable attention owing to their potent immunomodulatory capacity, low surface antigenicity, and favorable biosafety profile. Accumulating evidence indicates that HUMSCs-Exo can attenuate ferroptosis in target tissues across a spectrum of pathological conditions, including inflammatory bowel disease and viral cardiomyopathy, thereby mitigating tissue injury, improving organ function, and prolonging host survival. Nevertheless, the regulatory effects of HUMSCs-Exo on sepsis-associated liver injury (SALI) and hepatocellular ferroptosis, as well as the underlying molecular mechanisms, remain largely undefined. In this study, we identified pronounced differential gene expressions between control and septic mice hepatocytes, particularly within pathways related to iron metabolism, lipid metabolism, and ferroptosis. Building on these findings, we systematically characterized the dynamic progression of hepatocyte ferroptosis in septic mice through integrated in vivo and in vitro experiments, demonstrating a strong positive correlation between ferroptotic activity and the severity of liver injury. Using wild-type male C57BL/6J mice and the murine normal hepatocyte cell line NCTC1469, we further demonstrated that HUMSCs-Exo markedly upregulate the expression of FPN, xCT, GPX4, and FTH1 while concomitantly downregulating ACSL4 and TFRC. These molecular alterations reduced intracellular lipid peroxidation and labile iron accumulation, thereby robustly attenuating sepsis-induced hepatocyte ferroptosis and conferring significant hepatoprotective effects. Finally, these findings were validated in the immortalized human normal hepatocyte cell line THLE-2, in which HUMSCs-Exo similarly suppressed lipopolysaccharide-induced ferroptosis and cellular injury by modulating intracellular lipid peroxide and free iron levels. Collectively, our results demonstrate that HUMSCs-Exo exert potent inhibitory effects on sepsis-induced hepatocyte ferroptosis and confer protection against liver injury, primarily through the restoration of intracellular iron homeostasis and the suppression of lipid peroxidation. This study provides a novel therapeutic strategy for the treatment of SALI and ferroptosis.

Ferroptosis↗
PubMed2026

Single-nucleus profiling reveals hepatocyte identity and immune features associated with corticosteroid response in severe alcohol-related hepatitis.

BACKGROUND & AIMS: Severe alcohol-related hepatitis (sAH) is associated with high short-term mortality. However, 30-40% of patients fail to respond to corticosteroids, the only proven pharmacological treatment. The pathophysiological mechanisms underlying sAH and the marked heterogeneity in treatment response remain incompletely understood. We aimed to define cellular changes associated with corticosteroid response in sAH and to identify baseline markers predictive of treatment outcome. METHODS: Single-nucleus RNA sequencing was performed on liver biopsies from patients with biopsy-proven sAH (n = 17), including paired baseline and day 8 biopsies in a subset of patients (n = 8). Patients were classified as corticosteroid responders (sAH-R; Lille score <0.45) or non-responders (sAH-NR; Lille score &#x2265;0.45). Liver biopsies from patients with acute decompensation of alcohol-related cirrhosis (AD; n = 5) and healthy controls (n = 4) were included for comparison. Findings were validated using immunohistochemistry and spatial proteomics in a large multicenter validation cohort (n = 172). RESULTS: At baseline, sAH-R exhibited a significantly higher proportion of liver-infiltrating S100A8+ monocytes compared to sAH-NR, a difference that persisted at day 8. sAH livers showed a marked reduction in mature hepatocytes and an expansion of stressed and intermediate hepatocyte populations, indicating progressive loss of mature hepatocyte identity. This loss was more pronounced in sAH-NR, who also exhibited fewer cycling hepatocytes at day 8, consistent with impaired regenerative capacity. Expression of SULT2A1, a marker of mature hepatocyte identity, was significantly reduced in sAH-NR at baseline. Finally, liver biopsies with &#x2265;50% SULT2A1-positive hepatocytes at baseline were strongly predictive of corticosteroid response. CONCLUSIONS: This study delineates distinct immune and hepatocyte changes associated with corticosteroid response in sAH. Baseline SULT2A1 expression may facilitate stratified treatment approaches in sAH. IMPACT AND IMPLICATIONS: Severe alcohol-related hepatitis (sAH) represents one of the most devastating manifestations of alcohol-related disorders. sAH is characterized by acute hepatic inflammation and high short-term mortality. Clinical management remains challenging, as corticosteroids - the only pharmacological therapy currently applied - are ineffective in a substantial proportion of patients and are associated with significant adverse effects. These limitations highlight the need for a more detailed understanding of sAH pathophysiology and for approaches that enable improved patient stratification and therapeutic decision-making. In this study, we identify distinct pre-treatment differences between corticosteroid responders and non-responders at the level of both hepatocytes and myeloid cells, providing new insight into the cellular mechanisms underlying treatment heterogeneity in sAH. Furthermore, leveraging these findings, we developed a histology-based SULT2A1 scoring system using a commercially available antibody, which predicts corticosteroid response at baseline and may support stratified treatment approaches in clinical practice.

Humans↗
PubMed2025

Targeting hepatocyte-specific SLC2A8 blocks hepatic steatosis and dissociates TCA cycle flux inhibition from glutamine anaplerosis.

BACKGROUND: Excess TCA cycle and glutamine anaplerosis are hallmarks of metabolic dysfunction-associated steatotic liver disease and steatohepatitis. Blocking glutamine metabolism attenuates metabolic dysfunction-associated steatohepatitis. However, inhibiting TCA cycle flux by blocking plasma membrane carbohydrate transport is limited by the ubiquitous tissue distribution, function, and homology among the SLC2A family of facilitative carbohydrate transporters, and the potential for carbohydrate blockade to invoke or exacerbate glutamine anaplerosis. Here, we quantify alterations in hepatocyte carbon flux, define the broader metabolic consequences of hepatocyte-specific GLUT8/SLC2A8 inhibition, and delineate the antisteatotic efficacy of a novel small-molecule GLUT8-selective inhibitor. METHODS: We generated mice with floxed SLC2A8 alleles and expressed hepatocyte-specific Cre by breeding these mice with albumin-Cre transgenic mice, or by administering AAV8 encoding hepatocyte-specific iCre. We performed stable-isotope glucose, fructose, and glutamine metabolic labeling in isolated GLUT8WT and GLUT8LKO hepatocytes and performed metabolic phenotyping in lean and diet-induced obese GLUT8WT and GLUT8LKO mice. Finally, we performed high-throughput screening to identify a GLUT8-selective inhibitor, which we characterized using in vitro models of triglyceride accumulation. RESULTS: Hepatocyte-specific SLC2A8 deletion reduced diet-induced hepatic and peripheral fat accumulation and increased thermogenesis during ZT12-24 (eg, the dark phase). It also disrupted TCA cycle flux without inducing compensatory glutamine utilization. High-throughput screening identified a small-molecule, GLUT8-selective inhibitor, P20, which blocked hepatocyte TG accumulation and inflammation in in vitro steatotic and inflammatory models. CONCLUSIONS: Deleting the hepatocyte carbohydrate transporter GLUT8 suppresses TCA cycle flux without inducing compensatory glutamine anaplerosis. The net effect of this is liver protection against multiple forms of dietary insult. Given that selective pharmacological GLUT8 inhibition is feasible, GLUT8 may be a viable target to abate metabolic dysfunction-associated steatohepatitis and other complications of obesity.

Animals↗
PubMed2025

Alcohol-induced KDM5B activation in hepatocytes drives pathogenic cell-cell communication, leading to loss of liver function.

BACKGROUND: Alcohol-associated liver disease (ALD) is a major cause of alcohol-associated mortality. Previously, we identified KDM5B as a sex-specific mediator of ALD development; however, the mechanism behind KDM5B-induced pathological changes is not established. METHODS: Kdm5b flox/flox female mice were fed a western diet and 20% alcohol in the drinking water for 8-16 weeks (WDA). To induce KO, mice received 2&#xd7;1011 genome copies of AAV8-CMV-Cre, AAV8-TBG-Cre, or AAV8-control. To test the role of myeloid C/EBP&#x3b2;, Cebpbfl/fl, or Cebpbfl/fl Lyz2-Cre mice were fed WDA for 16 weeks. RESULTS: We found that Kdm5b KO prevented alcohol-induced liver fibrosis and liver inflammation in female mice. These changes were in part mediated by hepatocyte-to-non-parenchymal cell communication changes. KDM5B in hepatocytes promoted pro-inflammatory and pro-fibrotic changes in liver macrophages, endothelial cells, and stellate cells. Moreover, KDM5B promoted alcohol-induced early increase in EpCAM-positive liver progenitors and loss of liver function at later time points of alcohol feeding. We found that loss of liver function was dependent on a hepatocyte-to-macrophage communication feedback loop. KDM5B in hepatocytes inhibited macrophage C/EBP&#x3b2; expression, which in turn resulted in loss of the mature KCs phenotype and prevented the ability of KCs to support hepatocyte differentiation, ultimately leading to loss of liver synthetic function. CONCLUSIONS: KDM5B activation in hepatocytes drives pathogenic cell-cell communication, leading to alcohol-induced loss of liver function in ALD.

Animals↗
PubMed2025

Hepatocyte-specific CLSTN3B ablation impairs lipid droplet maturation and alleviates diet-induced steatohepatitis in mice.

Excessive lipid accumulation in hepatocytes, a hallmark of metabolic dysfunction-associated steatotic liver disease (MASLD), can lead to progressive liver damage. Understanding the molecular mechanisms governing lipid storage in hepatocytes is essential for identifying therapeutic targets to halt MASLD progression. Here, we show a pivotal role for the protein calsyntenin 3&#x3b2; (CLSTN3B) in promoting lipid droplet (LD) maturation and lipid storage in hepatocytes. Previously characterized as an endoplasmic reticulum (ER)-LD contact protein that facilitates LD maturation in adipocytes, we now show that CLSTN3B expression is strongly induced in mouse hepatocytes by peroxisome proliferator-activated receptor gamma (PPAR&#x3b3;) in response to dietary caloric excess. Hepatocyte-specific deletion of CLSTN3B in mice significantly increases energy expenditure, reduces metabolic efficiency, and protects against diet-induced hepatic steatosis and fibrosis. Mechanistically, CLSTN3B deficiency causes reduced LD phospholipid coverage and increased lipase recruitment. This results in enhanced fatty acid oxidation driven by a futile cycle of lipolysis and re-esterification. Notably, human clinical data reveal a positive correlation between hepatic CLSTN3B expression and MASLD severity and progression, emphasizing its relevance to human disease. Together, our findings establish CLSTN3B as a key regulator of hepatocyte lipid storage and metabolic efficiency and highlight its potential as a therapeutic target in MASLD.

Journal Article↗
PubMed2025

Hepatocyte dedifferentiation in 2D culture reveals extensive transcriptomic and proteomic rewiring.

BACKGROUND: Primary hepatocytes are commonly used in vitro to model liver metabolism, but prolonged culturing results in dedifferentiation and potentially limits the applicability of this model. METHODS: We characterized the transcriptome and proteome of full liver and primary hepatocytes as either freshly isolated cells or after 24 hours of 2D-culturing. RESULTS: We found that 2D-culturing for 24 hours changes more than 10,000 genes and 3000 proteins compared with freshly isolated cells, accompanied by a decrease in transcriptional heterogeneity and a loss of zonal markers. Moreover, there were changes in proteins associated with the extracellular matrix, in mitochondrial and ribosomal protein abundances, as well as an increase in the abundance of acute-phase response proteins. CONCLUSION: Collectively, primary mouse hepatocytes in culture rewire the transcriptome and proteome, which may affect the utility of this model to study physiological and molecular mechanisms related to the liver. We developed the Shiny app "Hepamorphosis" (https://cbmr.ku.dk/research/resources/shiny-apps/), which allows users to explore RNA/protein correlations, zonation profiles, and cell-type-specific transcription in full liver and cultured hepatocytes.

Hepatocytes↗
PubMed2026

Hepatocyte-derived LRG1 primes the liver for metastasis and impairs immunotherapy.

The liver undergoes active remodeling by the primary tumor prior to metastatic spread. However, the mechanisms by which hepatocytes dictate the liver-specific tropism of tumors remain elusive. Here, we identify hepatocyte-derived leucine-rich alpha-2-glycoprotein 1 (LRG1) as a key mediator of liver premetastatic niche (PMN) formation. Clinically, elevated serum LRG1 levels are correlated with an increased risk of liver metastasis in patients and multiple mouse models. Mechanistically, LRG1 remodels the hepatic microenvironment by driving immunosuppressive neutrophil accumulation, impairing the function of effector T cells and dendritic cells, and enhancing angiogenesis in the liver, thereby fostering a prometastatic landscape. Hepatocyte-specific ablation of LRG1 dampens premetastatic niche formation and significantly reduces the metastatic burden in vivo. Hepatic LRG1 induced by tumor-associated inflammation via IL-6/STAT3 signaling promotes liver metastasis through the formation of TGFBR/PI3K/AKT axis-driven neutrophil extracellular traps (NETs). Importantly, therapeutic blockade of LRG1 not only suppressed liver metastasis but also reprogrammed the hepatic niche toward an immune-activated state, sensitizing tumors to anti-PD-1 therapy. Collectively, our findings reveal a hepatocyte-LRG1 axis that drives liver premetastatic niche remodeling and highlight LRG1 as a promising target for the prevention and treatment of liver metastasis.

Animals↗
PubMed2025

HBO1 functions as an epigenetic barrier to hepatocyte plasticity and reprogramming during liver injury.

Hepatocytes can reprogram into biliary epithelial cells (BECs) during liver injury, but the underlying epigenetic mechanisms remain poorly understood. Here, we define the chromatin dynamics of this process using single-cell ATAC-seq and identify YAP/TEAD activation as a key driver of chromatin remodeling. An in vivo CRISPR screen highlights the histone acetyltransferase HBO1 as a critical barrier to reprogramming. HBO1 is recruited by YAP to target loci, where it promotes histone H3 lysine 14 acetylation (H3K14ac) and engages the chromatin reader zinc-finger MYND-type containing 8 (ZMYND8) to suppress YAP/TEAD-driven transcription. Loss of HBO1 accelerates chromatin remodeling, enhances YAP binding, and enables a more complete hepatocyte-to-BEC transition. Our findings position HBO1 as an epigenetic brake that restrains YAP-mediated reprogramming, suggesting that targeting HBO1 may enhance hepatocyte plasticity for liver regeneration.

Hepatocytes↗
PubMed2025

Identification of a robust promoter in mouse and human hepatocytes by in vivo biopanning of a barcoded AAV library.

Recombinant adeno-associated viruses (AAVs) are leading vectors for in vivo human gene therapy. An integral vector element is promoters, which control transgene expression in either a ubiquitous or cell-type-selective manner. Identifying optimal capsid-promoter combinations is challenging, especially when considering on- versus off-target expression. Here, we report a pipeline for in vivo promoter biopanning in AAV building on our AAV capsid barcoding technology and illustrate its potential by screening 53 promoters in 16 murine tissues using an AAV9 vector. Surprisingly, the 2.2-kb human glial fibrillary acidic protein (GFAP) promoter was the top hit in the liver, where it outperformed robust benchmarks such as the human &#x3b1;-1-antitrypsin promoter or the clinically used liver-specific promoter 1 (LP1). Analysis of hepatic cell populations revealed preferred GFAP promoter activity in hepatocytes. Notably, the GFAP promoter also surpassed the LP1 and cytomegalovirus promoters in human hepatocytes engrafted in an immune-deficient mouse. These findings establish the GFAP promoter as an exciting alternative for research and clinical applications requiring efficient and specific transgene expression in hepatocytes. Our pipeline expands the arsenal of technologies for high-throughput in vivo screening of viral vector components and is compatible with capsid barcoding, facilitating the combinatorial interrogation of complex AAV libraries.

Dependovirus↗
PubMed2026

Tfr2 is necessary for acute iron-dependent hepcidin induction in mice with Tfr1-deficient hepatocytes.

In hepatocytes, transferrin receptor 1 (Tfr1) plays a limited role in iron acquisition but negatively regulates signaling to the iron hormone hepcidin (Hamp) through its interaction with the hemochromatosis protein Hfe. Its homolog, transferrin receptor 2 (Tfr2), operates as an iron sensor and direct positive regulator of hepcidin expression. We generated TfrcAlb-Cre;Tfr2Alb-Cre mice with hepatocyte-specific ablation of both Tfr1 and Tfr2 to study their effects on iron homeostasis. These animals are viable and develop systemic iron overload, recapitulating a key feature of Tfr2Alb-Cre mice, albeit with milder hepatic iron accumulation and relatively higher residual hepcidin expression, presumably driven by liberated Hfe. Only Tfr1-expressing primary hepatocytes from Tfrcfl/fl;Tfr2fl/fl and Tfr2Alb-Cre mice internalized fluorescent holo-transferrin (AF647-Tf), arguing against a significant contribution of Tfr2 or other receptors in transferrin-bound iron uptake. Under dietary iron restriction, Hamp mRNA suppression and hepatic iron depletion were comparable in Tfr2-deficient livers from TfrcAlb-Cre;Tfr2Alb-Cre and Tfr2Alb-Cre mice despite compensatory Tfr1 upregulation in the latter, which likely sequesters Hfe. Conversely, Tfr1-deficient but Tfr2-expressing livers from TfrcAlb-Cre mice displayed relatively elevated Hamp mRNA, as expected. Following an acute dietary iron challenge, Hamp mRNA induction and Smad1,5,9 phosphorylation occurred only in the liver of Tfr2-expressing TfrcAlb-Cre but not in TfrcAlb-Cre;Tfr2Alb-Cre mice, indicating that "liberated" Hfe requires Tfr2 to become functionally active. Collectively, these findings demonstrate that transferrin receptors are dispensable for hepatocellular iron supply, and Tfr2 and Hfe exhibit nonredundant functions under chronic iron loading but act cooperatively to induce hepcidin in response to an acute iron challenge.

Animals↗
PubMed2026

mRNA vaccine immunity is enhanced by hepatocyte detargeting and not dependent on dendritic cell expression.

Proteins encoded by mRNA vaccines can be expressed by a diversity of transfected cell types but how cell-type-specific expression influences immunity is poorly understood. To investigate this, we incorporated synthetic microRNA target sites (miRT) into lipid nanoparticle (LNP)-delivered mRNA vaccines to silence mRNA expression specifically in professional antigen-presenting cells (pAPCs), hepatocytes or myocytes. We found that mRNA expression in pAPCs was dispensable for priming antigen-specific T cells, whereas mRNA expression in myocytes induced similar or stronger immune responses, including for SARS-CoV-2, suggesting that antigen cross-presentation or cross-dressing may be more impactful than direct mRNA expression in pAPCs. In contrast, mRNA expression in hepatocytes suppressed the antigen-specific T cell response, partly through PD1/PDL1. In mice bearing tumor-associated antigen (TAA)-expressing lymphoma cells, miRT-mediated hepatocyte-silenced TAA mRNA vaccine enhanced immune response and reduced tumor burden. Thus, non-pAPC expression shapes immunity to mRNA-encoded protein and inclusion of miRTs can boost or blunt mRNA-LNP immunogenicity.

Journal Article↗
PubMed2025

VDAC2 and Bak scarcity in liver mitochondria enables targeting hepatocarcinoma while sparing hepatocytes.

Differences between normal tissues and invading tumors that allow tumor targeting while saving normal tissue are much sought after. Here we show that scarcity of VDAC2, and the consequent lack of Bak recruitment to mitochondria, renders hepatocyte mitochondria resistant to permeabilization by truncated Bid (tBid), a Bcl-2 Homology 3 (BH3)-only, Bcl-2 family protein. Increased VDAC2 and Bak is found in most human liver cancers and mitochondria from tumors and hepatic cancer cell lines exhibit VDAC2- and Bak-dependent tBid sensitivity. Exploring potential therapeutic targeting, we find that combinations of activators of the tBid pathway with inhibitors of the Bcl-2 family proteins that suppress Bak activation enhance VDAC2-dependent death of hepatocarcinoma cells with little effect on normal hepatocytes. Furthermore, in vivo, combination of S63845, a selective Mcl-1 inhibitor, with tumor-nectrosis factor-related, apoptosis-induncing ligand (TRAIL) peptide reduces tumor growth, but only in tumors expressing VDAC2. Thus, we describe mitochondrial molecular fingerprint that discriminates liver from hepatocarcinoma and allows sparing normal tissue while targeting tumors.

Voltage-Dependent Anion Channel 2↗
PubMed2026

Dual HBV cccDNA-linked HiBiT reporter hepatocyte models for screening of candidate cccDNA modulators.

Chronic hepatitis B remains difficult to cure because the viral covalently closed circular DNA (cccDNA) minichromosome can persist and sustain viral transcription, creating a need for scalable, reporter readouts that facilitate early discovery of cccDNA-modulating agents. Here, we developed two complementary hepatocyte HiBiT reporter models: a replication-competent HBV reporter in HepaRG cells (HepaRG-Hibit16), in which a secreted split-NanoLuc HiBiT signal is linked to cccDNA-associated expression, and a Cre/Lox-based recombinant cccDNA (rcccDNA) reporter in HepG2 cells (HepG2-Rccc1a) that rapidly generates rcccDNA with a matched HiBiT readout. Screening of 1,403 FDA-approved compounds across both models identified 13 concordant, non-cytotoxic hits. Palovarotene, a retinoic acid receptor-&#x3b3; agonist, was selected as an exemplar concordant hit and reduced HBV antigens, HBV DNA, and cccDNA and inhibited HBV infection in multiple hepatocyte-based in vitro systems without overt cytotoxicity at the tested concentrations. Together, this dual-reporter strategy supports efficient cross-model triage of candidate cccDNA modulators for subsequent orthogonal validation.

Humans↗
PubMed2025

In vivo expansion of gene-targeted hepatocytes through transient inhibition of an essential gene.

Homology-directed repair (HDR)-based genome editing is an approach that could permanently correct a broad range of genetic diseases. However, its utility is limited by inefficient and imprecise DNA repair mechanisms in terminally differentiated tissues. Here, we tested Repair Drive, a platform technology for selectively expanding HDR-corrected hepatocytes in adult mice in vivo. Repair Drive involves transient conditioning of the liver by knocking down an essential gene, fumarylacetoacetate hydrolase (Fah), and delivering an untargetable version of the essential gene in cis with a therapeutic transgene. We show that Repair Drive increased the percentage of correctly targeted hepatocytes in healthy wild-type mice up to 25%, which resulted in a fivefold increased expression of a therapeutic transgene, human factor IX (FIX). Repair Drive was well tolerated and did not induce toxicity or tumorigenesis during a 1-year follow-up. This approach may broaden the range of liver diseases that can be treated with somatic genome editing.

Animals↗
PubMed2025

Hepatocyte-Enriched miRNA-193b-3p Promotes Hepatitis B Virus Replication by Dual Activation of Viral Core Promoter Activity and Autophagy Induction by Targeting IGF-1R.

Hepatitis B virus (HBV) infection is a principal cause of severe liver disease in humans and is associated with increased levels of specific serum or intracellular microRNAs (miRNAs). Among these, miR-193b-3p is a liver-enriched miRNA; however, its role in HBV replication remains unknown. This study aimed to investigate the influence of chronic HBV infection on miR-193b-3p levels in the peripheral blood and liver tissues of patients with chronic hepatitis B (CHB), evaluate the effect of miR-193b-3p on HBV replication both in vitro and in vivo, and elucidate the potential underlying mechanisms. We showed that hepatic miR-193b-3p levels in patients with CHB were significantly elevated compared with those in healthy controls. Ectopic expression of miR-193b-3p significantly enhanced HBV replication and transcription in different hepatoma cell lines. Furthermore, we identified IGF-1R as a direct target through which miR-193b-3p regulates HBV replication. Mechanistically, miR-193b-3p increased HBV core promoter activity via the IGF-1R/FXR&#x3b1; axis, thereby enhancing HBV transcription. Additionally, miR-193b-3p increased IGF-1R/Akt/MDM2/p53 signaling-mediated autophagy induction, which in turn facilitated increased HBV post-transcriptional activity. Collectively, hepatocyte-enriched miR-193b-3p exerts a proviral effect on HBV replication through dual synergistic mechanisms, offering novel insights into its role in HBV replication and potential therapeutic implications in CHB infection.

Humans↗
PubMed2024

A novel molecular pathway of lipid accumulation in human hepatocytes caused by PFOA and PFOS.

Exposed to ubiquitously perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) has been associated with non-alcoholic fatty liver disease (NAFLD), yet the underlying molecular mechanism remains elusive. The extrapolation of empirical studies correlating per- and polyfluoroalkyl substance (PFAS) exposure with NAFLD occurrence to real-life exposure was hindered by the limited availability of mechanistic data at environmentally relevant concentrations. Herein, a novel pathway mediating hepatocyte lipid accumulation by PFOA and PFOS at human-relevant dose (<10&#xa0;&#x3bc;M) was identified by integrating CRISPR-Cas9 genome screening, concentration-dependent transcriptional assay in HepG2 cell and epidemiological data mining. 1) At genetic level, nudt7 showed the highest enriched potency among 569 NAFLD-related genes, and the transcription of nudt7 was significantly downregulated by PFOA and PFOS exposure (<7 &#x3bc;M). 2) At molecular pathway, upon exposure to&#xa0;&#x2264;10-4&#xa0;&#x3bc;M PFOA and PFOS, the downregulation of nudt7 transcriptional expression triggered the reduction of Ace-CoA hydrolase activity. 3) At cellular level, increased lipids were measured in HepG2 cells with PFOA and PFOS (<2&#xa0;&#x3bc;M). Overall, we identified a novel mechanism mediated by transcriptional downregulation of nudt7 gene in hepatocellular lipid increase treated with PFOA and PFOS, which could potentially explain the NAFLD occurrence associated with exposure to PFASs in humans.

Humans↗
PubMed2004

Hepatocyte growth factor-activated NF-kappaB regulates HIF-1 activity and ODC expression, implicated in survival, differently in different carcinoma cell lines.

Hepatocyte growth factor (HGF)-stimulated Met signaling influences tumor survival, growth and progression, all processes involving the transcription factor NF-kappaB. NF-kappaB plays a complex role in the control of survival due to the influence of cellular factors acting downstream. We undertook a comparative investigation of two human breast carcinoma cells with different grades of malignancy and HepG2 hepatoma cells, which present a biphasic response to HGF (proliferation followed by apoptosis). We found evidence that HGF induced gene patterns characteristic of survival rather than apoptosis depending on the cell type. The ability of NF-kappaB to regulate expression of hypoxia-inducible factor-1alpha (HIF-1alpha), a survival/anti-apoptotic gene in cancer, seemed to be critical. In the HepG2 and MCF-7 (low invasive breast carcinoma) cell lines increased transcription and translation were responsible for HIF-1alpha induction after HGF. The regulation by NF-kappaB was mainly at the level of the 5'-UTR of the HIF-1alpha message. HIF-1 (alpha/beta heterodimer) was likely to transactivate Mcl-1, another anti-apoptotic gene. Opposite results were observed in MDA-MB-231 cells (highly invasive breast carcinoma), which have high NF-kappaB activity, further inducible by HGF, because HIF-1alpha mRNA expression and HIF-1 transactivating capacity were HGF-insensitive while the alpha subunit seemed to be degraded after HGF. However, ornithine decarboxylase (ODC) and heme oxygenase mRNA expression persistently increased. By transiently transfecting two ODC gene reporters we demonstrated that ODC is a target gene of NF-kappaB in HGF-treated tumor cells. By regulating HIF-1 activity and specific gene expression downstream, NF-kappaB may influence the survival threshold, with an impact on the fate of carcinoma cells after prolonged HGF treatment.

Breast Neoplasms↗