Adaptation of Mitochondrial Substrate Flux in a Mouse Model of Nonalcoholic Fatty Liver Disease

Staňková, Pavla; Kučera, Otto; Peterová, E; Lotková, Halka; Maseko, Tumisang E.; Nozickova, K.; Červinková, Z

doi:10.3390/ijms21031101

Cited by 9 publications

(4 citation statements)

References 67 publications

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“…Significant reduction of basal levels of liver GSH has been reported in NAFLD, either in patients [ 101 , 102 ] or in some rodent models [ 103 , 104 ]. However, other animal investigations did not find any significant decrease in hepatic GSH content [ 49 , 50 , 105 , 106 ], although this was sometimes associated with higher levels of oxidized GSH (GSSG) [ 105 ].…”

Section: Factors Modulating Apap Hepatotoxicity In Obesity and Nafldmentioning

confidence: 99%

Acetaminophen-Induced Hepatotoxicity in Obesity and Nonalcoholic Fatty Liver Disease: A Critical Review

Begriche¹,

Penhoat²,

Bernabeu-Gentey³

et al. 2023

Livers

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The epidemic of obesity, type 2 diabetes and nonalcoholic liver disease (NAFLD) favors drug consumption, which augments the risk of adverse events including liver injury. For more than 30 years, a series of experimental and clinical investigations reported or suggested that the common pain reliever acetaminophen (APAP) could be more hepatotoxic in obesity and related metabolic diseases, at least after an overdose. Nonetheless, several investigations did not reproduce these data. This discrepancy might come from the extent of obesity and steatosis, accumulation of specific lipid species, mitochondrial dysfunction and diabetes-related parameters such as ketonemia and hyperglycemia. Among these factors, some of them seem pivotal for the induction of cytochrome P450 2E1 (CYP2E1), which favors the conversion of APAP to the toxic metabolite N-acetyl-p-benzoquinone imine (NAPQI). In contrast, other factors might explain why obesity and NAFLD are not always associated with more frequent or more severe APAP-induced acute hepatotoxicity, such as increased volume of distribution in the body, higher hepatic glucuronidation and reduced CYP3A4 activity. Accordingly, the occurrence and outcome of APAP-induced liver injury in an obese individual with NAFLD would depend on a delicate balance between metabolic factors that augment the generation of NAPQI and others that can mitigate hepatotoxicity.

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Section: Factors Modulating Apap Hepatotoxicity In Obesity and Nafldmentioning

confidence: 99%

Acetaminophen-Induced Hepatotoxicity in Obesity and Nonalcoholic Fatty Liver Disease: A Critical Review

Begriche¹,

Penhoat²,

Bernabeu-Gentey³

et al. 2023

Livers

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“…89 Mice fed with a "Western" diet for 24 weeks developed liver steatosis with decreased mitochondrial respiration but no changes in FA β-oxidation and no traces of ROS, suggesting that mitochondria adapted to the excess substrate. 83 Mice fed for 16 weeks with three different hypercaloric diets HF, high sucrose or HF-high sucrose diet presented hepatic steatosis regardless of no changes in mitochondrial oxidative capacity, FA β-oxidation or ROS production. 90 The discrepancy in the results may be linked to the different animal models and the different stages of the disease of human subjects.…”

Section: Dysfunction Responsible For Progression From Nafl To Nash?mentioning

confidence: 96%

“…72 Recently, it was reported that high fat-fed animals have decreased mitochondrial respiration with succinate, but no change in FA oxidation. 83 Some reports showed that mitochondrial respiration decreases during NASH development, 73,77 with reduced synthesis of ATP. [84][85][86][87] Others have shown that despite impairment in lipids or glucose metabolism, NAFL/NASH mitochondria were not dysfunctional.…”

Section: Dysfunction Responsible For Progression From Nafl To Nash?mentioning

confidence: 99%

Adipose tissue insulin resistance and lipidome alterations as the characterizing factors of non‐alcoholic steatohepatitis

Guerra

Mocciaro

Gastaldelli

2021

Eur J Clin Investigation

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Non-alcoholic fatty liver disease (NAFLD) is defined as excessive triglyceride accumulation into the hepatocytes in the absence of excessive alcohol consumption and defined by the presence of steatosis in >5% of hepatocytes according to histological analysis or by >5.6% hepatic fat assessed by magnetic resonance imaging (MRI) or spectroscopy (MRS). 1 It is estimated that the prevalence of non-alcoholic fatty liver disease (NAFLD) in the general

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“…Having established that FFA stimulates mitochondrial respiration in HepaRG cells, but not in HepG2 cells, the present study then investigated which pathway leading into the Q-junction may be responsible for causing these outcomes. Our previously published studies on mouse models of NASH revealed a decreased complex II-driven respiration (38,39). Therefore, the present study evaluated OXPHOS, MRc and LEAK respiration in the presence of complex I-driven respiration substrates [pyruvate/malate and glutamate/malate (Fig.…”

Section: Ffas Increase Complex I and Ii-driven Respiration And β-Oxid...mentioning

confidence: 98%

Comparison of HepaRG and HepG2 cell lines to model mitochondrial respiratory adaptations in non‑alcoholic fatty liver disease

Maseko,

Elkalaf,

Peterová

et al. 2023

Int J Mol Med

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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.

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Adaptation of Mitochondrial Substrate Flux in a Mouse Model of Nonalcoholic Fatty Liver Disease

Cited by 9 publications

References 67 publications

Acetaminophen-Induced Hepatotoxicity in Obesity and Nonalcoholic Fatty Liver Disease: A Critical Review

Acetaminophen-Induced Hepatotoxicity in Obesity and Nonalcoholic Fatty Liver Disease: A Critical Review

Adipose tissue insulin resistance and lipidome alterations as the characterizing factors of non‐alcoholic steatohepatitis

Comparison of HepaRG and HepG2 cell lines to model mitochondrial respiratory adaptations in non‑alcoholic fatty liver disease

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