Despite its widespread use as a stabilizer across various industries over the past several decades, the health effects of chronic exposure to PFOA are still unclear. We administered PFOA by oral gavage (0, 12.5, 50, and 200 μg/day/mouse, eight groups) to male and female mice for six months. Body weight gain decreased with dose accompanied by increased liver weight, and PFOA altered liver damage-related-blood biochemical indicators and induced pathological lesions, including hepatocellular hypertrophy, cholangiofibrosis, and centrilobular hepatocellular vacuolation. Loss of the Golgi apparatus, formation of lamellar body-like structures, and lipid accumulation were observed in the liver of PFOA-treated mice. We also cohabited five pairs of male and female mice for the last ten days of administration, dosed PFOA to dam up to 28 days after birth, and investigated effects on reproduction and development. The survival rate of pups and the sex ratio of surviving mice decreased significantly at the highest dose. PFOA tissue concentration increased with the dose in the parent mice\'s liver and the pups\' blood and brain. Taken together, we suggest that PFOA primarily affects the liver and reproduction system and that disturbance in lipid metabolism and Golgi\'s structural stability may be involved in PFOA-induced toxicity.

Intestinal disease is one of the earliest manifestations of cystic fibrosis (CF) in children and is closely tied to deficits in growth and nutrition, both of which are directly linked to future mortality. Patients are treated aggressively with pancreatic enzyme replacement therapy and a high-fat diet to circumvent fat malabsorption, but this does not reverse growth and nutritional defects. We hypothesized that defects in chylomicron production could explain why CF body weights and nutrition are so resistant to clinical treatments. We used gold standard intestinal lipid absorption and metabolism approaches, including mouse mesenteric lymph cannulation, in vivo chylomicron secretion kinetics, transmission electron microscopy, small intestinal organoids, and chylomicron metabolism assays to test this hypothesis. In mice expressing the G542X mutation in cystic fibrosis transmembrane conductance regulator (CFTR-/- mice), we find that defective FFA trafficking across the epithelium into enterocytes drives a chylomicron formation defect. Furthermore, G542X mice secrete small, triglyceride-poor chylomicrons into the lymph and blood. These defective chylomicrons are cleared into extraintestinal tissues at ∼10-fold faster than WT chylomicrons. This defect in FFA absorption resulting in dysfunctional chylomicrons cannot be explained by steatorrhea or pancreatic insufficiency and is maintained in primary small intestinal organoids treated with micellar lipids. These studies suggest that the ultrahigh-fat diet that most people with CF are counselled to follow may instead make steatorrhea and malabsorption defects worse by overloading the absorptive capacity of the CF small intestine.

Type 2 diabetes (T2D) is a chronic metabolic disorder characterized by hyperglycemia and dyslipidemia. The termite fungus comb is an integral component of nests of termites, which are a global pest. Termite fungus comb polysaccharides (TFCPs) have been identified to possess antioxidant, anti-aging, and immune-enhancing properties. However, their physicochemical characteristics and their role in fighting diabetes have not been previously reported. In the current study, TFCPs were isolated and structurally characterized. The yield of TFCPs was determined to be 2.76%, and it was found to be composed of a diverse array of polysaccharides with varying molecular weights. The hypoglycemic and hypolipidemic effects of TFCPs, as well as their potential mechanisms of action, were investigated in a T2D mouse model. The results demonstrated that oral administration of TFCPs could alleviate fasting blood glucose levels, insulin resistance, hyperlipidemia, and the dysfunction of pancreatic islets in T2D mice. In terms of mechanisms, the TFCPs enhanced hepatic glycogenesis and glycolysis while inhibiting gluconeogenesis. Additionally, the TFCPs suppressed hepatic de novo lipogenesis and promoted fatty acid oxidation. Furthermore, the TFCPs altered the composition of the gut microbiota in the T2D mice, increasing the abundance of beneficial bacteria such as Allobaculum and Faecalibaculum, while reducing the levels of pathogens like Mailhella and Acetatifactor. Overall, these findings suggest that TFCPs may exert anti-diabetic effects by regulating hepatic glucose and lipid metabolism and the composition of the gut microbiota. These findings suggest that TFCPs can be used as a promising functional ingredient for the prevention and treatment of T2D.

Achilles tendinopathy (TP) is characterized as the third most common disease of the musculoskeletal system, and occurs in three phases. There is currently no evidence of effective treatment for this medical condition. In this study, the modulatory effects of the minimally invasive technique intratissue percutaneous electrolysis (EPI) and combinations of EPI with four nutritional factors included in the diet, hydroxytyrosol (HT), maslinic acid (MA), glycine, and aspartate (AA), on hepatic intermediary metabolism was examined in Wistar rats with induced tendinopathy at various stages of TP. Results obtained showed that induced tendinopathy produced alterations in the liver intermediary metabolisms of the rats. Regarding carbohydrate metabolism, a reduction in the activity of pro-inflammatory enzymes in the later stages of TP was observed following treatment with EPI alone. Among the combined treatments using nutritional factors with EPI, HT+EPI and AA+EPI had the greatest effect on reducing inflammation in the late stages of TP. In terms of lipid metabolism, the HT+EPI and AA+EPI groups showed a decrease in lipogenesis. In protein metabolism, the HT+EPI group more effectively reduced the inflammatory effects of induced TP. Treatment with EPI combined with nutritional factors might help regulate intermediary metabolism in TP disease and reduce the inflammation process.

The incidence of nonalcoholic fatty liver disease (NAFLD), or metabolic dysfunction-associated fatty liver disease (MAFLD), is increasing in adults and children. Unfortunately, effective pharmacological treatments remain unavailable. Single nucleotide polymorphisms (SNPs) in the patatin-like phospholipase domain-containing protein (PNPLA3 I148M) have the most significant genetic association with the disease at all stages of its progression. A roadblock to identifying potential treatments for PNPLA3-induced NAFLD is the lack of a human cell platform that recapitulates the PNPLA3 I148M-mediated onset of lipid accumulation. Hepatocyte-like cells were generated from PNPLA3-/- and PNPLA3I148M/M-induced pluripotent stem cells (iPSCs). Lipid levels were measured by staining with BODIPY 493/503 and were found to increase in PNPLA3 variant iPSC-derived hepatocytes. A small-molecule screen identified multiple compounds that target Src/PI3K/Akt signaling and could eradicate lipid accumulation in these cells. We found that drugs currently in clinical trials for cancer treatment that target the same pathways also reduced lipid accumulation in PNPLA3 variant cells.

Plant lipids are essential cell constituents with many structural, storage, signaling, and defensive functions. During plant-pathogen interactions, lipids play parts in both the preexisting passive defense mechanisms and the pathogen-induced immune responses at the local and systemic levels. They interact with various components of the plant immune network and can modulate plant defense both positively and negatively. Under biotic stress, lipid signaling is mostly associated with oxygenated natural products derived from unsaturated fatty acids, known as oxylipins; among these, jasmonic acid has been of great interest as a specific mediator of plant defense against necrotrophic pathogens. Although numerous studies have documented the contribution of oxylipins and other lipid-derived species in plant immunity, their specific roles in plant-pathogen interactions and their involvement in the signaling network require further elucidation. This review presents the most relevant and recent studies on lipids and lipid-derived signaling molecules involved in plant-pathogen interactions, with the aim of providing a deeper insight into the mechanisms underpinning lipid-mediated regulation of the plant immune system.

Lipid mediators from fatty acid oxidation have been shown to be associated with the severity of Krabbe disease (KD), a disorder linked to mutations in the galactosylceramidase (GALC) gene. This study aims to investigate the effects of n-3 polyunsaturated fatty acid (PUFA) supplementation on KD traits and fatty acid metabolism using Twitcher (Tw) animals as a natural model for KD. Wild-type (Wt), heterozygous (Ht), and affected Tw animals were treated orally with 36 mg n-3 PUFAs/kg body weight/day from 10 to 35 days of life. The end product of PUFA peroxidation (8-isoprostane), the lipid mediator involved in the resolution of inflammatory exudates (resolvin D1), and the total amount of n-3 PUFAs were analyzed in the brains of mice. In Tw mice, supplementation with n-3 PUFAs delayed the manifestation of disease symptoms (p < 0.0001), and in the bran, decreased 8-isoprostane amounts (p < 0.0001), increased resolvin D1 levels (p < 0.005) and increased quantity of total n-3 PUFAs (p < 0.05). Furthermore, total brain n-3 PUFA levels were associated with disease severity (r = -0.562, p = 0.0001), resolvin D1 (r = 0.712, p < 0.0001), and 8-isoprostane brain levels (r = -0.690, p < 0.0001). For the first time in a natural model of KD, brain levels of n-3 PUFAs are shown to determine disease severity and to be involved in the peroxidation of brain PUFAs as well as in the production of pro-resolving lipid mediators. It is also shown that dietary supplementation with n-3 PUFAs leads to a slowing of the phenotypic presentation of the disease and restoration of lipid mediator production.

Thyroid cancer (TC) is a neoplasm with an increasing incidence worldwide. Its etiology is complex and based on a multi-layered interplay of factors. Among these, disorders of lipid metabolism have emerged as an important area of investigation. Cancer cells are metabolically reprogrammed to promote their rapid growth, proliferation, and survival. This reprogramming is associated with significant changes at the level of lipids, mainly fatty acids (FA), as they play a critical role in maintaining cell structure, facilitating signaling pathways, and providing energy. These lipid-related changes help cancer cells meet the increased demands of continued growth and division while adapting to the tumor microenvironment. In this review, we examine lipid metabolism at different stages, including synthesis, transport, and oxidation, in the context of TC and the effects of obesity and hormones on TC development. Recent scientific efforts have revealed disturbances in lipid homeostasis that are specific to thyroid cancer, opening up potential avenues for early detection and targeted therapeutic interventions. Understanding the intricate metabolic pathways involved in FA metabolism may provide insights into potential interventions to prevent cancer progression and mitigate its effects on surrounding tissues.

The ketogenic diet (KD) is characterized by minimal carbohydrate, moderate protein, and high fat intake, leading to ketosis. It is recognized for its efficiency in weight loss, metabolic health improvement, and various therapeutic interventions. The KD enhances glucose and lipid metabolism, reducing triglycerides and total cholesterol while increasing high-density lipoprotein levels and alleviating dyslipidemia. It significantly influences adipose tissue hormones, key contributors to systemic metabolism. Brown adipose tissue, essential for thermogenesis and lipid combustion, encounters modified UCP1 levels due to dietary factors, including the KD. UCP1 generates heat by uncoupling electron transport during ATP synthesis. Browning of the white adipose tissue elevates UCP1 levels in both white and brown adipose tissues, a phenomenon encouraged by the KD. Ketone oxidation depletes intermediates in the Krebs cycle, requiring anaplerotic substances, including glucose, glycogen, or amino acids, for metabolic efficiency. Methylation is essential in adipogenesis and the body\'s dietary responses, with DNA methylation of several genes linked to weight loss and ketosis. The KD stimulates FGF21, influencing metabolic stability via the UCP1 pathways. The KD induces a reduction in muscle mass, potentially involving anti-lipolytic effects and attenuating proteolysis in skeletal muscles. Additionally, the KD contributes to neuroprotection, possesses anti-inflammatory properties, and alters epigenetics. This review encapsulates the metabolic effects and signaling induced by the KD in adipose tissue and major metabolic organs.