Although some clinical studies have reported increased mitochondrial respiration in patients with fatty liver and early non‑alcoholic steatohepatitis (NASH), there is a lack of in vitro models of non‑alcoholic fatty liver disease (NAFLD) with similar findings. Despite being the most commonly used immortalized cell line for in vitro models of NAFLD, HepG2 cells exposed to free fatty acids (FFAs) exhibit a decreased mitochondrial respiration. On the other hand, the use of HepaRG cells to study mitochondrial respiratory changes following exposure to FFAs has not yet been fully explored. Therefore, the present study aimed to assess cellular energy metabolism, particularly mitochondrial respiration, and lipotoxicity in FFA‑treated HepaRG and HepG2 cells. HepaRG and HepG2 cells were exposed to FFAs, followed by comparative analyses that examained cellular metabolism, mitochondrial respiratory enzyme activities, mitochondrial morphology, lipotoxicity, the mRNA expression of selected genes and triacylglycerol (TAG) accumulation. FFAs stimulated mitochondrial respiration and glycolysis in HepaRG cells, but not in HepG2 cells. Stimulated complex I, II‑driven respiration and β‑oxidation were linked to increased complex I and II activities in FFA‑treated HepaRG cells, but not in FFA‑treated HepG2 cells. Exposure to FFAs disrupted mitochondrial morphology in both HepaRG and HepG2 cells. Lipotoxicity was induced to a greater extent in FFA‑treated HepaRG cells than in FFA‑treated HepG2 cells. TAG accumulation was less prominent in HepaRG cells than in HepG2 cells. On the whole, the present study demonstrates that stimulated mitochondrial respiration is associated with lipotoxicity in FFA‑treated HepaRG cells, but not in FFA‑treated HepG2 cells. These findings suggest that HepaRG cells are more suitable for assessing mitochondrial respiratory adaptations in the developed in vitro model of early‑stage NASH.

• Klíčová slova
• HepG2 cells, HepaRG cells, in vitro models, lipotoxicity, mitochondria, mitochondrial respiration, non‑alcoholic fatty liver disease, steatosis,
• MeSH
• buněčné linie MeSH
• buňky Hep G2 MeSH
• dýchání MeSH
• kyseliny mastné neesterifikované MeSH
• lidé MeSH
• mitochondrie MeSH
• nealkoholová steatóza jater * MeSH
• triglyceridy MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• kyseliny mastné neesterifikované MeSH
• triglyceridy MeSH

NF-E2-related factor 2 (NRF2) is a basic leucine zipper transcription factor, a master regulator of redox homeostasis regulating a variety of genes for antioxidant and detoxification enzymes. NRF2 was, therefore, initially thought to protect the liver from oxidative stress. Recent studies, however, have revealed that mutations in NRF2 cause aberrant accumulation of NRF2 in the nucleus and exert the upregulation of NRF2 target genes. Moreover, among all molecular changes in hepatocellular carcinoma (HCC), NRF2 activation has been revealed as a more prominent pathway contributing to the progression of precancerous lesions to malignancy. Nevertheless, how its activation leads to poor prognosis in HCC patients remains unclear. In this review, we provide an overview of how aberrant activation of NRF2 triggers HCC development. We also summarize the emerging roles of other NRF family members in liver cancer development.

• Klíčová slova
• NF-E2-related factor 2, hepatocellular carcinoma, oxidative stress, redox homeostasis, transcription factor,
• MeSH
• aktivace transkripce * MeSH
• analýza přežití MeSH
• faktor 2 související s NF-E2 genetika   metabolismus   MeSH
• genové regulační sítě MeSH
• hepatocelulární karcinom diagnóza   genetika   mortalita   patologie   MeSH
• karcinogeneze genetika   metabolismus   patologie   MeSH
• KEAP-1 genetika   metabolismus   MeSH
• lidé MeSH
• mutace MeSH
• nádorové buněčné linie MeSH
• nádory jater diagnóza   genetika   mortalita   patologie   MeSH
• oxidace-redukce MeSH
• oxidační stres MeSH
• prognóza MeSH
• regulace genové exprese u nádorů * MeSH
• signální transdukce MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• faktor 2 související s NF-E2 MeSH
• KEAP-1 MeSH
• KEAP1 protein, human MeSH Prohlížeč
• NFE2L2 protein, human MeSH Prohlížeč

Maladaptation of mitochondrial oxidative flux seems to be a considerable feature of nonalcoholic fatty liver disease (NAFLD). The aim of this work was to induce NAFLD in mice fed a Western-style diet (WD) and to evaluate liver mitochondrial functions. Experiments were performed on male C57BL/6J mice fed with a control diet or a WD for 24 weeks. Histological changes in liver and adipose tissue as well as hepatic expression of fibrotic and inflammatory genes and proteins were evaluated. The mitochondrial respiration was assessed by high-resolution respirometry. Oxidative stress was evaluated by measuring lipoperoxidation, glutathione, and reactive oxygen species level. Feeding mice a WD induced adipose tissue inflammation and massive liver steatosis accompanied by mild inflammation and fibrosis. We found decreased succinate-activated mitochondrial respiration and decreased succinate dehydrogenase (SDH) activity in the mice fed a WD. The oxidative flux with other substrates was not affected. We observed increased ketogenic capacity, but no impact on the capacity for fatty acid oxidation. We did not confirm the presence of oxidative stress. Mitochondria in this stage of the disease are adapted to increased substrate flux. However, inhibition of SDH can lead to the accumulation of succinate, an important signaling molecule associated with inflammation, fibrosis, and carcinogenesis.

• Klíčová slova
• mitochondria, nonalcoholic fatty liver disease, oxidative phosphorylation, respirometry,
• MeSH
• dieta s vysokým obsahem tuků škodlivé účinky   MeSH
• glutathion metabolismus   MeSH
• jaterní mitochondrie metabolismus   MeSH
• játra metabolismus   patologie   MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• nealkoholová steatóza jater etiologie   metabolismus   MeSH
• peroxidace lipidů * MeSH
• sukcinátdehydrogenasa metabolismus   MeSH
• tuková tkáň metabolismus   patologie   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• glutathion MeSH
• sukcinátdehydrogenasa MeSH