TNF‐α and IL‐6 Synergistically Inhibit Ketogenesis From Fatty Acids and α‐Ketoisocaproate in Isolated Rat Hepatocytes

Pailla, Karine; Lim, Soo-Kyung; Bandt, Jean‐Pascal De; Aussel, Christian; Giboudeau, J; Troupel, S; Cynober, Luc; Blonde-Cynober, F.

doi:10.1177/0148607198022005286

Cited by 16 publications

(7 citation statements)

References 30 publications

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“…A coincidence between increased fatty acid synthesis and a decline in fatty acid β-oxidation has been found during influenza infection, which is attributed to a variety of mechanisms directly or indirectly related to viral replication. For instance, the sharp increase of proinflammatory cytokines during influenza infection [106] causes decreased hepatic fatty acid β-oxidation both in vitro and in vivo [107,108], most likely through excessive nitric oxide and other related free radicals [109]. In addition, increased temperature of cells during infection (which could be the result of virus replication and fever) causes heat stress which in turn can considerably downregulate carnitine palmitoyltransferase II (CPT II) activity and reduce the β-oxidation and ATP levels in fibroblasts of influenza-associated encephalopathy patients and healthy volunteers [110].…”

Section: Lipid Metabolismmentioning

confidence: 99%

Metabolic host response and therapeutic approaches to influenza infection

et al. 2020

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Based on available metabolomic studies, influenza infection affects a variety of cellular metabolic pathways to ensure an optimal environment for its replication and production of viral particles. Following infection, glucose uptake and aerobic glycolysis increase in infected cells continually, which results in higher glucose consumption. The pentose phosphate shunt, as another glucose-consuming pathway, is enhanced by influenza infection to help produce more nucleotides, especially ATP. Regarding lipid species, following infection, levels of triglycerides, phospholipids, and several lipid derivatives undergo perturbations, some of which are associated with inflammatory responses. Also, mitochondrial fatty acid βoxidation decreases significantly simultaneously with an increase in biosynthesis of fatty acids and membrane lipids. Moreover, essential amino acids are demonstrated to decline in infected tissues due to the production of large amounts of viral and cellular proteins. Immune responses against influenza infection, on the other hand, could significantly affect metabolic pathways. Mainly, interferon (IFN) production following viral infection affects cell function via alteration in amino acid synthesis, membrane composition, and lipid metabolism. Understanding metabolic alterations required for influenza virus replication has revealed novel therapeutic methods based on targeted inhibition of these cellular metabolic pathways.

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Section: Lipid Metabolismmentioning

confidence: 99%

Metabolic host response and therapeutic approaches to influenza infection

et al. 2020

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“…The onset of liver dysfunction is mainly determined by cytokines released by the tumor, such as IL-6 and TNFα [ 37 – 39 ], and it generally provokes fever, weight loss and an unfavorable prognosis [ 59 ]. Interestingly, increased IL-6 and TNFα levels were associated in vivo and in vitro with reduced hepatic ketogenesis [ 60 , 61 ], and this could explain the lower plasma ketone levels in the RCC bearing mice under KD, compared to healthy control mice.…”

Section: Discussionmentioning

confidence: 99%

The ketogenic diet is not feasible as a therapy in a CD-1 nu/nu mouse model of renal cell carcinoma with features of Stauffer's syndrome

et al. 2017

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The ketogenic diet (KD), a high-fat low-carbohydrate diet, has shown some efficacy in the treatment of certain types of tumors such as brain tumors and neuroblastoma. These tumors are characterized by the Warburg effect. Because renal cell carcinoma (RCC) presents similar energetic features as neuroblastoma, KD might also be effective in the treatment of RCC. To test this, we established xenografts with RCC 786-O cells in CD-1 nu/nu mice and then randomized them to a control diet or to KDs with different triglyceride contents. Although the KDs tended to reduce tumor growth, mouse survival was dramatically reduced due to massive weight loss. A possible explanation comes from observations of human RCC patients, who often experience secondary non-metastatic hepatic dysfunction due to secretion of high levels of inflammatory cytokines by the RCCs. Measurement of the mRNA levels of tumor necrosis factor alpha (TNFα) and interleukin-6 revealed high expression in the RCC xenografts compared to the original 786-O cells. The expression of TNFα, interleukin-6 and C-reactive protein were all increased in the livers of tumor-bearing mice, and KD significantly boosted their expression. KDs did not cause weight loss or liver inflammation in healthy mice, suggesting that KDs are per se safe, but might be contraindicated in the treatment of RCC patients presenting with Stauffer's syndrome, because they potentially worsen the associated hepatic dysfunction.

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“…On the basis of previous studies [10][11][12], chromatographic parameters were optimized for better resolution of OPD-derivatized BCKAs and the internal standard. Optimized LC conditions are described in the Methods section.…”

Section: Methods Optimization and Analysis Of Cell Extractsmentioning

confidence: 99%

“…Recently, we reported that the aberrant activation of BCAT1 promotes transformation of hematopoietic progenitors and thereby drives cancer progression in myeloid leukemia [9]. Prior techniques for the quantification of BCKAs include high-performance liquid chromatography (HPLC)-fluorescence detection [10][11][12][13], liquid chromatography-mass spectrometry (LC-MS) [14][15][16], and gas chromatography-mass spectrometry (GC-MS) [17]. These methods have been applied to various biological fluids such as plasma and serum; but very few methods [12], and Olson et al developed an ultra-fast LC-MS method for the quantification of BCKAs in mouse tissues [14].…”

Section: Introductionmentioning

confidence: 99%

Analysis of Branched-Chain Keto Acids in Cell Extracts by HPLC-Fluorescence Detection

2017

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An analytical method for quantifying branched-chain keto acids (BCKAs) -namely α-keto-isovaleric acid (KIV), α-keto-isocaproic acid (KIC), and α-keto-β-methylvaleric acid (KMV) -in cell extracts was developed and applied to a human chronic myelogenous leukemia cell line. Reversed-phase liquid chromatography was conducted for separation of the BCKAs after derivatization into fluorescent quinoxalines by reaction with o-phenylenediamine. The calibration curve was linear over the range from 0.5 to 50 μM. The precision values in intra-and inter-day assays were less than 3.1% and 5.6% (n = 4), respectively. Intracellular concentrations of KIV, KIC, and KMV in K562 cells were 47.6 ± 10.2, 312.4 ± 40.6, and 282.4 ± 71.6 pmol/1 x 10 6 cells, respectively (n = 5 for each BCKAs). Furthermore, this method was applied to study the effect of gabapentin -an inhibitor of branched-chain amino acid aminotransferase 1 -on intracellular BCKA levels.

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TNF‐α and IL‐6 Synergistically Inhibit Ketogenesis From Fatty Acids and α‐Ketoisocaproate in Isolated Rat Hepatocytes

Abstract: In our experimental conditions, cytokines mediate an inhibition of ketogenesis; this process could be explained by a direct effect of cytokines on metabolic pathways of octanoic acid and KIC oran indirect effect by modification of the mitochondrial redox state.

Cited by 16 publications

References 30 publications

Metabolic host response and therapeutic approaches to influenza infection

Metabolic host response and therapeutic approaches to influenza infection

The ketogenic diet is not feasible as a therapy in a CD-1 nu/nu mouse model of renal cell carcinoma with features of Stauffer's syndrome

Analysis of Branched-Chain Keto Acids in Cell Extracts by HPLC-Fluorescence Detection

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