ArticleMetabolism: clinical and experimental2014
Palmitate-induced activation of mitochondrial metabolism promotes oxidative stress and apoptosis in H4IIEC3 rat hepatocytes.
Article in Metabolism: clinical and experimental, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 86 papers.
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Who cites it
86 citing papers in PubMed, 159 citations in OpenAlex.
- Treatment with saponins fromNutrition research and practice · 2026Article
- Advances in Lipid Metabolism Reprogramming in Hepatocellular Carcinoma.Journal of clinical and translational hepatology · 2026Review
- Short-, medium-, versus long-chain fatty acids: mechanisms of immunomodulation and disease pathogenesis.Cellular & molecular immunology · 2026Review
- Palmitate and oleate differentially regulate oxidative stress and drug resistance markers in steatotic HepG2 cells.Molecular biology reports · 2026Article
- The HepG2 Cell Line as a Model for Studying Metabolic Dysfunction-Associated Steatotic Liver Disease.International journal of molecular sciences · 2026Review
- Polymer-lipid hybrid nanoparticles incorporating green coffee extract: enhancing treatment for hepatic steatosis and fibrosis through metabolomic insights.RSC advances · 2025Article
- ZFHX3 Knockdown Enhances Metabolic Distress in Atrial Myocytes Through Mitochondrial and Calcium Dysregulation: Mitigation by Trimetazidine.International journal of molecular sciences · 2025Article
- Role of amino acids in the regulation of hepatic gluconeogenesis and lipogenesis in metabolic dysfunctionassociated steatotic liver disease.Clinical and molecular hepatology · 2025Review
- Ferroptosis in Hypertriglyceridemic Acute Pancreatitis: Mechanisms and Therapeutic Implications.Journal of inflammation research · 2025Review
- The triglyceride-glucose index is associated with coronary plaque features and clinical outcomes in patients with ST-segment elevation myocardial infarction.Frontiers in endocrinology · 2025Article
- Extracellular vesicles released from microglia after palmitate exposure impact brain function.Journal of neuroinflammation · 2024Article
- Metabolic Fluxes in the Renal Cortex Are Dysregulated In Vivo in Response to High-Fat Diet.Diabetes · 2024Article
- Mechanism of Obesity-Related Lipotoxicity and Clinical Perspective.Advances in experimental medicine and biology · 2024Review
- Reconstituting gut microbiota-colonocyte interactions reverses diet-induced cognitive deficits: The beneficial ofTheranostics · 2024Article
- Impact of Chromium Picolinate on Leydig Cell Steroidogenesis and Antioxidant Balance Using an In Vitro Insulin Resistance Model.Antioxidants (Basel, Switzerland) · 2023Article
- Hepatoprotective Mechanisms Induced by Spinach Methanolic Extract in Rats with Hyperglycemia-An Immunohistochemical Analysis.Antioxidants (Basel, Switzerland) · 2023Article
- The Coumarin-Derivative Esculetin Protects against Lipotoxicity in Primary Rat Hepatocytes via Attenuating JNK-Mediated Oxidative Stress and Attenuates Free Fatty Acid-Induced Lipid Accumulation.Antioxidants (Basel, Switzerland) · 2023Article
- Iron oxide nanoparticles trigger endoplasmic reticulum damage in steatotic hepatic cells.Nanoscale advances · 2023Article
- Role of Oxidative Stress on Insulin Resistance in Diet-Induced Obesity Mice.International journal of molecular sciences · 2023Article
- Effect of Lard or Plus Soybean Oil on Markers of Liver Function in Healthy Subjects: A Randomized Controlled-Feeding Trial.Foods (Basel, Switzerland) · 2023Article
26 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
5 authors at 2 institutions in 2 countries.
Funding
Abstract
objectiveHepatic lipotoxicity is characterized by reactive oxygen species (ROS) accumulation, mitochondrial dysfunction, and excessive apoptosis, but the precise sequence of biochemical events leading to oxidative damage and cell death remains unclear. The goal of this study was to delineate the role of mitochondrial metabolism in mediating hepatocyte lipotoxicity. MATERIALS/
methodsWe treated H4IIEC3 rat hepatoma cells with free fatty acids in combination with antioxidants and mitochondrial inhibitors designed to block key events in the progression toward apoptosis. We then applied (13)C metabolic flux analysis (MFA) to quantify mitochondrial pathway alterations associated with these treatments.
resultsTreatment with palmitate alone led to a doubling in oxygen uptake rate and in most mitochondrial fluxes. Supplementing culture media with the antioxidant N-acetyl-cysteine (NAC) reduced ROS accumulation and caspase activation and partially restored cell viability. However, (13)C MFA revealed that treatment with NAC did not normalize palmitate-induced metabolic alterations, indicating that neither elevated ROS nor downstream apoptotic events contributed to mitochondrial activation. To directly limit mitochondrial metabolism, the complex I inhibitor phenformin was added to cells treated with palmitate. Phenformin addition eliminated abnormal ROS accumulation, prevented the appearance of apoptotic markers, and normalized mitochondrial carbon flow. Further studies revealed that glutamine provided the primary fuel for elevated mitochondrial metabolism in the presence of palmitate, rather than fatty acid beta-oxidation, and that glutamine consumption could be reduced through co-treatment with phenformin but not NAC.
conclusionOur results indicate that ROS accumulation in palmitate-treated H4IIEC3 cells occurs downstream of altered mitochondrial oxidative metabolism, which is independent of beta-oxidation and precedes apoptosis initiation.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.