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Fatty acid uptake and altered metabolism constitute hallmarks of metastasis 1 , 2 , yet evidence of the underlying biology, as well as whether all dietary fatty acids are prometastatic, is lacking. Here we show that dietary palmitic acid (PA), but not oleic acid or linoleic acid, promotes metastasis in oral carcinomas and melanoma in mice. Tumours from mice that were fed a short-term palm-oil-rich diet (PA), or tumour cells that were briefly exposed to PA in vitro, remained highly metastatic even after being serially transplanted (without further exposure to high levels of PA). This PA-induced prometastatic memory requires the fatty acid transporter CD36 and is associated with the stable deposition of histone H3 lysine 4 trimethylation by the methyltransferase Set1A (as part of the COMPASS complex (Set1A/COMPASS)). Bulk, single-cell and positional RNA-sequencing analyses indicate that genes with this prometastatic memory predominantly relate to a neural signature that stimulates intratumoural Schwann cells and innervation, two parameters that are strongly correlated with metastasis but are aetiologically poorly understood 3 , 4 . Mechanistically, tumour-associated Schwann cells secrete a specialized proregenerative extracellular matrix, the ablation of which inhibits metastasis initiation. Both the PA-induced memory of this proneural signature and its long-term boost in metastasis require the transcription factor EGR2 and the glial-cell-stimulating peptide galanin. In summary, we provide evidence that a dietary metabolite induces stable transcriptional and chromatin changes that lead to a long-term stimulation of metastasis, and that this is related to a proregenerative state of tumour-activated Schwann cells. Palmitic acid induces stable transcriptional and chromatin changes that lead to long-term stimulation of metastasis in orthotopic models of cancer through the secretion by tumour-associated Schwann cells of a specialized proregenerative extracellular matrix, the ablation of which inhibits metastasis initiation.

The article examines the molecular mechanism of the Ca(2+)-dependent cyclosporin A (CsA)-insensitive permeability transition in rat liver mitochondria induced by α,ω-dioic acids. The addition of α,ω-hexadecanedioic acid (HDA) to Ca(2+)-loaded liver mitochondria was shown to induce a high-amplitude swelling of the organelles, a drop of membrane potential and the release of Ca(2+) from the matrix, the effects being insensitive to CsA. The experiments with liposomes loaded with sulforhodamine B (SRB) revealed that, like palmitic acid (PA), HDA was able to cause permeabilization of liposomal membranes. However, the kinetics of HDA- and PA-induced release of SRB from liposomes was different, and HDA was less effective than PA in the induction of SRB release. Using the method of ultrasound interferometry, we also showed that the addition of Ca(2+) to HDA-containing liposomes did not change the phase state of liposomal membranes-in contrast to what was observed when Ca(2+) was added to PA-containing vesicles. It was suggested that HDA/Ca(2+)- and PA/Ca(2+)-induced permeability transition occurs by different mechanisms. Using the method of dynamic light scattering, we further revealed that the addition of Ca(2+) to HDA-containing liposomes induced their aggregation/fusion. Apparently, these processes result in a partial release of SRB due to the formation of fusion pores. The possibility that this mechanism underlies the HDA/Ca(2+)-induced permeability transition of the mitochondrial membrane is discussed.

The fact that the identity of the cells that initiate metastasis in most human cancers is unknown hampers the development of antimetastatic therapies. Here we describe a subpopulation of CD44 bright cells in human oral carcinomas that do not overexpress mesenchymal genes, are slow-cycling, express high levels of the fatty acid receptor CD36 and lipid metabolism genes, and are unique in their ability to initiate metastasis. Palmitic acid or a high-fat diet specifically boosts the metastatic potential of CD36 + metastasis-initiating cells in a CD36-dependent manner. The use of neutralizing antibodies to block CD36 causes almost complete inhibition of metastasis in immunodeficient or immunocompetent orthotopic mouse models of human oral cancer, with no side effects. Clinically, the presence of CD36 + metastasis-initiating cells correlates with a poor prognosis for numerous types of carcinomas, and inhibition of CD36 also impairs metastasis, at least in human melanoma- and breast cancer-derived tumours. Together, our results indicate that metastasis-initiating cells particularly rely on dietary lipids to promote metastasis. Human oral carcinoma cells expressing high levels of the fatty acid receptor CD36 initiate metastasis in mouse models, and metastasis is increased by palmitic acid or a fatty diet and decreased by blockade of CD36. Metastasis-initiating cells in oral carcinoma The ability to identify cells with metastatic potential is of clinical importance for the development of anti-metastatic treatment. Salvador Aznar Benitah and colleagues have identified high metastatic potential in a population of cells expressing high levels of the fatty acid receptor CD36 in human oral carcinoma samples. The cells initiate metastasis in mouse models. Metastasis is increased by palmitic acid or a fatty diet, and decreased by CD36 blockade.

Reactive oxygen species (ROS) contribute to the development of non-alcoholic fatty liver disease. ROS generation by infiltrating macrophages involves multiple mechanisms, including Toll-like receptor 4 (TLR4)-mediated NADPH oxidase (NOX) activation. Here, we show that palmitate-stimulated CD11b + F4/80 low hepatic infiltrating macrophages, but not CD11b + F4/80 high Kupffer cells, generate ROS via dynamin-mediated endocytosis of TLR4 and NOX2, independently from MyD88 and TRIF. We demonstrate that differently from LPS-mediated dimerization of the TLR4–MD2 complex, palmitate binds a monomeric TLR4–MD2 complex that triggers endocytosis, ROS generation and increases pro-interleukin-1β expression in macrophages. Palmitate-induced ROS generation in human CD68 low CD14 high macrophages is strongly suppressed by inhibition of dynamin. Furthermore, Nox2 -deficient mice are protected against high-fat diet-induced hepatic steatosis and insulin resistance. Therefore, endocytosis of TLR4 and NOX2 into macrophages might be a novel therapeutic target for non-alcoholic fatty liver disease. Reactive species of oxygen promote the development of hepatic steatosis. Here, Kim et al. demonstrate that palmitate stimulates macrophage infiltration and increases oxidative stress during steatosis by binding to the TLR4–MD2 complex, which results in the activation of NOX2.

Background Non-alcoholic fatty liver disease (NAFLD) is a multifaceted metabolic disorder, whose global prevalence is rapidly increasing. Acetyl CoA carboxylases 1 (ACACA) is the key enzyme that controls the rate of fatty acid synthesis. Hence, it is crucial to investigate the function of ACACA in regulating lipid metabolism during the progress of NAFLD. Methods Firstly, a fatty liver mouse model was established by high-fat diet at 2nd, 12th, and 20th week, respectively. Then, transcriptome analysis was performed on liver samples to investigate the underlying mechanisms and identify the target gene of the occurrence and development of NAFLD. Afterwards, lipid accumulation cell model was induced by palmitic acid and oleic acid (PA ∶ OA molar ratio = 1∶2). Next, we silenced the target gene ACACA using small interfering RNAs (siRNAs) or the CMS-121 inhibitor. Subsequently, experiments were performed comprehensively the effects of inhibiting ACACA on mitochondrial function and lipid metabolism, as well as on AMPK- PPARα- CPT1A pathway. Results This data indicated that the pathways significantly affected by high-fat diet include lipid metabolism and mitochondrial function. Then, we focus on the target gene ACACA. In addition, the in vitro results suggested that inhibiting of ACACA in vitro reduces intracellular lipid accumulation, specifically the content of TG and TC. Furthermore, ACACA ameliorated mitochondrial dysfunction and alleviate oxidative stress, including MMP complete, ATP and ROS production, as well as the expression of mitochondria respiratory chain complex (MRC) and AMPK proteins. Meanwhile, ACACA inhibition enhances lipid metabolism through activation of PPARα/CPT1A, leading to a decrease in intracellular lipid accumulation. Conclusion Targeting ACACA can reduce lipid accumulation by mediating the AMPK- PPARα- CPT1A pathway, which regulates lipid metabolism and alleviates mitochondrial dysfunction.

One of the most common lipids in the human body is palmitic acid (PA), a saturated fatty acid with essential functions in brain cells. PA is used by cells as an energy source, besides being a precursor of signaling molecules and protein tilting across the membrane. Although PA plays physiological functions in the brain, its excessive accumulation leads to detrimental effects on brain cells, causing lipotoxicity. This mechanism involves the activation of toll-like receptors (TLR) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathways, with the consequent release of pro-inflammatory cytokines, increased production of reactive oxygen species (ROS), endoplasmic reticulum (ER) stress, and autophagy impairment. Importantly, some of the cellular changes induced by PA lead to an augmented susceptibility to the development of Alzheimer’s and Parkinson´s diseases. Considering the complexity of the response to PA and the intrinsic differences of the brain, in this review, we provide an overview of the molecular and cellular effects of PA on different brain cells and their possible relationships with neurodegenerative diseases (NDs). Furthermore, we propose the use of other fatty acids, such as oleic acid or linoleic acid, as potential therapeutic approaches against NDs, as these fatty acids can counteract PA’s negative effects on cells.

The relationship between systemic immunity and neuroinflammation is widely recognised. Infiltration of peripheral immune cells to the CNS during certain chronic inflammatory states contributes significantly to neuropathology. Obesity and its co-morbidities are primary risk factors for neuroinflammatory and neurodegenerative conditions, including Alzheimer’s disease (AD). Dietary fats are among the most proinflammatory components of the obesogenic diet and play a prominent role in the low-grade systemic inflammation associated with the obese state. Saturated fatty acid (SFA) is largely implicated in the negative consequences of obesity, while the health benefits of monounsaturated fatty acid (MUFA) are widely acknowledged. The current study sought to explore whether SFA and MUFA differently modulate inflammatory responses in the brain, compared with peripheral immune cells. Moreover, we assessed the neuroinflammatory impact of high-fat-induced obesity and hypothesised that a MUFA-rich diet might mitigate inflammation despite obesogenic conditions. Toll-like receptor (TLR)2 mediates the inflammation associated with both obesity and AD. Using the TLR2 agonist lipoteichoic acid (LTA), we report that pre-exposure to either palmitic acid (PA) or oleic acid (OA) attenuated cytokine secretion from microglia, but heightened sensitivity to nitric oxide (NO) production. The reduction in cytokine secretion was mirrored in LTA-stimulated macrophages following exposure to PA only, while effects on NO were restricted to OA, highlighting important cell-specific differences. An obesogenic diet over 12 weeks did not induce prominent inflammatory changes in either cortex or hippocampus, irrespective of fat composition. However, we reveal a clear disparity in the effects of MUFA under obesogenic and non-obesogenic conditions.

Background Dihydromyricetin (DHM), a flavonoid compound of natural origin, has been identified in high concentrations in ampelopsis grossedentata and has a broad spectrum of biological and pharmacological functions, particularly in regulating glucose and lipid metabolism. The objective of this research was to examine how DHM affected nonalcoholic fatty liver disease (NAFLD) and its underlying mechanisms involved in the progression of NAFLD in a rat model subjected to a high-fat diet (HFD). Additionally, the study examines the underlying mechanisms in a cellular model of steatohepatitis using palmitic acid (PA)-treated HepG2 cells, with a focus on the potential correlation between autophagy and hepatic insulin resistance (IR) in the progress of NAFLD. Methods SD rats were exposed to a HFD for a period of eight weeks, followed by a treatment with DHM (at doses of 50, 100, and 200 mg·kg −1 ·d −1 ) for additional six weeks. The HepG2 cells received a 0.5 mM PA treatment for 24 h, either alone or in conjunction with DHM (10 µM). The histopathological alterations were assessed by the use of Hematoxylin–eosin (H&E) staining. The quantification of glycogen content and lipid buildup in the liver was conducted by the use of PAS and Oil Red O staining techniques. Serum lipid and liver enzyme levels were also measured. Autophagic vesicle and autolysosome morphology was studied using electron microscopy. RT-qPCR and/or western blotting techniques were used to measure IR- and autophagy-related factors levels. Results The administration of DHM demonstrated efficacy in ameliorating hepatic steatosis, as seen in both in vivo and in vitro experimental models. Moreover, DHM administration significantly increased GLUT2 expression, decreased G6Pase and PEPCK expression, and improved IR in the hepatic tissue of rats fed a HFD and in cells exhibiting steatosis. DHM treatment elevated Beclin 1, ATG 5, and LC3-II levels in hepatic steatosis models, correlating with autolysosome formation. The expression of AMPK levels and its downstream target PGC-1α, and PPARα were decreased in HFD-fed rats and PA-treated hepatocytes, which were reversed through DHM treatment. AMPK/ PGC-1α and PPARα knockdown reduced the impact of DHM on hepatic autophagy, IR and accumulation of hepatic lipid. Conclusions Our findings revealed that AMPK/ PGC-1α, PPARα-dependent autophagy pathways in the pathophysiology of IR and hepatic steatosis has been shown, suggesting that DHM might potentially serve as a promising treatment option for addressing this disease. Graphical Abstract

A central paradox in type 2 diabetes is the apparent selective nature of hepatic insulin resistance—wherein insulin fails to suppress hepatic glucose production yet continues to stimulate lipogenesis, resulting in hyperglycemia, hyperlipidemia, and hepatic steatosis. Although efforts to explain this have focused on finding a branch point in insulin signaling where hepatic glucose and lipid metabolism diverge, we hypothesized that hepatic triglyceride synthesis could be driven by substrate, independent of changes in hepatic insulin signaling. We tested this hypothesis in rats by infusing [U- ¹³C] palmitate to measure rates of fatty acid esterification into hepatic triglyceride while varying plasma fatty acid and insulin concentrations independently. These experiments were performed in normal rats, high fat-fed insulin-resistant rats, and insulin receptor 2′- O -methoxyethyl chimeric antisense oligonucleotide-treated rats. Rates of fatty acid esterification into hepatic triglyceride were found to be dependent on plasma fatty acid infusion rates, independent of changes in plasma insulin concentrations and independent of hepatocellular insulin signaling. Taken together, these results obviate a paradox of selective insulin resistance, because the major source of hepatic lipid synthesis, esterification of preformed fatty acids, is primarily dependent on substrate delivery and largely independent of hepatic insulin action. Significance The paradox of selective hepatic insulin resistance, wherein the insulin-resistant liver fails to suppress glucose production but continues to produce triglycerides, is central to the pathophysiology of type 2 diabetes. We hypothesized that hepatic triglyceride synthesis is regulated mostly by fatty acid delivery to the liver and independent of changes in hepatic insulin signaling. To examine this hypothesis, we used a novel LC-MS/MS method to measure rates of hepatic fatty acid esterification in vivo. In contrast to hepatic de novo hepatic lipogenesis, rates of hepatic esterification of fatty acids into triglyceride was primarily dependent on fatty acid delivery and independent of hepatic insulin action, providing an explanation for increased hepatic triglyceride synthesis in the presence of hepatic insulin resistance.

ObjectiveFibroblast growth factor 15/19 (FGF15/19), an enterokine that regulates synthesis of hepatic bile acids (BA), has been proposed to influence fat metabolism. Without FGF15/19, mouse liver regeneration after partial hepatectomy (PH) is severely impaired. We studied the role of FGF15/19 in response to a high fat diet (HFD) and its regulation by saturated fatty acids. We developed a fusion molecule encompassing FGF19 and apolipoprotein A-I, termed Fibapo, and evaluated its pharmacological properties in fatty liver regeneration.Design Fgf15−/− mice were fed a HFD. Liver fat and the expression of fat metabolism and endoplasmic reticulum (ER) stress-related genes were measured. Influence of palmitic acid (PA) on FGF15/19 expression was determined in mice and in human liver cell lines. In vivo half-life and biological activity of Fibapo and FGF19 were compared. Hepatoprotective and proregenerative activities of Fibapo were evaluated in obese db/db mice undergoing PH.ResultsHepatosteatosis and ER stress were exacerbated in HFD-fed Fgf15−/− mice. Hepatic expression of Pparγ2 was elevated in Fgf15−/− mice, being reversed by FGF19 treatment. PA induced FGF15/19 expression in mouse ileum and human liver cells, and FGF19 protected from PA-mediated ER stress and cytotoxicity. Fibapo reduced liver BA and lipid accumulation, inhibited ER stress and showed enhanced half-life. Fibapo provided increased db/db mice survival and improved regeneration upon PH.ConclusionsFGF15/19 is essential for hepatic metabolic adaptation to dietary fat being a physiological regulator of Pparγ2 expression. Perioperative administration of Fibapo improves fatty liver regeneration.