De novo lipogenesis prolongs the lifespan and supports the immunosuppressive phenotype of neutrophils in HCC metastasis.
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ABSTRACT:
SUBMITTER: Hu C
PROVIDER: S-EPMC9293710 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Increased de novo lipogenesis is being increasingly recognized as a hallmark of cancer. Despite recent advances in fluorescence microscopy, autoradiography and mass spectrometry, direct observation of de novo lipogenesis in living systems remains to be challenging. Here, by coupling stimulated Raman scattering (SRS) microscopy with isotope labeled glucose, we were able to trace the dynamic metabolism of glucose in single living cells with high spatial-temporal resolution. As the first direct visualization, we observed that glucose was largely utilized for lipid synthesis in pancreatic cancer cells, which occurs at a much lower rate in immortalized normal pancreatic epithelial cells. By inhibition of glycolysis and fatty acid synthase (FAS), the key enzyme for fatty acid synthesis, we confirmed the deuterium labeled lipids in cancer cells were from de novo lipid synthesis. Interestingly, we also found that prostate cancer cells exhibit relatively lower level of de novo lipogenesis, but higher fatty acid uptake compared to pancreatic cancer cells. Together, our results demonstrate a valuable tool to study dynamic lipid metabolism in cancer and other disorders.
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Project description:Dietary free sugars have received much attention over the past few years. Much of the focus has been on the effect of fructose on hepatic de novo lipogenesis (DNL). Therefore the aim of the present study was to investigate the effects of meals high and low in fructose on postprandial hepatic DNL and fatty acid partitioning and dietary fatty acid oxidation. Sixteen healthy adults (eight men, eight women) participated in this randomised cross-over study; study days were separated by a 4-week wash-out period. Hepatic DNL and dietary fatty acid oxidation were assessed using stable-isotope tracer methodology. Consumption of the high fructose meal significantly increased postprandial hepatic DNL to a greater extent than consumption of the low fructose meal and this effect was evident in women but not men. Despite an increase in hepatic DNL, there was no change in dietary fatty acid oxidation. Taken together, our data show that women are more responsive to ingestion of higher amounts of fructose than men and if continued over time this may lead to changes in hepatic fatty acid partitioning and eventually liver fat content.
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Project description:ObjectiveMetformin is a first-line pharmacotherapy in the treatment of type 2 diabetes, a condition closely associated with non-alcoholic fatty liver disease (NAFLD). Although metformin promotes weight loss and improves insulin sensitivity, its effect on intrahepatic triglyceride (IHTG) remains unclear. We investigated the effect of metformin on IHTG, hepatic de novo lipogenesis (DNL), and fatty acid (FA) oxidation in vivo in humans.Design and methodsMetabolic investigations, using stable-isotope tracers, were performed in ten insulin-resistant, overweight/obese human participants with NAFLD who were treatment naïve before and after 12 weeks of metformin treatment. The effect of metformin on markers of s.c. adipose tissue FA metabolism and function, along with the plasma metabolome, was investigated.ResultsTwelve weeks of treatment with metformin resulted in a significant reduction in body weight and improved insulin sensitivity, but IHTG content and FA oxidation remained unchanged. Metformin treatment was associated with a significant decrease in VLDL-triglyceride (TG) concentrations and a significant increase in the relative contribution of DNL-derived FAs to VLDL-TG. There were subtle and relatively few changes in s.c. adipose tissue FA metabolism and the plasma metabolome with metformin treatment.ConclusionsWe demonstrate the mechanisms of action of metformin whereby it improves insulin sensitivity and promotes weight loss, without improvement in IHTG; these observations are partly explained through increased hepatic DNL and a lack of change in FA oxidation.
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Project description:BACKGROUND:Obesity is defined as excessive fat mass and is a major cause of many chronic diseases such as diabetes, cardiovascular disease, and cancer. Increasing energy expenditure and regulating adipose tissue metabolism are important targets for the treatment of obesity. Serotonin (5-hydroxytryptophan [5-HT]) is a monoamine metabolite of the essential amino acid tryptophan. Here, we demonstrated that 5-HT in mature adipocytes regulated energy expenditure and lipid metabolism. METHODS:Tryptophan hydroxylase 1 (TPH1) is the rate-limiting enzyme during 5-HT synthesis in non-neural peripheral tissues. We generated adipose tissue-specific Tph1 knockout (Tph1 FKO) mice and adipose tissue-specific serotonin receptor 2A KO (Htr2a FKO) mice and analyzed their phenotypes during high-fat diet (HFD) induced obesity. RESULTS:Tph1 FKO mice fed HFD exhibited reduced lipid accumulation, increased thermogenesis, and resistance to obesity. In addition, Htr2a FKO mice fed HFD showed reduced lipid accumulation in white adipose tissue and resistance to obesity. CONCLUSION:These data suggest that the inhibition of serotonin signaling might be an effective strategy in obesity.
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