Impact of Lipid Metabolism on Macrophage Polarization: Implications for Inflammation and Tumor Immunity.

Macrophage polarization is influenced by lipids, which also exert significant control over macrophage functions. Lipids and their metabolites are players in intricate signaling pathways that modulate macrophages' responses to pathogens, phagocytosis, ferroptosis, and inflammation. This review focuses on lipid metabolism and macrophage functions and addresses potential molecular targets for the treatment of macrophage-related diseases. While lipogenesis is crucial for lipid accumulation and phagocytosis in M1 macrophages, M2 macrophages likely rely on fatty acid ß-oxidation to utilize fatty acids as their primary energy source. Cholesterol metabolism, regulated by factors such as SREBPs, PPARs, and LXRs, is associated with the cholesterol efflux capacity and the formation of foam cells (M2-like macrophages). Foam cells, which are targets for atherosclerosis, are associated with an increase in inflammatory cytokines. Lipolysis and fatty acid uptake markers, such as CD36, also contribute to the production of cytokines. Enhancing the immune system through the inhibition of lipid-metabolism-related factors can potentially serve as a targeted approach against tumor cells. Cyclooxygenase inhibitors, which block the conversion of arachidonic acid into various inflammatory mediators, influence macrophage polarization and have generated attention in cancer research.

Plant bioactive compounds from Mediterranean diet improve risk factors for metabolic syndrome.

Mediterranean (Med) dietary pattern consists of moderate or high consumption of foods that are linked to reduced risk factors for metabolic syndrome (MetS). This comprehensive review evaluates studies on Med diet-representative foods and beverages, such as red wine and olive oil, to understand the inverse associations of Med diet and MetS. The intake of dietary fibre, unsaturated fatty acids, vitamins, and polyphenols - including flavonoids and stilbenes - help to explain the benefits of Med diet on abdominal adiposity, glucose intolerance, hyperlipidaemia, and high blood pressure to some extent. Antioxidant and anti-inflammatory properties of polyphenols as well as the effects of unsaturated fatty acids on lipid metabolism are part of the underlying mechanisms. Overall, this review shows that dietary interventions using Med diet components improve MetS health markers in humans and/or rodents.

Moringa isothiocyanate-1 inhibits LPS-induced inflammation in mouse myoblasts and skeletal muscle.

This study aims to investigate the anti-inflammatory effects of moringa isothiocyanate-1 (MIC-1) extracted from seeds of Moringa oleifera Lam. in lipopolysaccharide (LPS)-induced inflammation models. MIC-1 decreased nitric oxide production and reduced the expression of pro-inflammatory markers (TNF-α, Ifn-α, IL-1ß, IL-6) in C2C12 myoblasts. The daily oral treatment of MIC-1 (80 mg/kg) for three days significantly reduced the expression of pro-inflammatory markers in gastrocnemius muscle tissue of LPS-treated C57BL/6 male mice. Transcriptomic analysis provided further insights into the inhibitory effects of MIC-1 on the LPS-induced inflammation, which suggested that MIC-1 affects inflammation and immunity-related genes in myoblasts and skeletal muscle tissue. MIC-1 inhibited the nuclear accumulation of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) in the LPS-treated myoblasts. Our data support the hypothesis that the MIC-1's effects in the muscle cells are mediated through the inhibition of the NF-κB translocation in the nucleus, which, in turn, results in immunomodulating and anti-inflammatory responses at the gene expression levels.

Maternal preconception PFOS exposure of Drosophila melanogaster alters reproductive capacity, development, morphology and nutrient regulation.

Perfluorooctanesulfonic acid (PFOS) is a persistent synthetic surfactant widely detected in the environment. Developmental PFOS exposures are associated with low birth weight and chronic exposures increase risk for obesity and type 2 diabetes. As an obesogen, PFOS poses a major public health exposure risk and much remains to be understood about the critical windows of exposure and mechanisms impacted, especially during preconception. Here, we leverage evolutionarily conserved pathways and processes in the fruit fly Drosophila melanogaster (wild-type Canton-S and megalin-UAS RNAi transgenic fly lines) to investigate the window of maternal preconception exposure to PFOS on reproductive and developmental toxicity, and examine receptor (megalin)-mediated endocytosis of nutrients and PFOS into the oocyte as a potential mechanism. Preconception exposure to 2 ng PFOS/female resulted in an internal concentration of 0.081 ng/fly over two days post exposure, no mortality and reduced megalin transcription. The number of eggs laid 1-3 days post exposure was reduced and contained 0.018 ng PFOS/egg. Following heat shock, PFOS was significantly reduced in eggs from megalin-knockdown transgenic females. Cholesterol and triglycerides were increased in eggs laid immediately following PFOS exposure by non-heat shocked transgenic females whereas decreased cholesterol and increased protein levels were found in eggs laid by heat shocked transgenic females. Preconception exposure likewise increased cholesterol in early emerging wildtype F1 adults and also resulted in progeny with a substantial developmental delay, a reduction in adult weights, and altered transcription of Drosophila insulin-like peptide genes. These findings support an interaction between PFOS and megalin that interferes with normal nutrient transport during oocyte maturation and embryogenesis, which may be associated with later in life developmental delay and reduced weight.

Azelaic Acid Promotes Caenorhabditis elegans Longevity at Low Temperature Via an Increase in Fatty Acid Desaturation.

PURPOSE: Azelaic acid (AzA) is a dicarboxylic acid naturally occurring in various grains having anti-inflammatory and anti-oxidation properties. Recently, AzA is shown to reduce high-fat diet-induced adiposity in animals. However, its physiological role in lipid metabolism and aging in various environmental stresses is unknown. METHODS AND RESULTS: Using C. elegans as an invertebrate animal model, we demonstrate that AzA suppresses fat accumulation with no effect on lifespan at normal temperatures. Moreover, AzA promotes lifespan at low temperatures by elevation of unsaturated long-chain fatty acids and expression of genes in fatty acid desaturation. We further find that genes encoding fatty acid desaturases such as fat-1, fat-5, fat-6, and fat-7 are crucial for the lifespan-extending effect of AzA at low temperature. CONCLUSIONS: Taken together, our results suggest that AzA promotes adaption to low temperature in C. elegans via shifting fatty acid profile to unsaturated long-chain fatty acids.

Fat-lowering effects of isorhamnetin are via NHR-49-dependent pathway in Caenorhabditis elegans.

Isorhamnetin (3-O-methylquercetin), a flavonol found in dill weed, sea buckthorn berries, kale and onions, has been suggested to have anti-obesity effects, but there is limited evidence of its mechanisms of action on lipid metabolism. The goal of this study was to investigate the effects of isorhamnetin on lipid metabolism using Caenorhabditis elegans as an animal model. Isorhamnetin reduced fat accumulation without affecting food intake or energy expenditure in C. elegans. The isorhamnetin's fat-lowering effects were dependent on nhr-49, a homolog of the human peroxisome proliferator-activated receptor alpha (PPARα). Isorhamnetin upregulated an enoyl-CoA hydratase (ech-1.1, involved in fatty acid ß-oxidation) and adipose triglyceride lipase (atgl-1, involved in lipolysis) via NHR-49-dependent pathway at transcriptional levels. Isorhamnetin also upregulated the C. elegans AMP-activated protein kinase (AMPK) subunits homologs (aak-1 and aak-2), involved in energy homeostasis. These results suggest that isorhamnetin reduces body fat by increasing fat oxidation in part via NHR-49/PPARα-dependent pathway.

Kahweol Reduces Food Intake of Caenorhabditis elegans.

The coffee diterpene kahweol may contribute to the anti-obesity effects of coffee but its physiological effects have yet to be elucidated. Caenorhabditis elegans is used as an animal model in obesity research because its lipid metabolism is conserved in humans. The goal was to investigate kahweol's effects on lipid metabolism in C. elegans. Kahweol at 120 µM reduced fat accumulation by 17% compared to the control, which was associated with a reduced food intake. Kahweol did not reduce fat in eat-2 mutants, which have a disrupted pharynx contraction rate, suggesting that the fat-lowering effects of kahweol were dependent on food intake. Lipid metabolism-related gene homologues of tubby protein (tub-1), enoyl-CoA hydratase (ech-1.1), adipose triglyceride lipase (atgl-1), insulin/insulin-like growth receptor (daf-2), and forkhead box O transcription factor (daf-16) were also associated with changes in food intake by kahweol. Therefore, kahweol's fat-lowering effects are due to a reduction of food intake in C. elegans.

Butein inhibits lipogenesis in Caenorhabditis elegans.

Butein, a flavonoid found in annatto seeds and lacquer trees, may be used for many health benefits, including the prevention of obesity. However, its anti-obesity effects are not completely understood; in particular, the effects of butein on the regulation of lipid metabolism have not been explained. Thus, the goal of the current study was to determine the effects of butein on lipid metabolism in Caenorhabditis elegans, which is a multi-organ nematode used as an animal model in obesity research. Butein at 70 µM reduced triglyceride content by 27% compared to the control without altering food intake and energy expenditure. The reduced triglyceride content by butein was associated with the downregulation of sbp-1, fasn-1, and fat-7, the lipogenesis-related homologs of sterol regulatory element-binding proteins, fatty acid synthase and stearoyl-CoA desaturase, respectively. Furthermore, fat-7 and skn-1, a homolog of nuclear respiratory factors, were identified as genetic requirements for butein's effects on triglyceride content in C. elegans. The effects of butein on sbp-1 and fasn-1 were dependent on skn-1, but the downregulation of fat-7 was independent of skn-1. These results suggest that the inhibitory effects of butein on lipogenesis are via SKN-1- and FAT-7-dependent pathways in C. elegans.

C. elegans ACAT regulates lipolysis and its related lifespan in fasting through modulation of the genes in lipolysis and insulin/IGF-1 signaling.

Overly active acyl-coenzyme A: cholesterol acyltransferases (ACATs) are known to contribute to the development of atherosclerosis, cancer cell proliferation and de novo lipogenesis. However, the role of ACAT in systemic lipid metabolism and its consequence of aging is unknown. Using avasimibe, a clinically proven ACAT inhibitor, and mboa-1 mutant strain, a homologous to mammalian ACAT, herein, we found that Ava treatment and mboa-1 mutant exhibited a decreased fat accumulation during feeding and increased lipolysis with extended lifespan of C. elegans during fasting. Our study highlights the essential role of ACAT inhibitor and mboa-1 in fat mobilization and the survival of C. elegans in fasting through the modulation of the genes involved in lipolysis and insulin/IGF-1 signaling.

Cafestol increases fat oxidation and energy expenditure in Caenorhabditis elegans via DAF-12-dependent pathway.

Cafestol, a coffee diterpene, is a known agonist of farnesoid X receptors (FXR), which are involved in cholesterol homeostasis. FXR plays critical roles in other lipid metabolic pathways, including fat oxidation; however, little is known about cafestol's effects on fatty acid metabolism. Thus, the goal was to investigate cafestol's effects on fatty acid metabolism using Caenorhabditis elegans. Cafestol at 60 µM reduced fat accumulation and increased locomotor activity (an indicator of energy expenditure) by 20% and 38%, respectively, compared to the control. Cafestol's effects were dependent on daf-12 (a functional homolog of the human FXR) with upregulation of ech-1.1 (a homolog of enoyl-CoA hydratase involved in fatty acid ß-oxidation) and tub-1 (an ortholog of the human TUBBY involved in the neurological regulation of energy expenditure) without any effects on lipogenesis, lipolysis or lipid uptake and transport. Therefore, cafestol increased fat oxidation and energy expenditure via DAF-12-dependent pathway in C. elegans.

Mechanisms of action of coffee bioactive components on lipid metabolism.

Coffee consumption is associated with reduced risk of metabolic syndrome, obesity and diabetes, which may be related to the effects of coffee and its bioactive components on lipid metabolism. Coffee contains caffeine, a known neuromodulator that acts as an adenosine receptor antagonist, as well as other components, such as chlorogenic acids, trigonelline, cafestol and kahweol. Thus, this review discusses the up-to-date knowledge of mechanisms of action of coffee and its bioactive compounds on lipid metabolism. Although there is evidence that coffee and/or its bioactive compounds regulate transcription factors (e.g. peroxisome proliferator-activated receptors and sterol regulatory element binding proteins) and enzymes (e.g. AMP-activated protein kinase) involved in lipogenesis, lipid uptake, transport, fatty acid ß-oxidation and/or lipolysis, needs for the understanding of coffee and its effects on lipid metabolism in humans remain to be answered.

Permethrin and ivermectin modulate lipid metabolism in steatosis-induced HepG2 hepatocyte.

Recent studies have reported the positive association between exposure to insecticides and increased risk of obesity and type 2 diabetes, which are closely associated with non-alcoholic fatty liver disease (NAFLD). However, it is not known if insecticide exposure can contribute to NAFLD. Thus, the goal of the current study was to determine if insecticide exposures can exacerbate the physiological conditions of NAFLD by modulating hepatic lipid metabolism. The effects of 12 insecticides on triglycerides (TG) accumulation were tested using palmitic acid (PA)-induced HepG2 hepatoma steatosis model. Results showed that among tested insecticides, permethrin and ivermectin significant interacted with palmitic acid to potentiate (permethrin) or decrease (ivermectin) TG accumulation. Further study showed that permethrin significantly promoted fatty acid synthesis, while suppressed lipid oxidation-related genes only under steatosis conditions. In comparison, ivermectin inhibited lipogenesis-related genes and promoted farnesoid X receptor, which upregulates fatty acid oxidation. Results in this study suggested that hepatic lipid metabolism may be more susceptible to insecticide exposure in the presence of excessive fatty acids, which can be associated with the development of NAFLD.