Glucose fluctuation increased hepatocyte apoptosis under lipotoxicity and the involvement of mitochondrial permeability transition opening
Open accessAbstract
Oxidative stress is considered to be an important factor in producing lethal hepatocyte injury associated with nonalcoholic fatty liver disease (NAFLD). Glucose fluctuation, more pronounced in patients with diabetes, has been recognized as an even stronger oxidative stress inducer than the sustained hyperglycemia. Here, we investigated the role of glucose variability in the development of the NAFLD based on hepatocyte apoptosis and possible mechanisms. To achieve this goal we studied C57BL/6J mice that were maintained on a high fat diet (HFD) and injected with glucose (3 g/kg) twice daily to induce intermittent high glucose (IHG). We also studied hepatic L02 cells incubated with palmitic acid (PA) to induce steatosis. The following experimental groups were compared: normal glucose (NG), sustained high glucose (SHG) and IHG with or without PA. We found that, although hepatic enzyme levels and liver lipid deposition were comparable between HFD mice injected with glucose or saline, the glucose injected mice displayed marked hepatocyte apoptosis and inflammation, accompanied by increased lipid peroxide in liver. In vitro , in the presence of PA, IHG increased L02 cell apoptosis and oxidative stress and produced pronounced mitochondrial dysfunction relative to the NG and SHG groups. Furthermore, treatment with the mitochondrial permeability transition (MPT) inhibitor, cyclosporin A (1.5 μmol/l), prevented mitochondrial dysfunction, oxidative stress and hepatocyte apoptosis. Our data suggests that IHG under lipotoxicity might contribute to the development of NAFLD by increasing oxidative stress and hepatocyte apoptosis via MPT and its related mitochondrial dysfunction.
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Accumulation of fatty acids leads to collapse of the mitochondrial membrane potential, cessation of electron transport and subsequent activation of pro-apoptotic signalling via factors such as TNFα and NF-κB.
“Accumulation of fatty acids leads to the collapse of the mitochondrial membrane potential, cessation of electron transport and subsequent activation of pro-apoptotic signalling via factors such as tumour necrosis factor (TNF)α and NF-κB (the latter having both pro and anti-apoptotic potential).25,26”
From Understanding the cellular interactome of non-alcoholic fatty liver disease (2022) · cites this paper as [26]
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Understanding the cellular interactome of non-alcoholic fatty liver disease
Wallace, S. J., Tacke, F., Schwabe, R. F., & Henderson, N. C. (2022) · JHEP Reports · doi:10.1016/j.jhepr.2022.100524 · Cited by 116 · see citing works
- Authors
- Yin, X., Zheng, F., Pan, Q., Zhang, S., Yu, D., Xu, Z., & Li, H.
- Affiliations
- Sir Run Run Shaw Hospital (CN)
- Venue
- Journal of Molecular Endocrinology
- Publisher
- Bioscientifica
- Published
- 2015-12
- Volume
- 55
- Issue
- 3
- Pages
- 169-181
- ISSN
- 0952-5041 (ISSN-L)
- 1479-6813
- OpenAlex
- W2243636450
- Cited by
- 67
- References
- 48
- Citations by year
- 2026: 2 · 2025: 5 · 2024: 7 · 2023: 7 · 2022: 5 · 2021: 11 · 2020: 7 · 2019: 9 · 2018: 3 · 2017: 7 · 2016: 4
- FWCI
- 3.67
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Molecular Endocrinology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Sir Run Run Shaw Hospital
- National Natural Science Foundation of China (81471099, 81270924)
- Zhejiang University
- Topics
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
- Keywords
- glucose fluctuations, intermittent high glucose, hepatocyte apoptosis, non-alcoholic fatty liver disease, lipotoxicity, mitochondrial permeability transition, cyclosporine, oxidative stress, mitochondrial dysfunction, palmitic acid, hepatic steatosis, lipid peroxidation, liver inflammation, high-fat diet
- MeSH terms
- Animals, Blood Glucose, Body Weight, Disease Models, Animal, Fibrosis, Glucose, Inflammation, Liver Function Tests, Male, Mitochondria, Permeability, Superoxides, Apoptosis, Reactive Oxygen Species, Oxidative Stress, Hepatocytes, Lipid Metabolism, Mice, Membrane Potential, Mitochondrial, Non-alcoholic Fatty Liver Disease
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