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Dysregulation of bile acid metabolism exacerbates diet-induced MASLD development in HuR deficient male mouse livers.

ABSTRACT: Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) is a leading cause of hepatocellular carcinoma and liver transplantation worldwide, making identification of intervention strategies and therapeutic treatments essential to reducing morbidity and mortality associated with this disease. RNA binding proteins, like human antigen R (HuR), are ubiquitous and multi-faceted cell-stress regulators. HuR’s role in MASLD development is incompletely understood. This study aims to determine how hepatocyte HuR deficiency drives MASLD progression to Metabolic dysfunction-associated steatohepatitis (MASH). To model MASLD, we fed male hepatocyte-specific HuR knockout mice (HuRHep-/-) and WT control mice with the normal chow diet or the MASLD-inducing high fat, cholesterol, and fructose (HFCF) diet for 16 weeks. The liver transcriptomic profile was mapped using bulk RNA sequencing (RNA seq). After MASLD-inducing diet feeding, bile acid metabolism was modulated, while liver injury and fibrosis markers were increased in male HuRHep-/- mice, relative to WT. Our data suggests that hepatocyte HuR deficiency dysregulates bile acid metabolism and exacerbates MASLD progression.

ORGANISM(S): Mus musculus

PROVIDER: GSE287727 | GEO | 2026/06/03

REPOSITORIES: GEO

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Hepatic AKAP1 Deficiency Exacerbates Diet-Induced MASLD by Enhancing GPAT1-mediated Lysophosphatidic Acid Synthesis

Project description:Metabolic dysfunction-associated steatotic liver disease (MASLD), closely associated with obesity, can progress to metabolic dysfunction-associated steatohepatitis when the liver undergoes overt inflammatory damage. A-kinase anchoring protein 1 (AKAP1) has been shown to control lipid accumulation in brown adipocytes. However, the role of AKAP1 signaling in hepatic lipid metabolism and MASLD remains poorly understood. Here, we showed that hepatocyte-specific AKAP1 deficiency exacerbated hepatic steatosis and steatohepatitis in male mice subjected to a high-fat diet and fast-food diet, respectively. Mechanistically, AKAP1 directly phosphorylated and inactivated glycerol-3-phosphate acyltransferase 1 (GPAT1) in a PKA-dependent manner, thus suppressing lysophosphatidic acid (LPA) production. Increased endogenous LPA in hepatocytes promoted hepatocellular triglyceride (TG) synthesis and initiated pronounced inflammatory response in Kupffer cells. Restoring hepatic AKAP1 or repressing LPA levels via GPAT1 knockdown alleviated MASLD exacerbation. Overall, AKAP1 plays a protective role against MASLD by inhibiting GPAT1 activity, highlighting the potential of targeting AKAP1/PKA/GPAT1 signalosome for MASLD therapy.

2025-05-26 | PXD062388 | Pride

Effect of hepatocytic RKIP depletion on HFD-induced MASLD

Project description:High-fat diet (HFD) is a risk factor for metabolic dysfunction-associated steatotic liver disease (MASLD), yet the molecular pathways that connect dietary fats to liver dysfunction remain unclear. Hepatocyte-specific RKIP depletion in male mice exacerbates ER stress, resulting in lipid droplets accumulation and MASLD progression.

2025-09-03 | GSE300123 | GEO

E2F2 transcription factor promotes a cholestatic MASH phenotype by regulating hepatobiliary metabolism through miR-34a-5p

Project description:Background and Aims: Metabolic dysfunction–associated steatotic liver disease (MASLD) affects a heterogeneous group of patients. Among them, those with a cholestatic profile show worse outcomes. Here, we investigated whether E2F2 is involved in MASLD-associated cholestasis and, if so, the role of miRNAs. Methods: E2f2-knockout (E2f2 AQ5 −/−) and wild-type (WT) mice were fed a cholinedeficient high-fat diet (ChD-HFD) or an HFD after injection of diethylnitrosamine (DEN-HFD) to induce metabolic dysfunction–associated steatohepatitis (MASH). E2F2 was overexpressed in the liver by AAV8. Cholestasis was induced by bile duct ligation or by a 3,5-diethoxycarbonyl-1,4-dihydrocollidine-enriched diet. MicroRNA sequencing was performed. Two biopsy-proven MASLD patient cohorts were used. Results: E2F2 deficiency resulted in increased synthesis and excretion of cholesterol, phosphatidylcholine, and bile acids, reducing their storage in the liver while increasing their presence in feces. This was consistent with increased expression of genes involved in biliary lipid metabolism, reduced inflammation and fibrosis, and the generation of a distinct miRNA profile, thereby preventing MASH. Liver-specific induction of E2F2 in vivo hampered the transcriptional program involved in biliary lipid metabolism and upregulated miR-34a-5p, which was downregulated in E2f2−/− mice. The protective effects observed in E2f2−/− mice were lost when a miR-34a-5p mimic was used. Hepatic miR-34a-5p levels were elevated in patients with advanced fibrosis, inflammation, steatosis score, cholelithiasis, and increased serum bile acids and biliary lipids. E2f2 deficiency conferred protection against cholestatic liver injury. Conclusions: E2F2 deficiency protects against MASH and cholestasis, preventing cholesterol accumulation, fibrosis, and inflammation through modulation ofmiR- 34a-5p. This could provide therapeutic benefits for patients with cholestatic MASH.

2025-08-21 | GSE276277 | GEO

Liver-Targeted siRNA Therapy Reveals a Causal Role of Metabolic Dysfunction-Associated Steatotic Liver Disease in Brain Dysfunction

Project description:Metabolic-dysfunction-associated steatotic liver disease (MASLD) has traditionally been studied as a liver-centric condition. However, growing clinical and experimental evidence reveals a strong link between MASLD and cognitive impairment and sensorimotor alterations. The mechanisms underlying this liver-brain axis remain poorly defined, and whether hepatic dysfunction alone is sufficient to drive central nervous system deficits is unclear. Using diet-induced non-obese mouse models of MASLD, we performed comprehensive neurocognitive and behavioral assessments. MASLD was associated with marked alterations in social memory, sensorimotor processing, and hippocampal function, including decreased parvalbumin-positive interneurons, reduced dendritic spine density, and diminished indicators of neurogenesis in the hippocampal dentate gyrus. Then, we selectively modulated liver metabolism through a hepatocyte-targeted siRNA therapy against Cyclin M4 (CNNM4), a magnesium transporter dysregulated in MASLD, employing GalNAc-siRNA technology for targeted delivery. Notably, liver-specific intervention with siRNA-CNNM4 reversed features of impaired social memory and sensorimotor processing through recovery of hippocampal synaptogenesis and mitochondrial function pathways, alongside activation of neurogenesis-associated transcriptional programs. Our findings demonstrate that liver pathology is sufficient to drive neurobehavioral and hippocampal dysfunction in MASLD. Importantly, hepatic-specific intervention restores brain function, strongly supporting the existence of a causal and therapeutically targetable liver-brain axis. These results open new avenues for treating MASLD-associated neurological complications through liver-directed therapies.

2025-09-22 | PXD063321 | Pride

From LAL-D to MASLD: Insights into the role of LAL and Kupffer cells in liver inflammation and lipid metabolism

Project description:Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent liver pathology worldwide, closely associated with obesity and metabolic disorders. Increasing evidence suggests that macrophages play a crucial role in the development of MASLD. Several human studies have shown an inverse correlation between circulating lysosomal acid lipase (LAL) activity and MASLD. LAL is the sole enzyme known to degrade cholesteryl esters (CE) and triacylglycerols in lysosomes. Consequently, these substrates accumulate when their enzymatic degradation is impaired due to LAL deficiency (LAL-D). This study aimed to investigate the role of hepatic LAL activity and liver-resident macrophages (i.e., Kupffer cells (KC)) in MASLD. To this end, we analyzed lipid metabolism in hepatocyte-specific (hep)Lal-/- mice and depleted KC with clodronate treatment. When fed a high-fat/high-cholesterol diet (HF/HCD), hepLal-/- mice exhibited CE accumulation and an increased number of macrophages in the liver without significantly affecting liver injury. KC were depleted upon clodronate administration, whereas infiltrating/proliferating CD68-expressing macrophages were less affected. This led to exacerbated hepatic CE accumulation and dyslipidemia, as evidenced by increased LDL-cholesterol concentrations. The results suggest that hepatic LAL-D in HF/HCD-fed mice leads to macrophage infiltration into the liver, and KC depletion further aggravates hepatic CE levels and dyslipidemia, a finding also supported by our proteomics analysis.

2024-12-01 | PXD056343 | Pride

Complementary gene regulation by NRF1 and NRF2 safeguard hepatic cholesterol detoxification

Project description:Metabolic-associated steatohepatitis is a progressive fatty liver disease caused, in part, by hepatocyte stress linked to cholesterol overload. Counteracting this stress may be beneficial but there is insufficient understanding of underlying stress defenses to develop a therapeutic strategy. Here, we aimed to elucidate how stress-adaptive transcription factors, nuclear factor erythroid 2 related factor-1 (NRF1) and -2 (NRF2), counteract hepatic cholesterol overload and determine whether they function cooperatively. C57bl/6 mice were fed high fat, fructose, and cholesterol diet (HFFC). Expression profiling and phenotypic analyses were done on liver of mice with adult-onset and hepatocyte-specific deficiency of NRF1, NRF2, or both, and results compared to control. Chromatin immunoprecipitation (ChIP) sequencing was done and combined with expression profiles to identify genes that NRF1 and NRF2 interact with and regulate in vivo. Three weeks HFFC diet feeding to mice with NRF1 and NRF2 deficiency caused severe steatohepatitis and increased hepatic cholesterol storage. These outcomes did not occur in single gene-deficient mice or control. Expression profiling at a time preceding hepatic cholesterol overload and ChIP sequencing profiling revealed complementary gene regulation by NRF1 and NRF2 to promote cholesterol excretion and mitigate hazardous metabolic biproducts generated from converting cholesterol to bile acid. Consequently, combined gene deficiency, and not single-gene deficiency, increased liver oxidized protein level, decreased cholesterol in bile, and increased unconjugated bile acid in liver and bile. We discover, for the first time, that NRF1 and NRF2 work together to protect liver against damaging effects of excess cholesterol. Targeting these combined actions may prove an effective therapeutic strategy

2023-03-22 | PXD032069 | Pride

Coagulation protease-activated receptor-2 (PAR2) promotes dyslipidemia, obesity and MASLD through suppression of a hepatic pioneer factor HNF4a

Project description:MASLD and its more severe version, MASH, are attributable to metabolic dysfunction and are associated with cardiometabolic disease, atherothrombosis, and obesity. The exact pathophysiological mechanisms linking MASLD and CVD have yet to be elucidated but share common metabolic abnormalities that could interact synergistically to increase the risk of both heart disease and liver disease. Protease-activated receptor 2 (PAR2), a receptor activated by prothrombotic coagulation proteases that are dysregulated in inflammatory and fibrotic diseases, is emerging as a new drug target for MASH. Using patient samples, we discovered that expression of liver PAR2 is increased in the livers of obese patients with MASLD and MASH.To address the direct contribution of hepatocyte PAR2 to progression of MASLD and obesity, we fed hepatocyte-specific PAR2 knockout mice(PAR2dHep), whole-body PAR2-deficient mice(PAR2 KO), and control floxed WT mice(PAR2fl/fl) high-fat diet and conducted metabolic, biochemical and RNA-seq analyses. Hepatocyte-specific deletion of PAR2 caused a reduction in body weight and significantly lowered triglycerides and cholesterol levels in plasma and livers of mice fed high-fat diet. Analysis of bulk liver RNA seq data showed that global or hepatocyte-specific deletion of PAR2 resulted in significant improvements in fatty acid metabolic and reverse cholesterol transport pathways in liver.These data provide support that targeting hepatic PAR2 may potentially provide broad liver and cardiometabolic benefits to patients with MASLD and MASH.

2026-05-20 | GSE319296 | GEO

Loss of PPARα function promotes epigenetic dysregulation of lipid homeostasis driving ferroptosis and pyroptosis lipotoxicity in Metabolic Dysfunction Associated Steatotic Liver Disease (MASLD) [MouseMethylation]

Project description:Metabolic Dysfunction Associated Steatotic Liver Disease (MASLD) is a growing epidemic with an estimated prevalence of 20‑30% in Europe and the most common cause of chronic liver disease worldwide. The onset and progression of MASLD are orchestrated by an interplay of the metabolic environment with genetic and epigenetic factors. Emerging evidence suggests altered DNA methylation pattern as a major determinant of MASLD pathogenesis coinciding with progressive DNA hypermethylation and gene silencing of the liver‑specific nuclear receptor PPARα, a key regulator of lipid metabolism. To investigate how PPARα loss of function contributes to epigenetic dysregulation in MASLD pathology, we studied DNA methylation changes in liver biopsies of WT and hepatocyte‑specific PPARα KO mice, following a 6‑week CDAHFD (choline-deficient, L-amino acid-defined, high-fat diet) or chow diet. Interestingly, genetic loss of PPARα function in hepatocyte‑specific KO mice could be phenocopied by a 6-week CDAHFD diet in WT mice which promotes epigenetic silencing of PPARα function via DNA hypermethylation, similar to MASLD pathology. Remarkably, genetic and lipid diet‑induced loss of PPARα function triggers compensatory activation of multiple lipid sensing transcription factors and epigenetic writer-eraser-reader proteins, which promotes the epigenetic transition from lipid metabolic stress towards ferroptosis and pyroptosis lipid hepatoxicity pathways associated with advanced MASLD. In conclusion, we show that PPARα function is essential to support lipid homeostasis and to suppress the epigenetic progression of ferroptosis‑pyroptosis lipid damage associated pathways towards MASLD fibrosis.

2024-03-01 | GSE238173 | GEO

Project description:Metabolic Dysfunction Associated Steatotic Liver Disease (MASLD) is a growing epidemic with an estimated prevalence of 20‑30% in Europe and the most common cause of chronic liver disease worldwide. The onset and progression of MASLD are orchestrated by an interplay of the metabolic environment with genetic and epigenetic factors. Emerging evidence suggests altered DNA methylation pattern as a major determinant of MASLD pathogenesis coinciding with progressive DNA hypermethylation and gene silencing of the liver‑specific nuclear receptor PPARα, a key regulator of lipid metabolism. To investigate how PPARα loss of function contributes to epigenetic dysregulation in MASLD pathology, we studied transcriptome profile changes that could induce changes in DNA methylation in liver biopsies of WT and hepatocyte‑specific PPARα KO mice, following a 6‑week CDAHFD (choline-deficient, L-amino acid-defined, high-fat diet) or chow diet. Interestingly, genetic loss of PPARα function in hepatocyte‑specific KO mice could be phenocopied by a 6-week CDAHFD diet in WT mice which promotes epigenetic silencing of PPARα function via DNA hypermethylation, similar to MASLD pathology. Remarkably, genetic and lipid diet‑induced loss of PPARα function triggers compensatory transcription of multiple lipid sensing transcription factors and epigenetic writer-eraser-reader proteins, which promotes the epigenetic transition from lipid metabolic stress towards ferroptosis and pyroptosis lipid hepatoxicity pathways associated with advanced MASLD. In conclusion, we show that PPARα function is essential to support lipid homeostasis and to suppress the epigenetic progression of ferroptosis‑pyroptosis lipid damage associated pathways towards MASLD fibrosis.

2024-03-01 | GSE238201 | GEO

The Mechanism by which HIF-2a Promotes MASLD

Project description:Metabolic dysfunction-associated steatotic liver disease (MASLD) is characterized by imbalance of lipid metabolism and autoimmune inflammation. The relationship between Hypoxia-inducible Factor 2α (HIF-2α) and the progression of MASLD has been well-documented. However, the mechanistic linkage between HIF-2α and steatohepatitis progression remains largely elusive. Here, hepatocyte-specific HIF-2α knockout mice were used to identify underlying pathophysiological relevance in MASLD. Through multiple gain- and loss-of-function experiments in primary hepatocytes and established human hepatocyte cell lines to investigate the molecular mechanism of HIF-2α in MASLD progression. Compared to their wild-type littermates, hepatocyte-specific HIF-2α knockout mice exhibited a substantial reduction in hepatic steatosis and inflammatory pathway induced by high fat diet (HFD). Furthermore, the HIF-2ɑ deficiency in primary hepatocytes and both L02 and MIHA cell lines markedly inhibited the lipid accumulation, inflammation and endoplasmic reticulum stress in vitro under FFAs challenge. Mechanistically, HIF-2 directly bound to the promoter region of protein kinase RNA-like ER kinase (PERK), leading to the activation of the activating transcription Factor 4 (ATF4) signaling under metabolic stress, thereby aggravating lipogenesis while inhibiting lipid oxidation in hepatocytes.These data indicate that HIF-2α acts as a contributing factor to MASLD progression via ATF4 signaling.

2025-12-10 | GSE267155 | GEO

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