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Western Diet induces MASLD and major transcriptional reprogramming in the liver-gut axis of early zebrafish larvae

ABSTRACT: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a common condition associated with western diet and sedentary lifestyle. Larval zebrafish is widely used as disease model and drug testing platform for liver diseases. Here, it was aimed to generate MASLD model of zebrafish at an early developmental stage of 9 – 12 dpf, by feeding larvae with high fat high cholesterol egg yolk (BEY) or custom designed palmitate, cholesterol and fructose rich, low fiber western diet (WD) and different diets. Diet induced fat accumulation and histopathological changes in gut-liver axis were defined in a time dependent manner. Whole organism level transcriptomic changes were determined with a bulk sequencing approach, that enabled comparison across diets and time points in an affordable manner. Both diets induced an upregulation of lipid/cholesterol transport genetic signatures. Interestingly cholesterol biosynthesis was activated in BEY fed larvae, while it was suppressed in WD-fed larvae. WD diet suppressed lipid synthesis and oxidoreductase activity gene signatures, activated a large network of ribosome biogenesis and translation genes, and suppressed cell cycle in the organism. Cyp7a1 was induced upon egg yolk feeding while it was suppressed in the WD group. WD diet induced lipid droplet formation in the intestinal tissue, as well as structural changes. This study provides an elaborate investigation of western diet induced zebrafish MASLD model by reflecting structural alterations in the liver-gut axis and important gene expression. It features western diet as an effective inducer of early larval MASLD.

ORGANISM(S): Danio rerio

PROVIDER: GSE334507 | GEO | 2026/09/01

REPOSITORIES: GEO

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Project description:Metabolic dysfunction-associated steatotic liver disease (MASLD) is a leading cause of hepatocellular carcinoma (HCC), particularly in obesity, yet mechanisms linking hepatocyte dysfunction to tumorigenesis remain unclear. Mixed lineage kinase domain-like protein (MLKL), the effector of necroptosis, is elevated in MASLD, but its hepatocyte-intrinsic role in obesity-driven MASLD-HCC is unknown. Using a long-term Western diet (WD)-induced MASLD-HCC model in hepatocyte-specific MLKL knockout (MlklHepKO) mice, we defined MLKL’s hepatocyte-intrinsic function. WD increased hepatocyte MLKL protein expression without detectable necroptosis activation, indicating a necroptosis-independent role. MLKL deficiency did not alter WD-induced inflammation, fibrosis, or liver injury but increased hepatic lipid accumulation while reducing lipotoxic lipid species and preserving mitochondrial function. WD-fed MlklHepKO mice developed fewer and smaller tumors with reduced incidence, multiplicity, proliferation, and stemness. Transcriptomic analysis revealed upregulation of mitochondrial oxidative phosphorylation pathways in MlklHepKO livers. WD suppressed the mitochondrial fusion protein and tumor suppressor MFN2, whereas MLKL deficiency restored MFN2 expression post-translationally. In HCC cells, MLKL deletion reduced proliferation, improved mitochondrial respiration, and decreased glycolysis; these effects were reversed by MFN2 deletion. MLKL localized to nuclear and mitochondrial compartments, consistent with organelle-intrinsic functions. The human MLKL inhibitor necrosulfonamide (NSA) suppressed HepG2 xenograft growth, and elevated MLKL expression in human HCC correlated with poorer overall survival. Hepatocyte MLKL promotes MASLD-associated HCC through a non-canonical, RIPK3-independent mechanism involving MFN2 suppression, impaired mitochondrial function, and increased tumor proliferation and stemness. These findings identify MLKL as a potential therapeutic target in MASLD-associated HCC.

Project description:Background and aims Metabolic dysfunction-associated steatotic liver disease (MASLD), the most prevalent liver disease worldwide, continues to rise. More effective therapeutic strategies are urgently needed. We investigated how targeting two key nuclear receptors involved in hepatic energy metabolism, peroxisome proliferator-activated receptor alpha (PPARα) and estrogen-related receptor alpha (ERRα), ameliorates MASLD. Methods The PPARα agonist pemafibrate and/or ERRα inverse agonist C29 were administered in a short- and long-term Western diet plus fructose model, and a diabetic-background streptozotocin-Western diet model (STZ-WD). Liver and adipose tissue morphology, histological samples, serum metabolites, RNA and protein levels were analysed and scanning electron microscopy was performed. In addition, we performed cell-based assays and immunohistochemistry and immunofluorescence stainings with light and super-resolution confocal microscopy of healthy, MASLD and MASH human livers. Results The ligand combinations' efficacy was highlighted by reduced liver steatosis across all mouse models, alongside improvements in body weight, inflammation, and fibrosis in both long-term models. Additionally, tumour formation was prevented in the STZ-WD mice model. Cell-based assays demonstrated that ERRα inhibits PPARα's activity, explaining why ERRα blockage improves inflammatory and lipid metabolism gene profiles and enhances lipid-lowering effects. Complementary RNA sequencing and shotgun proteomics, combined with enrichment analysis, jointly identified downregulated serum amyloid A1/A2 as essential components underlying the combination treatment's effectiveness. MASLD/MASH patient livers showed reduced PPARα and increased ERRα levels supporting disrupted NR crosstalk in the hepatocyte nucleus. Conclusion Our study supports that dual nuclear receptor targeting, which simultaneously increases PPARα and diminishes ERRα activity, may represent a viable novel strategy against MASLD.

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Western Diet induces MASLD and major transcriptional reprogramming in the liver-gut axis of early zebrafish larvae

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