Ethanol and C2 ceramide activate fatty acid oxidation in human hepatoma cells

Correnti, Jason; Gottshall, Lauren; Lin, Alex T.L.; Williams, Bianca; Oranu, Amanke; Beck, Jürgen; Chen, Jie; Bennett, Michael J.; Carr, Rotonya M.

doi:10.1038/s41598-018-31025-0

Cited by 14 publications

(8 citation statements)

References 74 publications

(90 reference statements)

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“…This is consistent with prior studies, which show that high fat diet increases levels of Pparα and its downstream target Fabp1 in rat jejunum (Suruga et al, 1999), as well as those showing that a PPARα antagonist induces organoid death (Stine et al, 2019). Moreover, it aligns with studies showing that sphingolipids increase PPARα-mediated transcription (Correnti et al, 2018;Murakami et al, 2011;Tsuji et al, 2009;Van Veldhoven et al, 2000). Ceramides, phytoceramides, and sphingoid bases have been identified as upstream activators of PPARα, with some synthetic sphingolipids showing direct binding capabilities (Murakami et al, 2011;Tsuji et al, 2009;Van Veldhoven et al, 2000).…”

Section: Discussionsupporting

confidence: 92%

Serine Palmitoyltransferase Controls Stemness of Intestinal Progenitors

Summers

Chaurasia

et al. 2020

Preprint

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SummaryCancers of the gastrointestinal tract including esophageal adenocarcinomas, colorectal cancers, and cancers of the gastric cardia are common comorbidities of obesity. Excessive delivery of macronutrients to the cells lining the gut can increase one’s risk for these cancer by inducing imbalances in the rate of intestinal stem cell proliferation vs. differentiation, which can produce polyps and other aberrant growths. We demonstrate that serine palmitoyltransferase (SPT), which diverts dietary fatty and amino acids into the sphingolipid biosynthesis pathway, is a critical modulator of intestinal stem cell homeostasis. SPT and other enzymes in the biosynthetic pathway are upregulated in human colon tumors. These enzymes produce sphingolipids that serve as pro-stemness signals that stimulate peroxisome-proliferator activated receptor alpha (PPARα)-mediated induction of fatty acid binding protein-1. This increases fatty acid uptake and oxidation and enhances the stemness program. Serine palmitoyltransferase thus serves as a critical link between dietary macronutrients, epithelial regeneration, and cancer risk.

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Section: Discussionsupporting

confidence: 92%

Serine Palmitoyltransferase Controls Stemness of Intestinal Progenitors

Summers

Chaurasia

et al. 2020

Preprint

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“…Additionally, other mechanisms, such as fatty acid oxidation, may be involved in meeting the energy demands of the cell due to EtOH exposure. However, studies in the liver suggest that chronic alcohol exposure promotes hepatic injury but does not increase the rate of fatty acid β-oxidation through inhibition of mitochondrial β-oxidation ( 35 – 37 ).…”

Section: Discussionmentioning

confidence: 99%

Alcohol-Induced Glycolytic Shift in Alveolar Macrophages Is Mediated by Hypoxia-Inducible Factor-1 Alpha

et al. 2022

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Excessive alcohol use increases the risk of developing respiratory infections partially due to impaired alveolar macrophage (AM) phagocytic capacity. Previously, we showed that chronic ethanol (EtOH) exposure led to mitochondrial derangements and diminished oxidative phosphorylation in AM. Since oxidative phosphorylation is needed to meet the energy demands of phagocytosis, EtOH mediated decreases in oxidative phosphorylation likely contribute to impaired AM phagocytosis. Treatment with the peroxisome proliferator-activated receptor gamma (PPARγ) ligand, pioglitazone (PIO), improved EtOH-mediated decreases in oxidative phosphorylation. In other models, hypoxia-inducible factor-1 alpha (HIF-1α) has been shown to mediate the switch from oxidative phosphorylation to glycolysis; however, the role of HIF-1α in chronic EtOH mediated derangements in AM has not been explored. We hypothesize that AM undergo a metabolic shift from oxidative phosphorylation to a glycolytic phenotype in response to chronic EtOH exposure. Further, we speculate that HIF-1α is a critical mediator of this metabolic switch. To test these hypotheses, primary mouse AM (mAM) were isolated from a mouse model of chronic EtOH consumption and a mouse AM cell line (MH-S) were exposed to EtOH in vitro. Expression of HIF-1α, glucose transporters (Glut1 and 4), and components of the glycolytic pathway (Pfkfb3 and PKM2), were measured by qRT-PCR and western blot. Lactate levels (lactate assay), cell energy phenotype (extracellular flux analyzer), glycolysis stress tests (extracellular flux analyzer), and phagocytic function (fluorescent microscopy) were conducted. EtOH exposure increased expression of HIF-1α, Glut1, Glut4, Pfkfb3, and PKM2 and shifted AM to a glycolytic phenotype. Pharmacological stabilization of HIF-1α via cobalt chloride treatment in vitro mimicked EtOH-induced AM derangements (increased glycolysis and diminished phagocytic capacity). Further, PIO treatment diminished HIF-1α levels and reversed glycolytic shift following EtOH exposure. These studies support a critical role for HIF-1α in mediating the glycolytic shift in energy metabolism of AM during excessive alcohol use.

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“…N ‐acetylsphingosine was shown the highest fold‐difference between two treatment‐groups, known to inhibit the accumulation of lipid droplets by promoting fatty acid oxidation. 51 Likewise, bilirubin was reported to reduce hepatic fat accumulation by promoting the transcriptional activity of peroxisome proliferator‐activated receptor α (PPARα). 52 Betulin has been linked to inhibitory activity on fat accumulation and pro‐inflammatory response by increasing the expression of PPARα plus suppressing NF‐κB and SREBP‐1.…”

Section: Discussionmentioning

confidence: 99%

Lactobacillus lactis and Pediococcus pentosaceus‐driven reprogramming of gut microbiome and metabolome ameliorates the progression of non‐alcoholic fatty liver disease

Youn

Choi

et al. 2021

Clinical & Translational Med

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Background Although microbioa‐based therapies have shown putative effects on the treatment of non‐alcoholic fatty liver disease (NAFLD), it is not clear how microbiota‐derived metabolites contribute to the prevention of NAFLD. We explored the metabolomic signature of Lactobacillus lactis and Pediococcus pentosaceus in NAFLD mice and its association in NAFLD patients. Methods We used Western diet‐induced NAFLD mice, and L. lactis and P. pentosaceus were administered to animals in the drinking water at a concentration of 10 9 CFU/g for 8 weeks. NAFLD severity was determined based on liver/body weight, pathology and biochemistry markers. Caecal samples were collected for the metagenomics by 16S rRNA sequencing. Metabolite profiles were obtained from caecum, liver and serum. Human stool samples (healthy control [ n = 22] and NAFLD patients [ n = 23]) were collected to investigate clinical reproducibility for microbiota‐derived metabolites signature and metabolomics biomarker. Results L. lactis and P. pentosaceus supplementation effectively normalized weight ratio, NAFLD activity score, biochemical markers, cytokines and gut‐tight junction. While faecal microbiota varied according to the different treatments, key metabolic features including short chain fatty acids (SCFAs), bile acids (BAs) and tryptophan metabolites were analogously restored by both probiotic supplementations. The protective effects of indole compounds were validated with in vitro and in vivo models, including anti‐inflammatory effects. The metabolomic signatures were replicated in NAFLD patients, accompanied by the comparable levels of Firmicutes / Bacteroidetes ratio, which was significantly higher (4.3) compared with control (0.6). Besides, the consequent biomarker panel with six stool metabolites (indole, BAs, and SCFAs) showed 0.922 (area under the curve) in the diagnosis of NAFLD. Conclusions NAFLD progression was robustly associated with metabolic dys‐regulations in the SCFAs, bile acid and indole compounds, and NAFLD can be accurately diagnosed using the metabolites. L. lactis and P. pentosaceus ameliorate NAFLD progression by modulating gut metagenomic and metabolic environment, particularly tryptophan pathway, of the gut‐liver axis.

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Ethanol and C2 ceramide activate fatty acid oxidation in human hepatoma cells

Cited by 14 publications

References 74 publications

Serine Palmitoyltransferase Controls Stemness of Intestinal Progenitors

Serine Palmitoyltransferase Controls Stemness of Intestinal Progenitors

Alcohol-Induced Glycolytic Shift in Alveolar Macrophages Is Mediated by Hypoxia-Inducible Factor-1 Alpha

Lactobacillus lactis and Pediococcus pentosaceus‐driven reprogramming of gut microbiome and metabolome ameliorates the progression of non‐alcoholic fatty liver disease

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