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Journal of Hematology & Oncology Aug 2022Metabolic reprogramming of cancer cells within the tumor microenvironment typically occurs in response to increased nutritional, translation and proliferative demands.... (Review)
Review
Metabolic reprogramming of cancer cells within the tumor microenvironment typically occurs in response to increased nutritional, translation and proliferative demands. Altered lipid metabolism is a marker of tumor progression that is frequently observed in aggressive tumors with poor prognosis. Underlying these abnormal metabolic behaviors are posttranslational modifications (PTMs) of lipid metabolism-related enzymes and other factors that can impact their activity and/or subcellular localization. This review focuses on the roles of these PTMs and specifically on how they permit the re-wiring of cancer lipid metabolism, particularly within the context of the tumor microenvironment.
Topics: Humans; Lipid Metabolism; Lipogenesis; Neoplasms; Protein Processing, Post-Translational; Tumor Microenvironment
PubMed: 36038892
DOI: 10.1186/s13045-022-01340-1 -
Indian Journal of Dermatology,... 2013There is increasing evidence in support of the interplay of growth hormone (GH), insulin, and insulin-like growth factor-1 (IGF-1) signaling during puberty, which have a... (Review)
Review
There is increasing evidence in support of the interplay of growth hormone (GH), insulin, and insulin-like growth factor-1 (IGF-1) signaling during puberty, which have a causal role in pathogenesis of acne by influencing adrenal and gonadal androgen metabolism. Milk consumption and hyperglycemic diets can induce insulin and IGF-1-mediated PI3K ⁄ Akt-activation inducing sebaceous lipogenesis, sebocyte, and keratinocyte proliferation, which can aggravate acne. Occurence of acne as part of various syndromes also provides evidence in favor of correlation between IGF-1 and acne.
Topics: Acne Vulgaris; Humans; Hyperglycemia; Insulin Resistance; Lipogenesis
PubMed: 23619434
DOI: 10.4103/0378-6323.110753 -
Nature Communications Jul 2022Basic processes of the fatty acid metabolism have an important impact on the function of intestinal epithelial cells (IEC). However, while the role of cellular fatty...
Basic processes of the fatty acid metabolism have an important impact on the function of intestinal epithelial cells (IEC). However, while the role of cellular fatty acid oxidation is well appreciated, it is not clear how de novo fatty acid synthesis (FAS) influences the biology of IECs. We report here that interfering with de novo FAS by deletion of the enzyme Acetyl-CoA-Carboxylase (ACC)1 in IECs results in the loss of epithelial crypt structures and a specific decline in Lgr5 intestinal epithelial stem cells (ISC). Mechanistically, ACC1-mediated de novo FAS supports the formation of intestinal organoids and the differentiation of complex crypt structures by sustaining the nuclear accumulation of PPARδ/β-catenin in ISCs. The dependency of ISCs on cellular de novo FAS is tuned by the availability of environmental lipids, as an excess delivery of external fatty acids is sufficient to rescue the defect in crypt formation. Finally, inhibition of ACC1 reduces the formation of tumors in colitis-associated colon cancer, together highlighting the importance of cellular lipogenesis for sustaining ISC function and providing a potential perspective to colon cancer therapy.
Topics: Acetyl Coenzyme A; Acetyl-CoA Carboxylase; Fatty Acids; Lipogenesis; Stem Cells
PubMed: 35810180
DOI: 10.1038/s41467-022-31725-2 -
The Journal of Clinical Investigation May 2023BACKGROUNDHepatic de novo lipogenesis (DNL) and β-oxidation are tightly coordinated, and their dysregulation is thought to contribute to the pathogenesis of... (Observational Study)
Observational Study
BACKGROUNDHepatic de novo lipogenesis (DNL) and β-oxidation are tightly coordinated, and their dysregulation is thought to contribute to the pathogenesis of nonalcoholic fatty liver (NAFL). Fasting normally relaxes DNL-mediated inhibition of hepatic β-oxidation, dramatically increasing ketogenesis and decreasing reliance on the TCA cycle. Thus, we tested whether aberrant oxidative metabolism in fasting NAFL subjects is related to the inability to halt fasting DNL.METHODSForty consecutive nondiabetic individuals with and without a history of NAFL were recruited for this observational study. After phenotyping, subjects fasted for 24 hours, and hepatic metabolism was interrogated using a combination of 2H2O and 13C tracers, magnetic resonance spectroscopy, and high-resolution mass spectrometry.RESULTSWithin a subset of subjects, DNL was detectable after a 24-hour fast and was more prominent in those with NAFL, though it was poorly correlated with steatosis. However, fasting DNL negatively correlated with hepatic β-oxidation and ketogenesis and positively correlated with citrate synthesis. Subjects with NAFL but undetectable fasting DNL (25th percentile) were comparatively normal. However, those with the highest fasting DNL (75th percentile) were intransigent to the effects of fasting on the concentration of insulin, non-esterified fatty acid, and ketones. Additionally, they sustained glycogenolysis and were spared the loss of oxaloacetate to gluconeogenesis in favor of citrate synthesis, which correlated with DNL and diminished ketogenesis.CONCLUSIONMetabolic flux analysis in fasted subjects indicates that shared metabolic mechanisms link the dysregulations of hepatic DNL, ketogenesis, and the TCA cycle in NAFL.TRIAL REGISTRATIONData were obtained during the enrollment/non-intervention phase of Effect of Vitamin E on Non-Alcoholic Fatty Liver Disease, ClinicalTrials.gov NCT02690792.FUNDINGThis work was supported by the University of Texas Southwestern NORC Quantitative Metabolism Core (NIH P30DK127984), the NIH/National Institute of Diabetes and Digestive and Kidney Diseases (R01DK078184, R01DK128168, R01DK087977, R01DK132254, and K01DK133630), the NIH/National Institute on Alcohol Abuse and Alcoholism (K01AA030327), and the Robert A. Welch Foundation (I-1804).
Topics: Humans; Non-alcoholic Fatty Liver Disease; Lipogenesis; Citric Acid; Liver; Ketone Bodies; Citrates; Fasting
PubMed: 36928190
DOI: 10.1172/JCI167442 -
The American Journal of Clinical... Dec 2019Comparative studies suggest that DHA may have stronger serum triglyceride-lowering effects than EPA; however, the molecular basis for this differential effect remains... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Comparative studies suggest that DHA may have stronger serum triglyceride-lowering effects than EPA; however, the molecular basis for this differential effect remains unexplored in humans. Differential regulation of lipogenesis and triglyceride clearance are 2 possible mechanisms of action.
OBJECTIVES
We compared the effects of EPA and DHA supplementation on serum triglycerides, markers of lipogenesis, and lipoprotein lipase (LPL) activity in adults participating in a double-blind, multiarm, placebo-controlled parallel-group randomized trial. Lipogenesis was assessed with the lipogenic index and compound specific isotope analysis (CSIA).
METHODS
Young, healthy normolipidemic men and women (n = 89; 21.6 ± 0.23 y; mean ± SEM) were randomly allocated into 1 of 3 supplement groups for 12 wk: 1) olive oil, 2) ∼3 g EPA/d, and 3) ∼3 g DHA/d. Omega-3 supplements were provided in triglyceride form. Blood was collected before and after supplementation for the analysis of fatty acids and preheparin LPL activity. Variations in the 13C:12C ratio (δ13C) of palmitate (16:0) and linoleate (18:2n-6) were measured by CSIA.
RESULTS
DHA supplementation reduced blood triglycerides (0.85 ± 0.04 mmol/L to 0.65 ± 0.03 mmol/L; P < 0.01), with no change seen with EPA supplementation. DHA supplementation did not change the lipogenic index or δ13C-16:0, whereas EPA supplementation increased the lipogenic index by 11% (P < 0.01) and δ13C-16:0 (P = 0.03) from -23.2 ± 0.2 to -22.8 ± 0.2 milliUrey ± SEM.
CONCLUSIONS
Reduced triglyceride concentrations after DHA supplementation are associated with increased LPL activity, whereas the null effect of EPA supplementation on blood triglycerides may stem from the concomitant increases in lipogenesis and LPL activity. Further investigation of the differential triglyceride-lowering effects of EPA and DHA is warranted in both normolipidemic and hyperlipidemic individuals. This trial was registered at clinicaltrials.gov as NCT03378232.
Topics: Adult; Dietary Supplements; Docosahexaenoic Acids; Eicosapentaenoic Acid; Female; Humans; Lipogenesis; Lipoprotein Lipase; Male; Triglycerides; Young Adult
PubMed: 31535138
DOI: 10.1093/ajcn/nqz234 -
Frontiers in Endocrinology 2023Non-alcoholic steatohepatitis (NASH) is an aggressive form of fatty liver disease with hepatic inflammation and fibrosis for which there is currently no drug treatment....
AN1284 attenuates steatosis, lipogenesis, and fibrosis in mice with pre-existing non-alcoholic steatohepatitis and directly affects aryl hydrocarbon receptor in a hepatic cell line.
Non-alcoholic steatohepatitis (NASH) is an aggressive form of fatty liver disease with hepatic inflammation and fibrosis for which there is currently no drug treatment. This study determined whether an indoline derivative, AN1284, which significantly reduced damage in a model of acute liver disease, can reverse steatosis and fibrosis in mice with pre-existing NASH and explore its mechanism of action. The mouse model of dietary-induced NASH reproduces most of the liver pathology seen in human subjects. This was confirmed by RNA-sequencing analysis. The Western diet, given for 4 months, caused steatosis, inflammation, and liver fibrosis. AN1284 (1 mg or 5 mg/kg/day) was administered for the last 2 months of the diet by micro-osmotic-pumps (mps). Both doses significantly decreased hepatic damage, liver weight, hepatic fat content, triglyceride, serum alanine transaminase, and fibrosis. AN1284 (1 mg/kg/day) given by mps or in the drinking fluid significantly reduced fibrosis produced by carbon tetrachloride injections. In human HUH7 hepatoma cells incubated with palmitic acid, AN1284 (2.1 and 6.3 ng/ml), concentrations compatible with those in the liver of mice treated with AN1284, decreased lipid formation by causing nuclear translocation of the aryl hydrocarbon receptor (AhR). AN1284 downregulated fatty acid synthase (FASN) and sterol regulatory element-binding protein 1c (SREBP-1c) and upregulated Acyl-CoA Oxidase 1 and Cytochrome P450-a1, genes involved in lipid metabolism. In conclusion, chronic treatment with AN1284 (1mg/kg/day) reduced pre-existing steatosis and fibrosis through AhR, which affects several contributors to the development of fatty liver disease. Additional pathways are also influenced by AN1284 treatment.
Topics: Animals; Mice; Humans; Non-alcoholic Fatty Liver Disease; Lipogenesis; Receptors, Aryl Hydrocarbon; Hepatocytes; Liver Cirrhosis; Inflammation
PubMed: 37664863
DOI: 10.3389/fendo.2023.1226808 -
Frontiers in Endocrinology 2022High-salt diet (HSD) is associated with dysregulated metabolism and metabolic disorders. Although previous studies have indicated its effect on metabolic tissues, the...
High-salt diet (HSD) is associated with dysregulated metabolism and metabolic disorders. Although previous studies have indicated its effect on metabolic tissues, the involving molecular mechanisms are not quite understood. In the present study, we provided a comprehensive transcriptome analysis on multiple metabolic tissues of HSD-fed mouse model by RNA sequencing. We observed that several genes associated with lipogenesis and cholesterol biosynthesis were significantly downregulated in white adipose tissue and liver tissue of HSD mice group, such as , , , and Furthermore, combined with secretome datasets, our results further demonstrated that HSD could alter expression levels of organokines in metabolic tissues, for example, and , in liver tissue and, thus, possibly mediate cross-talk between different metabolic tissues. Our study provided new insight about molecular signatures of HSD on multiple metabolic tissues.
Topics: Animals; Diet; Gene Expression Profiling; Lipogenesis; Liver; Metabolic Diseases; Mice; Nerve Growth Factors
PubMed: 35655797
DOI: 10.3389/fendo.2022.887843 -
Journal of Lipid Research Jan 2024Liver steatosis is a common metabolic disorder resulting from imbalanced lipid metabolism, which involves various processes such as de novo lipogenesis, fatty acid...
Liver steatosis is a common metabolic disorder resulting from imbalanced lipid metabolism, which involves various processes such as de novo lipogenesis, fatty acid uptake, fatty acid oxidation, and VLDL secretion. In this study, we discovered that KLF2, a transcription factor, plays a crucial role in regulating lipid metabolism in the liver. Overexpression of KLF2 in the liver of db/db mice, C57BL/6J mice, and Cd36-/- mice fed on a normal diet resulted in increased lipid content in the liver. Additionally, transgenic mice (ALB-Klf2) that overexpressed Klf2 in the liver developed liver steatosis after being fed a normal diet. We found that KLF2 promotes lipogenesis by increasing the expression of SCAP, a chaperone that facilitates the activation of SREBP, the master transcription factor for lipogenic gene expression. Our mechanism studies revealed that KLF2 enhances lipogenesis in the liver by binding to the promoter of SCAP and increasing the expression of genes involved in fatty acid synthesis. Reduction of KLF2 expression led to a decrease in SCAP expression and a reduction in the expression of SREBP1 target genes involved in lipogenesis. Overexpression of KLF2 also increased the activation of SREBP2 and the mRNA levels of its downstream target SOAT1. In C57BL/6J mice fed a high-fat diet, overexpression of Klf2 increased blood VLDL secretion, while reducing its expression decreased blood cholesterol levels. Our study emphasizes the novelty that hepatic KLF2 plays a critical role in regulating lipid metabolism through the KLF2/SCAP/SREBPs pathway, which is essential for hepatic lipogenesis and maintaining blood cholesterol homeostasis.
Topics: Mice; Animals; Lipogenesis; Sterol Regulatory Element Binding Protein 1; Mice, Inbred C57BL; Liver; Fatty Liver; Lipid Metabolism; Fatty Acids; Cholesterol; Homeostasis
PubMed: 37949368
DOI: 10.1016/j.jlr.2023.100472 -
Cell Reports May 2020Here, we show that β adrenergic signaling coordinately upregulates de novo lipogenesis (DNL) and thermogenesis in subcutaneous white adipose tissue (sWAT), and both...
Here, we show that β adrenergic signaling coordinately upregulates de novo lipogenesis (DNL) and thermogenesis in subcutaneous white adipose tissue (sWAT), and both effects are blocked in mice lacking the cAMP-generating G protein-coupled receptor Gs (Adipo-GsαKO) in adipocytes. However, UCP1 expression but not DNL activation requires rapamycin-sensitive mTORC1. Furthermore, β3-adrenergic agonist CL316243 readily upregulates thermogenic but not lipogenic genes in cultured adipocytes, indicating that additional regulators must operate on DNL in sWAT in vivo. We identify one such factor as thyroid hormone T3, which is elevated locally by adrenergic signaling. T3 administration to wild-type mice enhances both thermogenesis and DNL in sWAT. Mechanistically, T3 action on UCP1 expression in sWAT depends upon cAMP and is blocked in Adipo-GsαKO mice even as elevated DNL persists. Thus, T3 enhances sWAT thermogenesis by amplifying cAMP signaling, while its control of adipocyte DNL can be mediated independently of both cAMP and rapamycin-sensitive mTORC1.
Topics: Adipocytes; Adipose Tissue, Brown; Adipose Tissue, White; Adrenergic Agents; Animals; Lipogenesis; Mice, Transgenic; Signal Transduction; Thermogenesis; Thyroid Hormones
PubMed: 32375048
DOI: 10.1016/j.celrep.2020.107598 -
The Journal of Experimental Medicine Mar 2020Cancer cells often proliferate under hypoxia and reprogram their metabolism. However, how to find targets to effectively block the hypoxia-associated metabolic pathways...
Cancer cells often proliferate under hypoxia and reprogram their metabolism. However, how to find targets to effectively block the hypoxia-associated metabolic pathways remains unclear. Here, we developed a tool to conveniently calculate electrons dissipated in metabolic transformations. Based on the law of conservation of electrons in chemical reactions, we further built up an electron balance model for central carbon metabolism, and it can accurately outline metabolic plasticity under hypoxia. Our model specifies that glutamine metabolism reprogrammed for biosynthesis of lipid and/or proline actually acts as the alternative electron bin to enable electron transfer in proliferating cells under hypoxia. Inhibition of both proline biosynthesis and lipogenesis can synergistically suppress cancer cell growth under hypoxia and in vivo tumor onset. Therefore, our model helps to reveal combinations of potential targets to inhibit tumor growth by blocking hypoxia-rewired metabolism and provides a useful tool for future studies on cancer metabolism.
Topics: A549 Cells; Animals; Cell Hypoxia; Cell Line, Tumor; Cell Proliferation; Female; Glutamine; HeLa Cells; Hep G2 Cells; Humans; Lipogenesis; MCF-7 Cells; Metabolic Networks and Pathways; Mice; Mice, Nude; Neoplasms; Proline
PubMed: 31961917
DOI: 10.1084/jem.20191226