Experimental and clinical transplantation : official journal of the Middle East Society for Organ Transplantation · 2025
Lipid Droplet Dynamics in Hepatocytes During Lipotoxic Stress: Transition From Fatty Liver to Liver Transplantation.
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Baysan Cebi H Pinar, Erbas Deniz Ekin, Bascil Tutuncu Neslihan, Yalcin Yaprak, Verdi Hasibe, Kaymaz F Figen, Atac F Belgin
Аннотация
OBJECTIVES: Metabolic dysfunction-associated steatotic liver disease, the most common chronic liver disease worldwide, is a major cause of end-stage liver failure requiring transplant. Its hallmark, free fatty acid accumulation in hepatocytes, leads to lipotoxicity. We examined lipid droplet and mitochondrial changes in HepG2 cells under lipotoxic conditions.
MATERIALS AND METHODS: Lipotoxic stress was induced in HepG2 cells (ATCC HB8065) by treating cells with 1 mM palmitic acid. We studied cells at 0, 12, and 24 hours. Cells were fixed in 2.5% glutaraldehyde (pH 7.4), postfixed with 1% osmium tetroxide in 0.1 M phosphate buffer, dehydrated in ethanol, and embedded in Araldite/Epon812 resin. We prepared sections by using a microtome. Semi-thin sections were stained with methylene blue-azure II and analyzed with light microscopy. Ultrathin sections were double-stained with uranyl acetate and lead citrate and examined with a JEOL-JEM 1400 electron microscope with a charge-coupled device camera. We observed substantial mitochondrial and cellular alterations associated with palmitic acid-induced lipotoxic stress.
RESULTS: When morphological changes in HepG2 cells were analyzed at 0, 12, and 24 hours, treatment with palmitic acid caused substantial stress in HepG2 cells, with the most noticeable effects observed at 24 hours. Morphological analysis indicated increased lipid vacuoles by 12 hours posttreatment compared with at 0 hours (baseline). Structural changes in mitochondria, such as enlargement and elongation, were also noted. After 24 hours, the number of mitochondria and lipid vacuoles had further increased, showing clear signs of mitophagy, indicating activation of protective hepatocellular mechanisms to address organelle stress caused by lipotoxicity.
CONCLUSIONS: Palmitic acid-induced lipotoxicity activates mitophagy, which is crucial for mitigating cellular damage and maintaining hepatocyte homeostasis. Targeting mitophagy may restore mitochondrial function, alleviate lipotoxic stress, and delay transplant in metabolic liver diseases.
MATERIALS AND METHODS: Lipotoxic stress was induced in HepG2 cells (ATCC HB8065) by treating cells with 1 mM palmitic acid. We studied cells at 0, 12, and 24 hours. Cells were fixed in 2.5% glutaraldehyde (pH 7.4), postfixed with 1% osmium tetroxide in 0.1 M phosphate buffer, dehydrated in ethanol, and embedded in Araldite/Epon812 resin. We prepared sections by using a microtome. Semi-thin sections were stained with methylene blue-azure II and analyzed with light microscopy. Ultrathin sections were double-stained with uranyl acetate and lead citrate and examined with a JEOL-JEM 1400 electron microscope with a charge-coupled device camera. We observed substantial mitochondrial and cellular alterations associated with palmitic acid-induced lipotoxic stress.
RESULTS: When morphological changes in HepG2 cells were analyzed at 0, 12, and 24 hours, treatment with palmitic acid caused substantial stress in HepG2 cells, with the most noticeable effects observed at 24 hours. Morphological analysis indicated increased lipid vacuoles by 12 hours posttreatment compared with at 0 hours (baseline). Structural changes in mitochondria, such as enlargement and elongation, were also noted. After 24 hours, the number of mitochondria and lipid vacuoles had further increased, showing clear signs of mitophagy, indicating activation of protective hepatocellular mechanisms to address organelle stress caused by lipotoxicity.
CONCLUSIONS: Palmitic acid-induced lipotoxicity activates mitophagy, which is crucial for mitigating cellular damage and maintaining hepatocyte homeostasis. Targeting mitophagy may restore mitochondrial function, alleviate lipotoxic stress, and delay transplant in metabolic liver diseases.