ArticleJournal of cellular and molecular medicine2018
The TLR4-IRE1α pathway activation contributes to palmitate-elicited lipotoxicity in hepatocytes.
Article in Journal of cellular and molecular medicine, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed, 38 citations in OpenAlex.
- Saturated phosphatidic acids induce mTORC1-driven integrated stress response contributing to glucolipotoxicity in hepatocytes.American journal of physiology. Gastrointestinal and liver physiology · 2025Article
- Μetabolic dysfunction-associated steatotic liver disease: a condition of heterogeneous metabolic risk factors, mechanisms and comorbidities requiring holistic treatment.Nature reviews. Gastroenterology & hepatology · 2025Review
- Increasing cellular NADAmerican journal of physiology. Cell physiology · 2025Article
- Immortalized Schwann cell lines as useful tools for pathogenesis-based therapeutic approaches to diabetic peripheral neuropathy.Frontiers in endocrinology · 2024Review
- Thyroid-stimulating hormone may participate in insulin resistance by activating toll-like receptor 4 in liver tissues of subclinical hypothyroid rats.Molecular biology reports · 2023Article
- Saturated fatty acid-enriched small extracellular vesicles mediate a crosstalk inducing liver inflammation and hepatocyte insulin resistance.JHEP reports : innovation in hepatology · 2023Article
- Non-alcoholic fatty liver disease combined with rheumatoid arthritis exacerbates liver fibrosis by stimulating co-localization of PTRF and TLR4 in rats.Frontiers in pharmacology · 2023Article
- Article
- Genetic and pharmacological inhibition of XBP1 protects against APAP hepatotoxicity through the activation of autophagy.Cell death & disease · 2022Article
- Cimifugin Ameliorates Lipotoxicity-Induced Hepatocyte Damage and Steatosis through TLR4/p38 MAPK- and SIRT1-Involved Pathways.Oxidative medicine and cellular longevity · 2022Article
- Thioredoxin interacting protein, a key molecular switch between oxidative stress and sterile inflammation in cellular response.World journal of diabetes · 2021Review
- Article
- Position Statement on Fat Consumption and Cardiovascular Health - 2021.Arquivos brasileiros de cardiologia · 2021Article
- Alcohol Abstinence Rescues Hepatic Steatosis and Liver InjuryFrontiers in pharmacology · 2021Article
- Inositol-requiring enzyme 1α links palmitate-induced mTOR activation and lipotoxicity in hepatocytes.American journal of physiology. Cell physiology · 2020Article
- mTORC1-IRE1α pathway activation contributes to palmitate-elicited triglyceride secretion and cell death in hepatocytes.Experimental biology and medicine (Maywood, N.J.) · 2020Article
- TLR4-mediated pyroptosis in human hepatoma-derived HuH-7 cells induced by a branched-chain polyunsaturated fatty acid, geranylgeranoic acid.Bioscience reports · 2020Article
- Mutual interaction between endoplasmic reticulum and mitochondria in nonalcoholic fatty liver disease.Lipids in health and disease · 2020Review
- Review
- Sodium fluorocitrate having inhibitory effect on fatty acid uptake ameliorates high fat diet-induced non-alcoholic fatty liver disease in C57BL/6J mice.Scientific reports · 2019Article
Corrections and comments
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Authors and funding
6 authors at 3 institutions in 2 countries.
Funding
Abstract
Lipotoxicity induced by saturated fatty acids (SFAs) plays a pathological role in the development of non-alcoholic fatty liver disease (NAFLD); however, the exact mechanism(s) remain to be clearly elucidated. Toll-like receptor (TLR) 4 plays a fundamental role in activating the innate immune system. Intriguingly, hepatocytes express TLR4 and machinery for TLR4 signalling pathway. That liver-specific TLR4 knockout mice are protective against diet-induced NAFLD suggests that hepatocyte TLR4 signalling pathway plays an important role in NAFLD pathogenesis. Herein, using cultured hepatocytes, we sought to directly examine the role of TLR4 signalling pathway in palmitate-elicited hepatotoxicity and to elucidate underlying mechanism(s). Our data reveal that palmitate exposure up-regulates TLR4 expression at both mRNA and protein levels in hepatocytes, which are associated with NF-κB activation. The inhibition of TLR4 signalling pathway through both pharmacological and genetic approaches abolished palmitate-induced cell death, suggesting that TLR4 signalling pathway activation contributes to palmitate-induced hepatotoxicity. Mechanistic investigations demonstrate that inositol-requiring enzyme 1α (IRE1α), one of three major signal transduction pathways activated during endoplasmic reticulum (ER) stress, is the downstream target of palmitate-elicited TLR4 activation and mechanistically implicated in TLR4 activation-triggered cell death in response to palmitate exposure. Collectively, our data identify that the TLR4-IRE1α pathway activation contributes to palmitate-elicited lipotoxicity in hepatocytes. Our findings suggest that targeting TLR4-IRE1α pathway can be a potential therapeutic choice for the treatment of NAFLD as well as other metabolic disorders, with lipotoxicity being the principal pathomechanism.
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Registered trials
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