Biology subjects

Youhanna, S.

Publications and source records attributed to Youhanna, S..

5 recordsLinked to original sources

bioRxiv2026

Nicotinamide N-methyltransferase couples inflammation and epigenetic remodelling to hepatic fibrosis

Background & aimsChronic inflammation is a key driver of progression from benign steatosis to metabolic dysfunction-associated steatohepatitis (MASH) and liver fibrosis. The molecular mechanisms coupling inflammatory cytokine signaling to altered hepatocyte remodeling remain incompletely understood. Here, we report that nicotinamide N-methyltransferase (NNMT) is induced by specific inflammatory cytokines in hepatocytes and acts as a key hub to connect inflammation with fibrotic liver remodeling. Approach & resultsTranscriptomic profiling of primary human hepatocytes and human hepatoma cell lines identified NNMT as a selective downstream target of IL-1{beta} and IL-6, but not of TNF. Genetic silencing of NNMT markedly attenuated cytokine-induced inflammatory and fibrotic gene expression programs and partially reversed IL-6-mediated sensitization of IL-1{beta} responses. Integration of RNA-seq with ChIP-seq, CUT&Tag, and ATAC-seq revealed that inflammatory cytokines remodel the hepatocyte epigenome through coordinated changes in histone modifications. NNMT overexpression promoted selective remodeling of H3K4me2 chromatin landscapes, accompanied by activation of fibrosis-associated transcriptional programs. Nicotinamide supplementation partially suppressed inflammatory gene expression, supporting a role of NNMT-dependent NAD+ metabolism in this process. Importantly, cytokine-induced NNMT expression and its associated transcriptional program were conserved in primary human hepatocytes and 3D liver microtissues. ConclusionsNNMT functions as an inflammatory cytokine-inducible metabolic- epigenetic integrator that links IL-1{beta} and IL-6 signaling to chromatin remodeling and inflammatory transcriptional reprogramming in hepatocytes. These findings identify NNMT as a key regulator of inflammatory and profibrotic responses during MASLD progression and highlight NNMT as a potential therapeutic target for limiting liver inflammation and fibrosis. Impact and ImplicationsThis study identifies NNMT as a previously unrecognized metabolic-epigenetic integrator that selectively links IL-1{beta} and IL-6 signaling to chromatin remodeling and inflammatory transcriptional reprogramming in hepatocytes. Our findings establish a non-canonical mechanistic framework by which inflammatory cytokines drive profibrotic gene expression during MASLD progression through. By uncovering NNMT as a critical mediator of inflammatory-epigenetic crosstalk, this work broadens our understanding of hepatocyte-intrinsic mechanisms underlying liver fibrosis and highlights NNMT as a promising therapeutic target for preventing the transition from steatosis to progressive MASH and fibrosis. HighlightsO_LINNMT is selectively induced by IL-1{beta} and IL-6 in hepatocytes. C_LIO_LINNMT controls fibrogenic gene expression modules. C_LIO_LIIL-6 amplifies IL-1{beta} responses through an NNMT-dependent mechanism. C_LIO_LINNMT links inflammatory signaling to epigenetic remodeling in MASLD. C_LI

molecular biology↗

bioRxiv2025

HypoxamicroRNA-210 protects against hepatic steatosis by inhibiting CIDEC expression

Background and AimsMetabolic dysfunction-associated steatotic liver disease (MASLD) is a major global health burden. Although hypoxia is known to contribute to MASLD pathogenesis, the role of hypoxia signaling remains poorly defined. We investigated whether HypoxamicroRNA-210 (miR-210), a key hypoxia-inducible microRNA, regulates hepatic lipid metabolism and MASLD development. MethodsSerum miR-210 levels were quantified in MASLD patients and matched controls. Human hepatic spheroids and HepG2 cells were exposed to fatty acids to assess miR-210 induction and lipid accumulation. miR-210 knockout mice were fed a Western diet to evaluate hepatic steatosis and transcriptomic changes using RNA sequencing. RNA pull-down and 3UTR-driven luciferase reporter assays were employed to identify miR-210 targets. Functional effects of miR-210 mimic were examined in knockout mice, db/db mice, and in vitro human hepatic spheroid models. ResultsSerum miR-210 levels were significantly reduced in MASLD patients compared with matched controls. Consistently, human hepatic spheroids did not appropriately increase miR-210 expression in response to fatty acid-induced intracellular hypoxia. This blunted miR-210 response contributed to hepatic lipid accumulation, as loss of miR-210 in a mouse model of MASLD led to increased hepatic lipid deposition and activation of lipid metabolic pathways. We identified CIDEC as a direct miR-210 target mediating its inhibitory effects on hepatic lipid accumulation, and restoring miR-210 expression suppressed CIDEC and reduced hepatic lipid content in knockout mice on a Western diet. Moreover, miR-210 attenuated lipid accumulation in both in vitro human hepatic spheroids and in vivo db/db mice models of MASLD. ConclusionsmiR-210 protects against hepatic steatosis by inhibiting CIDEC expression, suggesting miR-210-CIDEC axis as a promising therapeutic target for reducing hepatic lipid accumulation and preventing MASLD progression. Impact and ImplicationsThis study addresses a critical gap in understanding how hypoxia signaling shapes MASLD and uncovers a novel pathogenic mechanism of hepatic steatosis arising from fatty acids-induced dysregulation of miR-210. Impaired hypoxia responses, via blunted miR-210 induction, contribute to hepatic lipid accumulation through upregulation of CIDEC, a newly identified target of miR-210. These findings establish miR-210 as a novel regulator of hepatic lipid homeostasis and underscore its therapeutic potential. Interventions aimed at restoring miR-210 function in the liver may offer a promising strategy to ameliorate hepatic steatosis and prevent MASLD progression.

molecular biology↗

bioRxiv2025

Omics-based insights into human liver reveal GTPase-driven mechanisms of MASLD progression in obesity

Metabolic dysfunction-associated steatotic liver disease (MASLD) is often asymptomatic early on but can progress to irreversible conditions like cirrhosis. Due to limited access to human liver biopsies, systematic and integrative molecular resources remain scarce. In this study, we performed transcriptomic analyses on liver and metabolomic analyses on liver and plasma samples from morbidly obese individuals without liver pathology or at early-stage MASLD. While, the plasma metabolomic profile did not fully mirror liver histological features, dual-omics integration of liver samples revealed significantly remodeled lipid and amino acid metabolism pathways. Integrative network analysis uncoupled metabolic remodeling and gene expression as independent features of hepatic steatosis and fibrosis progression, respectively. Notably, GTPases and their regulators emerged as a novel class of genes linked to early liver fibrosis. This study offers a detailed molecular landscape of early MASLD in obesity and highlights potential targets of obesity-linked liver fibrosis. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=136 SRC="FIGDIR/small/632747v3_ufig1.gif" ALT="Figure 1"> View larger version (25K): org.highwire.dtl.DTLVardef@1188eborg.highwire.dtl.DTLVardef@1340070org.highwire.dtl.DTLVardef@108d560org.highwire.dtl.DTLVardef@f0adda_HPS_FORMAT_FIGEXP M_FIG C_FIG

molecular biology↗

bioRxiv2021

Cytoskeleton-extracellular matrix interaction is required to maintain mitochondrial Ca2+ control in mouse skeletal muscle fibre

Cells rapidly lose their physiological phenotype upon disruption of their extracellular matrix (ECM)-intracellular cytoskeleton interactions. Here, we investigated acute effects of ECM disruption on cellular and mitochondrial morphology, transcriptomic signatures, and Ca2+ handling in adult mouse skeletal muscle fibers. Adult skeletal muscle fibers were isolated from mouse toe muscle either by collagenase-induced dissociation of the ECM or by mechanical dissection that leaves the contiguous ECM intact. Experiments were generally performed four hours after cell isolation. At this time, there were striking differences in the gene expression patterns between fibers isolated with the two methods; 24h after cell isolation, enzymatically dissociated fibers had transcriptomic signatures resembling dystrophic phenotypes. Mitochondrial appearance was grossly similar in the two groups, but 3D electron microscopy revealed shorter and less branched mitochondria in enzymatically dissociated than in mechanically dissected fibers. Similar increases in free cytosolic [Ca2+] during repeated tetanic stimulation were accompanied by marked mitochondrial Ca2+ uptake only in enzymatically dissociated muscle fibers. The aberrant mitochondrial Ca2+ uptake was partially prevented by the mitochondrial Ca2+ uniporter inhibitor Ru360 and by cyclosporine A and NV556, which inhibit the mitochondrial protein Ppif (also called cyclophilin D). Importantly, inhibition of Ppif with NV556 significantly improved survival of mice with mitochondrial myopathy in which muscle mitochondria take up excessive amounts of Ca2+ even with an intact ECM. In conclusion, skeletal muscle fibers isolated by collagenase-induced dissociation of the ECM display aberrant mitochondrial Ca2+ uptake, which involves a Ppif-dependent mitochondrial Ca2+ influx resembling that observed in mitochondrial myopathies.

physiology↗

bioRxiv2017

Continuity and admixture in the last five millennia of Levantine history from ancient Canaanite and present-day Lebanese genome sequences

The Canaanites inhabited the Levant region during the Bronze Age and established a culture which became influential in the Near East and beyond. However, the Canaanites, unlike most other ancient Near Easterners of this period, left few surviving textual records and thus their origin and relationship to ancient and present-day populations remain unclear. In this study, we sequenced five whole-genomes from ~3,700-year-old individuals from the city of Sidon, a major Canaanite city-state on the Eastern Mediterranean coast. We also sequenced the genomes of 99 individuals from present-day Lebanon to catalogue modern Levantine genetic diversity. We find that a Bronze Age Canaanite-related ancestry was widespread in the region, shared among urban populations inhabiting the coast (Sidon) and inland populations (Jordan) who likely lived in farming societies or were pastoral nomads. This Canaanite-related ancestry derived from mixture between local Neolithic populations and eastern migrants genetically related to Chalcolithic Iranians. We estimate, using linkage-disequilibrium decay patterns, that admixture occurred 6,600-3,550 years ago, coinciding with massive population movements in the mid-Holocene triggered by aridification ~4,200 years ago. We show that present-day Lebanese derive most of their ancestry from a Canaanite-related population, which therefore implies substantial genetic continuity in the Levant since at least the Bronze Age. In addition, we find Eurasian ancestry in the Lebanese not present in Bronze Age or earlier Levantines. We estimate this Eurasian ancestry arrived in the Levant around 3,750-2,170 years ago during a period of successive conquests by distant populations such as the Persians and Macedonians.

genetics↗