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The Journal of Nutritional Biochemistry Feb 2023Squalene is a key minor component of virgin olive oil, the main source of fat in the Mediterranean diet, and had shown to improve the liver metabolism in rabbits and...
Dietary squalene supplementation decreases triglyceride species and modifies phospholipid lipidomic profile in the liver of a porcine model of non-alcoholic steatohepatitis.
Squalene is a key minor component of virgin olive oil, the main source of fat in the Mediterranean diet, and had shown to improve the liver metabolism in rabbits and mice. The present research was carried out to find out whether this effect was conserved in a porcine model of hepatic steatohepatitis and to search for the lipidomic changes involved. The current study revealed that a 0.5% squalene supplementation to a steatotic diet for a month led to hepatic accumulation of squalene and decreased triglyceride content as well as area of hepatic lipid droplets without influencing cholesterol content or fiber areas. However, ballooning score was increased and associated with the hepatic squalene content. Of forty hepatic transcripts related to lipid metabolism and hepatic steatosis, only citrate synthase and a non-coding RNA showed decreased expressions. The hepatic lipidome, assessed by liquid chromatography-mass spectrometry in a platform able to analyze 467 lipids, revealed that squalene supplementation increased ceramide, Cer(36:2), and phosphatidylcholine (PC[32:0], PC[33:0] and PC[34:0]) species and decreased cardiolipin, CL(69:5), and triglyceride (TG[54:2], TG[55:0] and TG[55:2]) species. Plasma levels of interleukin 12p40 increased in pigs receiving the squalene diet. The latter also modified plasma lipidome by increasing TG(58:12) and decreasing non-esterified fatty acid (FA 14:0, FA 16:1 and FA 18:0) species without changes in total NEFA levels. Together this shows that squalene-induced changes in hepatic and plasma lipidomic profiles, non-coding RNA and anti-inflammatory interleukin are suggestive of an alleviation of the disease despite the increase in the ballooning score.
Topics: Swine; Mice; Animals; Rabbits; Squalene; Lipidomics; Triglycerides; Phospholipids; Diet, High-Fat; Liver; Non-alcoholic Fatty Liver Disease; Dietary Supplements; RNA, Untranslated
PubMed: 36402249
DOI: 10.1016/j.jnutbio.2022.109207 -
Cancer Research Dec 2022HDAC5 is a class IIa histone deacetylase member that is downregulated in multiple solid tumors, including pancreatic cancer, and loss of HDAC5 is associated with...
UNLABELLED
HDAC5 is a class IIa histone deacetylase member that is downregulated in multiple solid tumors, including pancreatic cancer, and loss of HDAC5 is associated with unfavorable prognosis. In this study, assessment of The Cancer Genome Atlas pancreatic adenocarcinoma dataset revealed that expression of HDAC5 correlates negatively with arachidonic acid (AA) metabolism, which has been implicated in inflammatory responses and cancer progression. Nontargeted metabolomics analysis revealed that HDAC5 knockdown resulted in a significant increase in AA and its downstream metabolites, such as eicosanoids and prostaglandins. HDAC5 negatively regulated the expression of the gene encoding calcium-dependent phospholipase A2 (cPLA2), the key enzyme in the production of AA from phospholipids. Mechanistically, HDAC5 repressed cPLA2 expression via deacetylation of GATA1. HDAC5 knockdown in cancer cells enhanced sensitivity to genetic or pharmacologic inhibition of cPLA2 in vitro and in vivo. Fatty acid supplementation in the diet reversed the sensitivity of HDAC5-deficient tumors to cPLA2 inhibition. These data indicate that HDAC5 loss in pancreatic cancer results in the hyperacetylation of GATA1, enabling the upregulation of cPLA2, which contributes to overproduction of AA. Dietary management plus cPLA2-targeted therapy could serve as a viable strategy for treating HDAC5-deficient pancreatic cancer patients.
SIGNIFICANCE
The HDAC5-GATA1-cPLA2-AA signaling axis regulates sensitivity to fat restriction plus cPLA2 inhibition in pancreatic ductal adenocarcinoma, proposing dietary management as a feasible strategy for treating a subset of patients with pancreatic cancer.
Topics: Humans; Adenocarcinoma; Arachidonic Acid; Cytosol; Histone Deacetylases; Pancreatic Neoplasms; Phospholipases A2, Cytosolic; Phospholipids
PubMed: 36102738
DOI: 10.1158/0008-5472.CAN-21-4362 -
Cellular and Molecular Gastroenterology... 2022The prevalence of nonalcoholic fatty liver disease (NAFLD) has reached epidemic proportions globally as a result of the rapid increase in obesity. However, there is no...
BACKGROUND & AIMS
The prevalence of nonalcoholic fatty liver disease (NAFLD) has reached epidemic proportions globally as a result of the rapid increase in obesity. However, there is no Food and Drug Administration-approved pharmacotherapy available for NAFLD. This study investigated the role of autotaxin, a secreted enzyme that hydrolyzes lysophosphatidylcholine to produce lysophosphatidic acid (LPA), in the pathogenesis of NAFLD and to explore whether genetic or pharmacologic interventions targeting autotaxin ameliorate NAFLD.
METHODS
The clinical association of autotaxin with the severity of NAFLD was analyzed in 125 liver biopsy-proven NAFLD patients. C57BL/6N mice or fibroblast growth factor 21 (FGF21)-null mice were fed a high-fat diet or a choline-deficient diet to investigate the role of the autotaxin-FGF21 axis in NAFLD development by hepatic knockdown and antibody neutralization. Huh7 cells were used to investigate the autocrine effects of autotaxin.
RESULTS
Serum autotaxin levels were associated positively with histologic scores and NAFLD severity. Hepatocytes, but not adipocytes, were the major contributor to increased circulating autotaxin in both patients and mouse models with NAFLD. In mice, knocking-down hepatic autotaxin or treatment with a neutralizing antibody against autotaxin significantly reduced high-fat diet-induced NAFLD and high fat- and choline-deficient diet-induced nonalcoholic steatohepatitis and fibrosis, accompanied by a marked increase of serum FGF21. Mechanistically, autotaxin inhibited the transcriptional activity of peroxisome proliferator-activated receptor α through LPA-induced activation of extracellular signal-regulated kinas, thereby leading to suppression of hepatic FGF21 production. The therapeutic benefit of anti-autotaxin neutralizing antibody against NAFLD was abrogated in FGF21-null mice.
CONCLUSIONS
Liver-secreted autotaxin acts in an autocrine manner to exacerbate NAFLD through LPA-induced suppression of the peroxisome proliferator-activated receptor α-FGF21 axis and is a promising therapeutic target for NAFLD.
Topics: Animals; Mice; Antibodies, Neutralizing; Choline; Diet, High-Fat; Hepatocytes; Lysophosphatidylcholines; Mice, Inbred C57BL; Mice, Knockout; Non-alcoholic Fatty Liver Disease; PPAR alpha; Phosphoric Diester Hydrolases
PubMed: 35931383
DOI: 10.1016/j.jcmgh.2022.07.012 -
The Journal of Nutritional Biochemistry Nov 2019The identification of natural bioactive compounds aimed at promoting optimal gut health and improving lipid metabolism is paramount in the prevention of chronic disease.... (Review)
Review
The identification of natural bioactive compounds aimed at promoting optimal gut health and improving lipid metabolism is paramount in the prevention of chronic disease. In this review, we summarize basic science and clinical research examining the protective properties of milk sphingomyelin (SM) against dysfunctional lipid metabolism, gut dysbiosis, and inflammation. Dietary SM dose-dependently reduces the intestinal absorption of cholesterol, triglycerides, and fatty acids in cell culture and rodent studies. Overall, rodent feeding studies show dietary milk SM, milk polar lipid mixtures, and milk fat globule membrane reduce serum and hepatic lipid concentrations. Furthermore, these hypolipidemic effects are observed in some supplementation studies in humans, although the extent of reductions in serum cholesterol is typically smaller and only one trial was conducted with purified SM. Dietary milk SM has been reported to affect the gut microbiota in rodent studies and its hydrolytic product, sphingosine, displays bactericidal activity in vitro. Milk SM may also improve gut barrier function to prevent the translocation of inflammatory gut bacteria-derived molecules. Current evidence from pre-clinical studies indicates that dietary milk SM has protective properties against dysfunctional lipid metabolism, gut dysbiosis, and inflammation. The hypolipidemic effects of milk SM observed in animal studies have been reported in some human studies, although the magnitude of such effects is typically smaller. More research is warranted to clearly define how dietary milk SM influences lipid metabolism, gut microbiota, and inflammation in humans.
Topics: Animals; Cholesterol, Dietary; Diet; Diet, Western; Dietary Fats; Digestion; Dysbiosis; Gastrointestinal Microbiome; Humans; Inflammation; Intestinal Absorption; Lipid Metabolism; Lipids; Liver; Milk; Sphingomyelins
PubMed: 31654895
DOI: 10.1016/j.jnutbio.2019.108224 -
Food Chemistry Jul 2022Plasmalogens are functional and oxidation-sensitive phospholipids abundant in fish. Chilling and freezing are common storage methods for maintaining the quality of fish,...
Plasmalogens are functional and oxidation-sensitive phospholipids abundant in fish. Chilling and freezing are common storage methods for maintaining the quality of fish, but their effect on plasmalogen preservation has not been studied. Therefore, plasmalogen loss in ready-to-eat tuna meat during storage under different conditions was investigated. LC/MS was used to analyze the time- and temperature-dependent changes of plasmalogens, which was the most evident for the species with an ethanolamine headgroup and polyunsaturated fatty acyl chains. Moreover, a series of oxidized plasmalogen molecules were identified, and their storage-induced accumulation was observed. Plasmalogen loss was strongly correlated with total lipid oxidation and phospholipid degradation. Repeated freeze-thaw cycles were found to accelerate the loss of plasmalogens, whereas the different thawing methods did not. The present study provides a deeper understanding of changes in lipid nutrients from fish meat during storage and demonstrates the importance of using advanced strategies to maintain food quality.
Topics: Animals; Chromatography, Liquid; Meat; Plasmalogens; Tandem Mass Spectrometry; Tuna
PubMed: 35168046
DOI: 10.1016/j.foodchem.2022.132320 -
Molecular Nutrition & Food Research Sep 2021A growing number of studies have reported the effects of eicosapentaenoic acid (EPA) and terrestrial phospholipids on ameliorating mood disorders. Marine-derived... (Comparative Study)
Comparative Study
SCOPE
A growing number of studies have reported the effects of eicosapentaenoic acid (EPA) and terrestrial phospholipids on ameliorating mood disorders. Marine-derived EPA-enriched phospholipids (EPA-PL) exhibit the structural characteristics of EPA and phospholipids. However, the effect of dietary EPA-PL, and the differences between amphiphilic EPA-PL and lyophobic EPA on mood disorders had not been studied.
METHODS AND RESULTS
A comparative investigation to determine the effects of dietary EPA-enriched ethyl ester (EPA-EE) and EPA-PL on improving depression- and anxiety-like behavior in a mouse model is performed, induced by 4 week chronic unpredictable mild stress (CUMS) coupled with lipopolysaccharide (LPS) challenge. It is found that dietary 4 week 0.6% (w/w) EPA-PL rescued depression- and anxiety-like behavior to a greater extent than did EPA-EE. Moreover, dietary EPA-PL significantly reduced the immobility time by 56.6%, close to the normal level, in forced swimming test, which revealed a reversal of depression-like behavior. Further studies revealed that dietary EPA-PL regulated immunity, monoamine systems, and the hypothalamic-pituitary-adrenal (HPA) axis by multi-target interactions, including inhibition of neuroinflammation and apoptosis.
CONCLUSION
EPA-PL exerted superior effects to EPA-EE in alleviating depression- and anxiety-like behavior. The data suggest potential novel candidate or targeted dietary patterns to prevent and treat mood disorder.
Topics: Animals; Anxiety; Behavior, Animal; Brain; Corticosterone; Depression; Disease Models, Animal; Eicosapentaenoic Acid; Kynurenine; Lipopolysaccharides; Male; Mice, Inbred ICR; Neuroinflammatory Diseases; Neurotransmitter Agents; Phospholipids; Spleen; Stress, Psychological; Mice
PubMed: 34219360
DOI: 10.1002/mnfr.202100009 -
Food Chemistry Oct 2023Milk fat globule membrane (MFGM) contains lipids, which are essential for promoting infant brain development and improving cognition. In this study, the lipid...
Milk fat globule membrane (MFGM) contains lipids, which are essential for promoting infant brain development and improving cognition. In this study, the lipid differences between human MFGM and four dietary lipid sources (cow MFGM, soybean, krill, and yolk) were compared using the UHPLC-Q-Exactive MS-based lipidomics techniques. A total of 45 lipid classes and 5048 lipid species were detected. The analysis of phospholipid classes revealed that the lipid composition of human MFGM and cow MFGM was more similar than the other dietary-derived lipids. Additionally, the human MFGM lipid species were compared with cow MFGM, soybean, krill, and yolk, and 401, 416, 494, and 444 significantly different lipids were identified, respectively. Through lipid metabolic pathway analysis, differential lipids were mainly involved in the glycerophospholipid metabolic pathway. Overall, these results will provide a rationale for the future addition of lipids to infant formula to more closely approximate human MFGM lipid profiles.
Topics: Animals; Female; Cattle; Infant; Humans; Lipidomics; Glycolipids; Dietary Fats; Infant Formula; Phospholipids; Brain; Lipid Droplets
PubMed: 37130453
DOI: 10.1016/j.foodchem.2023.136236 -
International Journal of Molecular... Jun 2023Acid sphingomyelinase deficiency (ASMD) is a lysosomal storage disorder caused by mutations in the gene-encoding acid sphingomyelinase (ASM). ASMD impacts peripheral...
Acid sphingomyelinase deficiency (ASMD) is a lysosomal storage disorder caused by mutations in the gene-encoding acid sphingomyelinase (ASM). ASMD impacts peripheral organs in all patients, including the liver and spleen. The infantile and chronic neurovisceral forms of the disease also lead to neuroinflammation and neurodegeneration for which there is no effective treatment. Cellular accumulation of sphingomyelin (SM) is a pathological hallmark in all tissues. SM is the only sphingolipid comprised of a phosphocholine group linked to ceramide. Choline is an essential nutrient that must be obtained from the diet and its deficiency promotes fatty liver disease in a process dependent on ASM activity. We thus hypothesized that choline deprivation could reduce SM production and have beneficial effects in ASMD. Using acid sphingomyelinase knock-out (ASMko) mice, which mimic neurovisceral ASMD, we have assessed the safety of a choline-free diet and its effects on liver and brain pathological features such as altered sphingolipid and glycerophospholipid composition, inflammation and neurodegeneration. We found that the choline-free diet was safe in our experimental conditions and reduced activation of macrophages and microglia in the liver and brain, respectively. However, there was no significant impact on sphingolipid levels and neurodegeneration was not prevented, arguing against the potential of this nutritional strategy to assist in the management of neurovisceral ASMD patients.
Topics: Mice; Animals; Niemann-Pick Disease, Type A; Sphingomyelin Phosphodiesterase; Choline; Niemann-Pick Diseases; Sphingolipids; Sphingomyelins; Diet; Mice, Knockout; Disease Models, Animal
PubMed: 37298714
DOI: 10.3390/ijms24119756 -
Oxidative Medicine and Cellular... 2022Since the human and porcine digestive systems have similar anatomical structures and physiological functions, pigs are a useful animal model for studying human digestive...
Since the human and porcine digestive systems have similar anatomical structures and physiological functions, pigs are a useful animal model for studying human digestive diseases. By investigating intestinal metabolites in piglets after weaning, this study attempted to identify the inherent connection between dietary protein levels and changes in the intestinal microbiota of piglets. Casein was employed as the only source of protein for the piglets in this study to avoid the influence of other protein sources. 14 weaning at 28-day-old piglets (6.9 ± 0.19 kg) formed into two dietary groups: 17% casein fed group (LP) and 30% casein fed group (HP). Piglets were allowed to free food and water during the 2-week experiment. Throughout the trial, the piglets' diarrhea index (1: no diarrhea and 3: watery diarrhea) and food intake were noted during the experiment. We discovered piglets fed a high-protein diet developed diarrhea throughout the duration of the research, whereas piglets fed a normal protein diet did not. In addition, the HP group had lower feed intake and body weight than the control group ( < 0.05). The HP diet influenced the content of short-chain and branched-chain fatty acids in the colon, including acetate and isovaleric acid. The ileal microbiota's 16S rRNA gene was sequenced, and it was discovered that the relative abundance of gastrointestinal bacteria differed between the HP and control groups. Dietary protein levels influenced bile acid biosynthesis, alpha-linolenic acid metabolism, phospholipid biosynthesis, arachidonic acid metabolism, fatty acid biosynthesis, retinol metabolism, arginine and proline metabolism, pyrimidine metabolism, tryptophan metabolism, and glycine and serine metabolism, according to gas chromatography-mass spectrometry analysis. Furthermore, a correlation analysis of the pooled information revealed a possible link between intestinal metabolites and specific bacteria species. These findings demonstrate that weaned piglets' microbiota composition and metabolites are modified by a high-protein diet and thus inducing severe postweaning diarrhea and inhibiting growth performance. However, the potential molecular mechanism of this regulation in the growth of piglets remains unclear.
Topics: Animal Feed; Animals; Caseins; Diarrhea; Diet; Dietary Proteins; Dietary Supplements; RNA, Ribosomal, 16S; Swine; Weaning
PubMed: 35401925
DOI: 10.1155/2022/3355687 -
Developmental Cell Aug 2020Dietary lipids impact development, homeostasis, and disease, but links between specific dietary fats and cell fates are poorly understood. Ferroptosis is an...
Dietary lipids impact development, homeostasis, and disease, but links between specific dietary fats and cell fates are poorly understood. Ferroptosis is an iron-dependent form of nonapoptotic cell death associated with oxidized polyunsaturated phospholipids. Here, we show that dietary ingestion of the polyunsaturated fatty acid (PUFA) dihomogamma-linolenic acid (DGLA; 20:3n-6) can trigger germ-cell ferroptosis and sterility in the nematode Caenorhabditis elegans. Exogenous DGLA is also sufficient to induce ferroptosis in human cells, pinpointing this omega-6 PUFA as a conserved metabolic instigator of this lethal process. In both C. elegans and human cancer cells, ether-lipid synthesis protects against ferroptosis. These results establish C. elegans as a powerful animal model to study the induction and modulation of ferroptosis by dietary fats and indicate that endogenous ether lipids act to prevent this nonapoptotic cell fate.
Topics: 8,11,14-Eicosatrienoic Acid; Animals; Caenorhabditis elegans; Cell Death; Cell Differentiation; Cell Line, Tumor; Dietary Fats; Ferroptosis; Germ Cells; Homeostasis; Humans; Iron; Lipids; Neoplasms; Phospholipids
PubMed: 32652074
DOI: 10.1016/j.devcel.2020.06.019