Integrating the contributions of mitochondrial oxidative metabolism to lipotoxicity and inflammation in NAFLD pathogenesis

Hughey, Curtis C.; Puchalska, Patrycja; Crawford, Peter A.

doi:10.1016/j.bbalip.2022.159209

Cited by 19 publications

(23 citation statements)

References 207 publications

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“…Similar results regarding the higher terminal oxidation of the 13 C-octanoate were reported in patients with the NASH versus control group [ 18 , 21 ].…”

Section: Discussionsupporting

confidence: 82%

A Comparison of 13C-Methacetin and 13C-Octanoate Breath Test for the Evaluation of Nonalcoholic Steatohepatitis

Fierbinţeanu-Braticevici

Enciu

Calin-Necula

et al. 2023

JCM

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Background: While non-alcoholic fatty liver disease (NAFLD) is a wide-spread liver disease, only some patients progress towards steatohepatitis and cirrhosis. Aim: We comparatively analyzed the methacetin breath test (MBT) for the microsomal function of the liver and the octanoate breath test (OBT) for mitochondrial activity, in detecting patients with steatohepatitis and estimating fibrosis. Methods: 81 patients with histologically proven NAFLD (SAF score) were evaluated. The parameters used for both breath tests were the dose/h and the cumulative dose recovery at multiple timepoints. The statistical association between histological diagnosis and breath test results used Independent Samples t Test. The accuracy for diagnosis was evaluated using area under the receiver operator characteristic (AUROC) and the sensitivity and specificity were assessed using the Youden J method. Results: Both MBT and OBT were able to differentiate patients with simple steatosis from NASH and to stratify patients with significant fibrosis and cirrhosis (p-values < 0.001 for most analyzed timepoints). The best parameter for NASH diagnosis was OBT dose at 30 min. In the case of significant fibrosis, the most accurate test was MBT cumulative dose at 30 min. Conclusions: Both MBR and OBT tests are potentially useful tools in assessing patients with NAFLD.

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“…Similar results regarding the higher terminal oxidation of the 13 C-octanoate were reported in patients with the NASH versus control group [ 18 , 21 ].…”

Section: Discussionsupporting

confidence: 82%

A Comparison of 13C-Methacetin and 13C-Octanoate Breath Test for the Evaluation of Nonalcoholic Steatohepatitis

Fierbinţeanu-Braticevici

Enciu

Calin-Necula

et al. 2023

JCM

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“…FAO plays an important role in hepatic storage and consumption of lipids. Aberrant FAO activity in the liver is associated with diseases such as liver cancer and non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH). , Hence, we sought to detect FAO activity in the mouse liver using probe 3 . Mice were intraperitoneally administered probe 3 (50 mM in DMSO, 50 μL) and sacrificed after 1 h to harvest the liver sample.…”

Section: Resultsmentioning

confidence: 99%

Fluorescence-Based Detection of Fatty Acid β-Oxidation in Cells and Tissues Using Quinone Methide-Releasing Probes

et al. 2023

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Detection of metabolic activity enables us to reveal the inherent metabolic state of cells and elucidate mechanisms underlying cellular homeostasis and growth. However, a fluorescence approach for the study of metabolic pathways is still largely unexplored. Herein, we have developed a new chemical probe for the fluorescence-based detection of fatty acid β-oxidation (FAO), a key process in lipid catabolism, in cells and tissues. This probe serves as a substrate of FAO and forms a reactive quinone methide (QM) as a result of metabolic reactions. The liberated QM is covalently captured by intracellular proteins, and subsequent bio-orthogonal ligation with a fluorophore enables fluorescence analysis. This reaction-based sensing allowed us to detect FAO activity in cells at a desired emission wavelength using diverse analytical techniques including fluorescence imaging, in-gel fluorescence activity-based protein profiling (ABPP), and fluorescence-activated cell sorting (FACS). The probe was able to detect changes in FAO activity induced by chemical modulators in cultured cells. The probe was further employed for fluorescence imaging of FAO in mouse liver tissues and revealed the metabolic heterogeneity of FAO activity in hepatocytes by the combination of FACS and gene expression analysis, highlighting the utility of our probe as a chemical tool for fatty acid metabolism research.

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“…Hepatic terminal oxidation, as indicated by mitochondrial respiratory chain proteins, was not greater in KO mice undergoing exercise training. Beyond terminal oxidation of fatty acids via TCA cycle and oxidative phosphorylation, the liver can dispose of lipids through ketogenesis (45). Furthermore, ketone bodies are primarily synthesized by the liver and they become an increasingly important fuel source for extrahepatic tissues when glucose availability is limited (46).…”

Section: Discussionmentioning

confidence: 99%

Loss of hepatic phosphoenolpyruvate carboxykinase 1 dysregulates metabolic responses to acute exercise but enhances adaptations to exercise training in mice

Rome

Shobert

Voigt

et al. 2022

Preprint

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Acute exercise increases liver gluconeogenesis to supply glucose to working muscle. Concurrently, elevated liver lipid breakdown fuels the high energetic cost of gluconeogenesis. This functional coupling between liver gluconeogenesis and lipid oxidation has been proposed to underlie the ability of regular exercise to enhance liver mitochondrial oxidative metabolism and decrease liver steatosis in individuals with non-alcoholic fatty liver disease. Herein we tested whether repeated bouts of increased hepatic gluconeogenesis are necessary for exercise training to lower liver lipids. Experiments used diet-induced obese mice lacking hepatic phosphoenolpyruvate carboxykinase 1 (KO) to inhibit gluconeogenesis and wild type (WT) littermates. 2H/13C metabolic flux analysis quantified glucose and mitochondrial oxidative fluxes in untrained mice at rest and during acute exercise. Circulating and tissue metabolite levels were determined during sedentary conditions, acute exercise, and refeeding post-exercise. Mice also underwent six weeks of treadmill running protocols to define hepatic and extrahepatic adaptations to exercise training. Untrained KO mice were unable to maintain euglycemia during acute exercise resulting from an inability to increase gluconeogenesis. Liver triacylglycerides were elevated following acute exercise and circulating β-hydroxybutyrate was higher during post-exercise refeeding in untrained KO mice. In contrast, exercise training prevented liver triacylglyceride accumulation in KO mice. This was accompanied by pronounced increases in indices of skeletal muscle mitochondrial oxidative metabolism in KO mice. Together, these results show that hepatic gluconeogenesis is dispensable for exercise training to reduce liver lipids. This may be due to responses in ketone body metabolism and/or metabolic adaptations in skeletal muscle to exercise.

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Integrating the contributions of mitochondrial oxidative metabolism to lipotoxicity and inflammation in NAFLD pathogenesis

Cited by 19 publications

References 207 publications

A Comparison of 13C-Methacetin and 13C-Octanoate Breath Test for the Evaluation of Nonalcoholic Steatohepatitis

A Comparison of 13C-Methacetin and 13C-Octanoate Breath Test for the Evaluation of Nonalcoholic Steatohepatitis

Fluorescence-Based Detection of Fatty Acid β-Oxidation in Cells and Tissues Using Quinone Methide-Releasing Probes

Loss of hepatic phosphoenolpyruvate carboxykinase 1 dysregulates metabolic responses to acute exercise but enhances adaptations to exercise training in mice

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