Targeting EGFR to reverse PFOA-induced paradoxical hepatic lipotoxicity and cachexia-like phenotype
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus Musculus
SUBMITTER: 
Biran Zhu
PROVIDER: PXD081825 | iProX | Tue Jul 28 00:00:00 GMT+01:00 2026
REPOSITORIES: iProX
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Project description:Background: Non-alcoholic fatty liver disease (NAFLD) is a complex multifactorial disorder that is characterised by dysfunctional lipid metabolism and cholesterol homeostasis, and a related chronic inflammatory response. NAFLD has become the most common cause of chronic liver disease in many countries, and its prevalence continues to rise in parallel with increasing rates of obesity. Here, we evaluated the putative NAFLD-attenuating effects of a multicomponent medicine consisting of 24 ingredients: Hepar compositum (HC-24). Methods: Ldlr-/-.Leiden mice were fed a high-fat diet (HFD) with a macronutrient composition and cholesterol content comparable to human diets for 24 weeks to induce obesity-associated metabolic dysfunction, including hepatic steatosis and inflammation. HC-24 or vehicle control was administered intraperitoneally 3 times/week (1.5 ml/kg) for the last 18 weeks of the study. Histological analyses of liver and adipose tissue were combined with extensive hepatic transcriptomics analysis (next generation sequencing). Transcriptomics results were further substantiated with immunohistochemical and liver lipid analyses. Results: HFD feeding induced obesity and metabolic dysfunction that was associated with adipose tissue inflammation and increased gut permeability. In the liver, HFD-feeding resulted in a disturbance of cholesterol homeostasis and an associated inflammatory response. HC-24 did not affect body weight, metabolic risk factors, adipose tissue inflammation or gut permeability. While HC-24 did not affect total liver steatosis, there was a pronounced reduction in lobular inflammation in HC-24-treated animals, which was associated with modulation of genes involved in inflammation (e.g. neutrophil chemokine Cxcl1) and cholesterol homeostasis (i.e. predicted effect on 'cholesterol' as an upstream regulator, based on gene expression changes associated with cholesterol handling). These effects were confirmed by immunohistochemical staining of neutrophils and biochemical analysis of hepatic free cholesterol content. Intrahepatic free cholesterol levels were found to correlate significantly with the number of inflammatory aggregates in the liver, thereby providing a potential rationale for the observed anti-inflammatory effects of HC-24. Conclusions: Free cholesterol accumulates in the liver of Ldlr-/-.Leiden mice under physiologically translational dietary conditions, and this is associated with the development of hepatic inflammation. The multicomponent medicine HC-24 reduces accumulation of free cholesterol and has molecular and cellular anti-inflammatory effects in the liver.
2021-03-01 | GSE163652 | GEO
Project description:Circulating levels of the gut microbe-derived metabolite trimethylamine-N-oxide(TMAO) have recently been linked to cardiovascular disease (CVD) risk. Here we performed transcriptional profiling in mouse models of altered reverse cholesterol transport (RCT), and serendipitously identified the TMAO-generating enzyme flavin monooxygenase 3 (FMO3) as a powerful modifier of cholesterol metabolism and RCT. Knockdown of FMO3 in cholesterol-fed mice alters biliary lipid secretion, blunts intestinal cholesterol absorption, and limits the production of hepatic oxysterols and cholesteryl esters. Furthermore, FMO3 knockdown stimulates basal and liver X receptor (LXR)-stimulated macrophage RCT, thereby improving cholesterol balance. Conversely, FMO3 knockdown exacerbates hepatic ER stress and inflammation in part by decreasing hepatic oxysterol levels and subsequent LXR activation. FMO3 is thus identified as a central integrator of hepatic cholesterol and triacylglycerol metabolism, inflammation, and ER stress. These studies suggest that the gut microbiota-driven TMA/FMO3/TMAO pathway is a key regulator of lipid metabolism and inflammation. To identify potential regulators of macrophage reverse cholesterol transport (RCT), liver was isolated from two independent mouse models where the non-biliary RCT pathway known as transintestinal cholesterol excretion (TICE) was either chronically (NPC1L1-liver-transgenic mice) or acutely (ACAT2 antisense oligonucleotide treatment) stimulated. Total RNA was isolated and gene expression levels were profiled on the Affymetrix GeneAtlas MG-430 PM Array Strip (Affymetrix; Santa Clara, CA, USA)
2014-12-19 | E-GEOD-64326 | biostudies-arrayexpress
Project description:Non-alcoholic fatty liver disease (NAFLD) is characteristic by pathological lipid accumulation in hepatocytes. This study investigates how Cyanidin-3-rutinoside(C3R), a natural anthocyanin with antioxidant and metabolic regulatory properties, counteracts this process. In a free fatty acid (FFA)-induced HepG2 steatosis model, C3R significantly reduced intracellular triglycerides, total cholesterol, and LDL-C levels, suppressed lipid droplet formation, and alleviated oxidative stress by enhancing SOD/CAT activities and GSH content while lowering MDA and ROS. RNA-seq analysis revealed that C3R reversed FFA-induced transcriptomic alterations. Mechanistically, C3R inhibited SREBP2-mediated cholesterol synthesis, activated the PCSK9/LDLR pathway to promote cholesterol clearance, and upregulated PPARγ-dependent CYP7A1 expression to stimulate bile acid synthesis from cholesterol. C3R also enhanced autophagic flux, facilitating lipid droplet degradation. Molecular docking confirmed high-affinity binding of C3R to INSIG1, PCSK9, and PPARγ, with hydroxyl groups forming specific hydrogen bonds at active sites, supporting direct target engagement. These findings establish a multi-targeted mechanism for C3R in ameliorating hepatic steatosis and provide a molecular basis for anthocyanin-mediated regulation of lipid metabolism.
2026-01-23 | GSE316562 | GEO
Project description:Abnormalities in hepatic lipid metabolism are believed to play a critical role in the etiology of nonalcoholic steatohepatitis (NASH). Monoacylglycerol acyltransferase (MGAT) enzymes convert monoacylglycerol to diacylglycerol, which is the penultimate step in one pathway for triacylglycerol (TAG) synthesis. Hepatic expression of Mogat1, which encodes an MGAT enzyme, is increased in the livers of mice with hepatic steatosis and knocking down Mogat1 improves insulin sensitivity, but whether increased MGAT activity plays a role in the etiology of NASH is unclear. To examine the effects of knocking down Mogat1 in the liver on the development of NASH, C57BL/6 mice were placed on a diet containing high levels of trans fatty acids, fructose, and cholesterol (HTF-C diet) or a low fat control diet for 4 weeks. Mice were then injected with antisense oligonucleotides (ASO) to knockdown Mogat1 or a scrambled ASO control for 12 weeks while remaining on diet. HTF-C diet caused glucose intolerance, hepatic steatosis, and induced hepatic gene expression markers of inflammation, macrophage infiltration, and stellate cell activation. Mogat1 ASO treatment, which suppressed Mogat1 expression in liver, attenuated weight gain, improved glucose tolerance, and decreased hepatic TAG content compared to control ASO-treated mice on HTF-C chow. However, Mogat1 ASO treatment did not reduce hepatic DAG, cholesterol, or free fatty acid content, improve histologic measures of liver injury, or reduce expression of markers of stellate cell activation, liver inflammation, and injury. In conclusion, inhibition of hepatic Mogat1 in HTF-C diet-fed mice improves glucose tolerance and hepatic TAG accumulation without attenuating liver inflammation and injury. Total RNA obtained from liver of 4 control vs. 4 Mogat1 ASO treated higf-fat diet (HFD) fed mice.
2014-11-05 | E-GEOD-60349 | biostudies-arrayexpress
Project description:Lecithin-cholesterol acyltransferase (Lcat), the key enzyme in reverse cholesterol transport (RCT), has been traditionally recognized for its role in high-density lipoprotein (HDL) maturation and systemic cholesterol homeostasis. However, its hepatocyte-autonomous function in fatty acid metabolism remains elusive. Here, we established a hepatocyte-specific lcat-overexpressing zebrafish model (Tg(fabp10a:lcat-T2A-mCherry)) and integrated transcriptomic with metabolic phenotyping to reveal that lcat overexpression in zebrafish hepatocytes directly drives early-stage hepatic steatosis. lcat overexpression induces triglyceride (TG)-specific accumulation and cytoplasmic lipid droplet deposition. Surprisingly, transcriptomic profiling revealed unexpected upregulation of fatty acid elongation pathway. Crucially, genetic knockdown of hsd17b12a or pharmacological inhibition of Elovl1 partially rescued Lcat-induced hepatic steatosis. These findings decouple Lcat from classical RCT function, thereby providing a molecular rationale for targeted metabolic interventions in metabolic dysfunction-associated steatotic liver disease (MASLD).
2026-08-02 | GSE309314 | GEO
Project description:Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive liver disease characterized by steatosis, inflammation, and fibrosis. However, the mechanisms linking lipid droplet (LD) metabolism to MASH progression remain poorly understood. AF6 is a polarity protein known to regulate metabolic homeostasis, but its role in the development of MASH remains largely undefined. Here, we identify AF6 as a critical regulator of hepatic lipid accumulation and inflammation in MASH. Hepatic AF6 expression is elevated in MASH patients and diet-induced mouse models. Liver-specific deletion of AF6 attenuated steatosis, inflammation, and fibrosis in both high-fat, high-cholesterol (HFHC) and choline-deficient, amino acid-defined high-fat diet (CDA-HFD)-induced MASH models. Mechanistically, lipid overload promotes nuclear translocation of AF6, which interacts with the transcription factor C/EBPβ and enhances its nuclear accumulation. This interaction increases transcription of the lipid droplet fusion protein CIDEA, promoting LD growth and lipid deposition. AF6 also exacerbates MASH by enhancing C/EBPβ-mediated proinflammatory signaling. Restoration of CIDEA expression in AF6-deficient mice reverses the protective effects. In human liver biopsies and iPSC-derived liver organoids, the AF6–C/EBPβ–CIDEA axis is upregulated and correlates with disease severity. Importantly, a CRISPR-Cas9–based lipid nanoparticle (LNP) therapy targeting AF6 effectively reduced lipid accumulation, inflammation, and fibrosis in MASH mice and organoids. AF6 promotes MASH progression by facilitating C/EBPβ nuclear localization and transcriptional activation of CIDEA. Targeting the AF6–C/EBPβ–CIDEA axis represents a promising therapeutic strategy for treating MASH.
2026-02-18 | GSE305662 | GEO
Project description:Low-density lipoprotein receptors (LDLRs) are crucial for cholesterol metabolism. Dysregulation of lipid homeostasis can lead to atherosclerosis and contribute to steatohepatitis. This study investigated the effects of nitroxoline on LDLR expression and its protective effects against lipid dysregulation, hepatic steatosis, and atherosclerosis. A comprehensive screening of FDA-approved clinical drugs was conducted to identify candidates capable of modulating LDLR expression. Nitroxoline emerged as a promising agent and was further tested in various assays, including quantitative reverse transcription polymerase chain reaction (qRT-PCR), western blotting, flow cytometry, and RNA-seq analysis to evaluate the effects on LDLR expression and cholesterol uptake in Huh7 cells. In vivo studies were performed on Apoe-/- mice to assess the impact of nitroxoline on lipid metabolism, hepatic steatosis, and atherosclerosis progression. Nitroxoline significantly upregulated LDLR mRNA and protein levels in Huh7 cells, enhancing LDL uptake and binding. It enhanced SREBF2 by downregulating PPP2CA and stabilized LDLR mRNA through AMPK and JNK signaling pathways. RNA-seq analysis revealed upregulation of genes associated with cholesterol homeostasis and downregulation of genes involved in triglyceride biosynthesis. In Apoe-/- mice, nitroxoline reduced serum levels of total cholesterol, triglycerides, and LDL-C, while not affecting HDL-C levels. Histological analysis showed significantly reduced hepatic steatosis and a tendency to halt atherosclerotic plaque formation in nitroxoline-treated mice. Nitroxoline demonstrates a dual role in upregulating LDLR expression and improving hepatic lipid metabolism. By modulating lipids and providing hepatoprotection, nitroxoline highlights its potential for reducing atherosclerosis and treating lipid-related metabolic disorders.
2026-05-27 | GSE298582 | GEO
Project description:This study demonstrates that the thyroid hormone receptor-β (THR-β) agonist Resmetirom, the first FDA-approved anti-MASH drug, exerts potent therapeutic effects in a human relevant dietary mouse model of metabolic dysfunction–associated steatohepatitis (MASH) induced by fructose, palmitate, and cholesterol (FPC). Resmetirom treatment markedly improved hepatic steatosis, inflammation, and fibrosis, accompanied by reduced systemic inflammatory markers and hepatocyte death. Transcriptomic profiling revealed that Resmetirom profoundly reprograms hepatic gene expression, particularly suppressing pathways involved in lipid metabolism, inflammation, and multiple forms of programmed cell death, including apoptosis, pyroptosis, and necroptosis. These findings highlight a previously unrecognized role of THR-β activation in regulating hepatocyte survival and inflammation, providing mechanistic insight into the multifaceted hepatoprotective effects of Resmetirom in MASH.
2025-11-21 | GSE310831 | GEO
Project description:DNA damage, a hallmark of aging, is a major trigger of inflammation and age-related pathologies. Here, we show that vascular endothelial cells (ECs) exhibit a distinct response to DNA damage, characterized by dysregulation of endocrine signaling via ET-1. EC-specific DNA double strand breaks under high-fat diet conditions led to a rapid elevation of blood pressure, dyslipidemia, hepatic steatosis, visceral fat accumulation and kidney aging. Elevated EC-derived endothelin-1 (ET-1) triggered liver hypoxia and ET-A receptor (ETAR) activation, promoting lipid metabolic reprogramming via increased acetyl-CoA synthetase 2 (ACSS2), and ETAR inhibition mitigated these phenotypes. In humans, kidney EC DNA damage correlated with reduced eGFR and HDL-C, and increased hepatic steatosis indices. Collectively, EC DNA damage is a possible driver of cardio-kidney-metabolic dysfunction via ET-1-ACSS2 signaling, which is targetable by ETAR blockade. These findings highlight the organ-specific impact of endothelial cell DNA damage in driving cardio-kidney-metabolic dysfunction.
2026-02-11 | GSE318719 | GEO
Project description:Circulating levels of the gut microbe-derived metabolite trimethylamine-N-oxide(TMAO) have recently been linked to cardiovascular disease (CVD) risk. Here we performed transcriptional profiling in mouse models of altered reverse cholesterol transport (RCT), and serendipitously identified the TMAO-generating enzyme flavin monooxygenase 3 (FMO3) as a powerful modifier of cholesterol metabolism and RCT. Knockdown of FMO3 in cholesterol-fed mice alters biliary lipid secretion, blunts intestinal cholesterol absorption, and limits the production of hepatic oxysterols and cholesteryl esters. Furthermore, FMO3 knockdown stimulates basal and liver X receptor (LXR)-stimulated macrophage RCT, thereby improving cholesterol balance. Conversely, FMO3 knockdown exacerbates hepatic ER stress and inflammation in part by decreasing hepatic oxysterol levels and subsequent LXR activation. FMO3 is thus identified as a central integrator of hepatic cholesterol and triacylglycerol metabolism, inflammation, and ER stress. These studies suggest that the gut microbiota-driven TMA/FMO3/TMAO pathway is a key regulator of lipid metabolism and inflammation.
2014-12-19 | GSE64326 | GEO