This is a mechanism module, not a specific disease. Disorder entries reference individual nodes via conforms_to (e.g., "hepatic_steatosis_lipotoxicity#Lipotoxic Stress and Organelle Dysfunction"). The fibrosis arm of this module connects conceptually to the fibrotic_response module: a conforming hepatic disorder node may declare conformance both to this module's "Hepatic Stellate Cell Activation and Fibrosis" node and to "fibrotic_response#Mesenchymal Cell Activation". Key organ-specific cell types are fixed (liver): hepatocyte (CL:0000182), Kupffer cell/macrophage (CL:0000091/CL:0000235), and hepatic stellate cell (CL:0000632). Conforming disorder nodes substitute the disorder-specific initiating insult (overnutrition/insulin resistance in MASLD, ethanol metabolism in alcohol-associated disease, PNPLA3/TM6SF2 retention defects in genetic forms) while preserving the conserved chain.
Hepatocyte Lipid Overload
trigger
Hepatocyte intracellular lipid accumulates when the inflow of free fatty acids (from adipose lipolysis and dietary fat) plus de novo lipogenesis exceeds the capacity for fatty acid oxidation and very-low-density lipoprotein export. The resulting triglyceride accumulation in lipid droplets defines steatosis. This initiating imbalance is shared across metabolic, alcoholic, and genetic forms of steatotic liver disease.
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Lipotoxic Stress and Organelle Dysfunction
Lipotoxic Stress and Organelle Dysfunction
amplifier
Beyond inert triglyceride storage, the accumulation of toxic non-triglyceride lipid species (e.g., diacylglycerols, ceramides, free fatty acid metabolites) drives lipotoxicity. These metabolites induce endoplasmic reticulum stress, mitochondrial dysfunction, and accumulation of reactive oxygen species, sensitizing the hepatocyte to injury. This is the amplification step that converts simple steatosis toward steatohepatitis.
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Hepatocyte Injury and Inflammatory Activation
Hepatocyte Injury and Inflammatory Activation
central effector
Lipotoxic hepatocytes undergo apoptosis and other forms of regulated cell death, releasing damage signals that activate Kupffer cells and recruited macrophages. The resulting inflammatory response, with inflammasome activation and pro-inflammatory cytokine release, defines the transition from bland steatosis to steatohepatitis and is the central effector step of progressive liver injury.
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Hepatic Stellate Cell Activation and Fibrosis
Hepatic Stellate Cell Activation and Fibrosis
effector
Sustained hepatocyte injury and macrophage-driven inflammation activate hepatic stellate cells, which transdifferentiate into myofibroblast-like cells that deposit excessive extracellular matrix. This is the fibrotic effector arm of steatotic liver disease and connects conceptually to the conserved fibrotic_response module, with hepatic stellate cells serving as the organ-specific mesenchymal precursor.
Downstream
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Hepatic Steatosis Progressing to Steatohepatitis and Fibrosis
Hepatic Steatosis Progressing to Steatohepatitis and Fibrosis
consequence
The convergent outcome is the hepatic steatosis phenotype (fatty liver disease) and its progression: bland steatosis can advance to steatohepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma. This final node represents the disease-like phenotype of hepatic steatosis and its progressive sequelae shared across metabolic, alcoholic, and genetic forms of steatotic liver disease.