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Bergentall M, Tremaroli V, Sun C, Henricsson M, Khan MT, Mannerås Holm L, Olsson L, Bergh PO, Molinaro A, Mardinoglu A, Caesar R, Nieuwdorp M, Bäckhed F. Gut microbiota mediates SREBP-1c-driven hepatic lipogenesis and steatosis in response to zero-fat high-sucrose diet. Mol Metab 2025; 97:102162. [PMID: 40345386 DOI: 10.1016/j.molmet.2025.102162] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2025] [Revised: 04/23/2025] [Accepted: 05/02/2025] [Indexed: 05/11/2025] Open
Abstract
OBJECTIVES Sucrose-rich diets promote hepatic de novo lipogenesis (DNL) and steatosis through interactions with the gut microbiota. However, the role of sugar-microbiota dynamics in the absence of dietary fat remains unclear. This study aimed to investigate the effects of a high-sucrose, zero-fat diet (ZFD) on hepatic steatosis and host metabolism in conventionally raised (CONVR) and germ-free (GF) mice. METHODS CONVR and GF mice were fed a ZFD, and hepatic lipid accumulation, gene expression, and metabolite levels were analyzed. DNL activity was assessed by measuring malonyl-CoA levels, expression of key DNL enzymes, and activation of the transcription factor SREBP-1c. Metabolomic analyses of portal vein plasma identified microbiota-derived metabolites linked to hepatic steatosis. To further examine the role of SREBP-1c, its hepatic expression was knocked down using antisense oligonucleotides in CONVR ZFD-fed mice. RESULTS The gut microbiota was essential for sucrose-induced DNL and hepatic steatosis. In CONVR ZFD-fed mice, hepatic fat accumulation increased alongside elevated expression of genes encoding DNL enzymes, higher malonyl-CoA levels, and upregulation of SREBP-1c. Regardless of microbiota status, ZFD induced fatty acid elongase and desaturase gene expression and increased hepatic monounsaturated fatty acids. Metabolomic analyses identified microbiota-derived metabolites associated with hepatic steatosis. SREBP-1c knockdown in CONVR ZFD-fed mice reduced hepatic steatosis and suppressed fatty acid synthase expression. CONCLUSIONS Sucrose-microbiota interactions and SREBP-1c are required for DNL and hepatic steatosis in the absence of dietary fat. These findings provide new insights into the complex interplay between diet, gut microbiota, and metabolic regulation.
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Affiliation(s)
- Mattias Bergentall
- Wallenberg Laboratory, Department of Molecular and Clinical Medicine and Sahlgrenska Center for Cardiovascular and Metabolic Research, University of Gothenburg, Gothenburg, SE-413 45, Sweden
| | - Valentina Tremaroli
- Wallenberg Laboratory, Department of Molecular and Clinical Medicine and Sahlgrenska Center for Cardiovascular and Metabolic Research, University of Gothenburg, Gothenburg, SE-413 45, Sweden
| | - Chuqing Sun
- Wallenberg Laboratory, Department of Molecular and Clinical Medicine and Sahlgrenska Center for Cardiovascular and Metabolic Research, University of Gothenburg, Gothenburg, SE-413 45, Sweden
| | - Marcus Henricsson
- Wallenberg Laboratory, Department of Molecular and Clinical Medicine and Sahlgrenska Center for Cardiovascular and Metabolic Research, University of Gothenburg, Gothenburg, SE-413 45, Sweden
| | - Muhammad Tanweer Khan
- Wallenberg Laboratory, Department of Molecular and Clinical Medicine and Sahlgrenska Center for Cardiovascular and Metabolic Research, University of Gothenburg, Gothenburg, SE-413 45, Sweden
| | - Louise Mannerås Holm
- Wallenberg Laboratory, Department of Molecular and Clinical Medicine and Sahlgrenska Center for Cardiovascular and Metabolic Research, University of Gothenburg, Gothenburg, SE-413 45, Sweden
| | - Lisa Olsson
- Wallenberg Laboratory, Department of Molecular and Clinical Medicine and Sahlgrenska Center for Cardiovascular and Metabolic Research, University of Gothenburg, Gothenburg, SE-413 45, Sweden
| | - Per-Olof Bergh
- Wallenberg Laboratory, Department of Molecular and Clinical Medicine and Sahlgrenska Center for Cardiovascular and Metabolic Research, University of Gothenburg, Gothenburg, SE-413 45, Sweden
| | - Antonio Molinaro
- Wallenberg Laboratory, Department of Molecular and Clinical Medicine and Sahlgrenska Center for Cardiovascular and Metabolic Research, University of Gothenburg, Gothenburg, SE-413 45, Sweden
| | - Adil Mardinoglu
- Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, Sweden; Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral & Craniofacial Sciences, King's College London, London, SE1 9RT, UK
| | - Robert Caesar
- Wallenberg Laboratory, Department of Molecular and Clinical Medicine and Sahlgrenska Center for Cardiovascular and Metabolic Research, University of Gothenburg, Gothenburg, SE-413 45, Sweden.
| | - Max Nieuwdorp
- Department of (Experimental) Vascular Medicine, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands
| | - Fredrik Bäckhed
- Wallenberg Laboratory, Department of Molecular and Clinical Medicine and Sahlgrenska Center for Cardiovascular and Metabolic Research, University of Gothenburg, Gothenburg, SE-413 45, Sweden; Department of Clinical Physiology Region Västra Götaland, Sahlgrenska University Hospital Gothenburg Sweden, Sweden.
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Frankhouser DE, DeWees T, Snodgrass IF, Cole RM, Steck S, Thomas D, Kalu C, Belury MA, Clinton SK, Newman JW, Yee LD. Randomized dose-response trial of n-3 fatty acids in hormone receptor negative breast cancer survivors - impact on breast adipose oxylipin and DNA methylation patterns. Am J Clin Nutr 2025:S0002-9165(25)00239-4. [PMID: 40288580 DOI: 10.1016/j.ajcnut.2025.04.021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2024] [Revised: 03/30/2025] [Accepted: 04/21/2025] [Indexed: 04/29/2025] Open
Abstract
BACKGROUND Increasing evidence suggests the unique susceptibility of estrogen receptor and progesterone receptor negative [ERPR(-)] breast cancer to dietary fat amount and type. Dietary n-3 (ω-3) polyunsaturated fatty acids (PUFAs), such as docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), may modulate breast adipose fatty acids and downstream metabolites to counteract procarcinogenic signaling in the mammary microenvironment. OBJECTIVES We aimed to determine effects of ∼1 to 5 g/d EPA+DHA over 12 mo on breast adipose fatty acid and oxylipin profiles in survivors of ERPR(-) breast cancer, a high-risk molecular subtype. METHODS We conducted a proof-of-concept 12-mo randomized double-blind trial comparing ∼5 g/d and ∼1 g/d EPA+DHA supplementation in females within 5 y of completing standard therapy for ERPR(-) breast cancer Stages 0 to III. Blood and breast adipose tissue specimens were collected every 3 mo for fatty acid, oxylipin, and DNA methylation (DNAm) analyses. RESULTS A total of 51 participants completed the 12-mo intervention. Study treatments were generally well tolerated. Although both doses increased n-3 PUFAs from baseline in breast adipose, erythrocytes, and plasma, the 5 g/d supplement was more potent with differences (% total fatty acids) of 0.76 (95% confidence interval [CI]: 0.56, 0.96), 6.25 (95% CI: 5.02, 7.48), and 5.89 (95% CI: 4.53, 7.25), respectively. The 5 g/d dose also reduced plasma triglycerides from baseline, with changes (mg/dL) of 27.38 (95% CI: 10.99, 43.78) and 24.58 (95% CI: 9.05, 40.10) at 6 and 12 months, respectively. Breast adipose oxylipins showed dose-dependent increases in DHA and EPA metabolites. Distinct DNAm patterns in adipose tissue after 12 mo suggest potential downregulation of aberrant lipid metabolism pathways at the 5 g/d dose. CONCLUSIONS Over 1 y, EPA+DHA dose-dependently increased breast adipose concentrations of these fatty acids and their derivative oxylipin metabolites and produced differential DNAm profiles involved in metabolism-related pathways critical to ERPR(-) breast cancer development. This distinct metabolic and epigenetic modulation of the breast microenvironment is achievable with high-dose n-3 PUFA supplementation. This trial was registered at clinicaltrials.gov as NCT02295059.
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Affiliation(s)
- David E Frankhouser
- Department of Computational and Quantitative Medicine, City of Hope, Duarte, CA
| | - Todd DeWees
- Department of Computational and Quantitative Medicine, City of Hope, Duarte, CA; Department of Surgery, City of Hope, Duarte, CA
| | - Isabel F Snodgrass
- University of California Davis West Coast Metabolomics Center, Genome Center, University of California Davis, Davis, CA
| | - Rachel M Cole
- Department of Food Science and Technology, The Ohio State University, Columbus, OH
| | - Sarah Steck
- The Ohio State University Comprehensive Cancer Center, Columbus, OH
| | | | | | - Martha A Belury
- Department of Food Science and Technology, The Ohio State University, Columbus, OH; The Ohio State University Comprehensive Cancer Center, Columbus, OH
| | - Steven K Clinton
- The Ohio State University Comprehensive Cancer Center, Columbus, OH; Department of Internal Medicine, The Ohio State University, Columbus, OH
| | - John W Newman
- University of California Davis West Coast Metabolomics Center, Genome Center, University of California Davis, Davis, CA; Department of Nutrition, University of California Davis, Davis, CA; United States Department of Agriculture Agricultural Research Service, Western Human Nutrition Research Center, Davis, CA
| | - Lisa D Yee
- Department of Surgery, City of Hope, Duarte, CA; City of Hope Comprehensive Cancer Center, Duarte, CA.
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Varghese M, Thekkelnaycke R, Soni T, Zhang J, Maddipati K, Singer K. Sex differences in the lipid profiles of visceral adipose tissue with obesity and gonadectomy. J Lipid Res 2025; 66:100803. [PMID: 40245983 DOI: 10.1016/j.jlr.2025.100803] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2024] [Revised: 03/05/2025] [Accepted: 04/10/2025] [Indexed: 04/19/2025] Open
Abstract
In obesity, adipose tissue (AT) expansion is accompanied by chronic inflammation. Altered lipid composition in the visceral or gonadal white AT (GWAT) directly drive AT macrophage accumulation and activation to a proinflammatory phenotype. Sex steroid hormones modulate visceral versus subcutaneous lipid accumulation that correlates with metabolic syndrome, especially in men and postmenopausal women who are more prone to abdominal obesity. Prior studies demonstrated sex differences in GWAT lipid species in HFD-fed mice, but the role of sex hormones is still unclear. We hypothesized that sex hormone alterations with gonadectomy (GX) would further impact lipid composition in the obese GWAT. Untargeted lipidomics of obese GWAT identified sex differences in phospholipids, sphingolipids, sterols, fatty acyls, saccharolipids and prenol lipids. Males had significantly more precursor fatty acids (palmitic, oleic, linoleic, and arachidonic acid) than females and GX mice. Targeted lipidomics for fatty acids and oxylipins in the HFD-fed male and female GWAT stromal vascular fraction identified higher omega-6 to omega-3 free fatty acid profile in males and differences in PUFAs-derived prostaglandins, thromboxanes, and leukotrienes. Both obese male and female GWAT stromal vascular fraction showed increased levels of arachidonic acid-derived oxylipins compared to their lean counterparts. Bulk RNA-seq of sorted GWAT AT macrophages highlighted sex and diet differences in PUFA and oxylipin metabolism genes. These findings of sexual dimorphism in both stored lipid species and PUFA-derived mediators with diet and GX emphasize sex differences in lipid metabolism pathways that drive inflammation responses and metabolic disease risk in obesity.
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Affiliation(s)
- Mita Varghese
- Department of Pediatrics, Michigan Medicine, University of Michigan, Ann Arbor, MI, USA
| | - Rajendiran Thekkelnaycke
- Michigan Regional Comprehensive Metabolomics Resource Core, University of Michigan, Ann Arbor, MI, USA
| | - Tanu Soni
- Michigan Regional Comprehensive Metabolomics Resource Core, University of Michigan, Ann Arbor, MI, USA
| | - Jiayu Zhang
- Michigan Regional Comprehensive Metabolomics Resource Core, University of Michigan, Ann Arbor, MI, USA
| | | | - Kanakadurga Singer
- Department of Pediatrics, Michigan Medicine, University of Michigan, Ann Arbor, MI, USA.
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Joerg R, Itariu BK, Amor M, Bilban M, Langer F, Prager G, Joerg F, Stulnig TM. The effect of long-chain n-3 PUFA on liver transcriptome in human obesity. Prostaglandins Leukot Essent Fatty Acids 2025; 204:102663. [PMID: 39752839 DOI: 10.1016/j.plefa.2024.102663] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2024] [Revised: 12/10/2024] [Accepted: 12/10/2024] [Indexed: 03/14/2025]
Abstract
BACKGROUND AND AIMS Obesity is associated with a higher risk of severe diseases such as atherosclerotic cardiovascular disease, type 2 diabetes mellitus (T2DM), and metabolic dysfunction-associated steatotic liver disease (MASLD). Polyunsaturated fatty acids, of the omega-3 family (n-3 PUFA), have been shown to reduce adipose tissue inflammation in obesity, as well as to have lipid-lowering effects and improve insulin sensitivity. However, direct effects on liver transcriptome in humans have not been described. Our aim was to understand the impact of n-3 PUFA on gene expression in obese human liver. APPROACH AND RESULTS Patients with obesity (BMI ≥ 40 kg/m2) were treated for eight weeks with 3.36 g n-3 PUFAs (1.84 g eicosapentaenoic acid (EPA) and 1.53 g docosahexaenoic acid (DHA)), or with 5 g of butter as a control (n = 15 per group) before undergoing bariatric surgery where liver biopsies were taken. Liver samples were used for mRNA microarray analyses and subsequently Gene Set Enrichment Analysis (GSEA) was performed. This bioinformatic approach led us to identify 80 significantly dysregulated pathways that were divided into 9 different clusters including insulin and lipid metabolism, and immunity. N-3 PUFA treatment significantly affected pathways related to immunity, metabolism, and inflammation. Specifically, it upregulated pathways involved in T-cell and B-cell functions and lipid metabolism, while downregulating glucagon signalling. These findings highlight the impact of n-3 PUFAs on key metabolic and immune processes in the liver of patients with obesity. CONCLUSION This study provides further insights into the impact on n-3 PUFA on human liver gene expression, particularly in pathways associated with immunity, lipid metabolism, and inflammation, setting basis for further clinical research. SUMMARY Obesity increases the risk of diseases like atherosclerotic- cardiovascular disease, type 2 diabetes mellitus and metabolic dysfunction-associated steatotic liver disease (MASLD). Omega-3 polyunsaturated fatty acids (n-3 PUFA) are known for their anti-inflammatory and metabolic benefits, but their direct impact on liver gene expression in people with obesity, remains unclear. In this study, patients with obesity (BMI ≥ 40 kg/m2) were administered either n-3 PUFAs or butter before bariatric surgery. Liver biopsies were analysed for gene expression via Gene Set Enrichment Analysis (GSEA). The results revealed 80 dysregulated pathways across 9 clusters, including those related to insulin and lipid metabolism, and immunity. This sheds light on how n-3 PUFAs influence gene expression in the liver of patients with obesity, setting the groundwork for further clinical exploration.
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Affiliation(s)
- Rebeka Joerg
- Department of General Surgery, Division of Visceral Surgery, Medical University of Vienna, Austria.
| | - Bianca K Itariu
- Department of Medicine III, Division of Endocrinology and Metabolism, Medical University of Vienna, Austria; Metabolism Centre N12 Antonigasse, 1090 Vienna, Austria.
| | - Melina Amor
- Gottfried Schatz Research Center, Molecular Biology and Biochemistry, Medical University of Graz, Austria.
| | - Martin Bilban
- Department of Genomics, Medical University of Vienna, Austria.
| | - Felix Langer
- Department of General Surgery, Division of Visceral Surgery, Medical University of Vienna, Austria.
| | - Gerhard Prager
- Department of General Surgery, Division of Visceral Surgery, Medical University of Vienna, Austria.
| | - Florian Joerg
- Department of Computational Biological Chemistry, Faculty of Chemistry, University of Vienna, Austria.
| | - Thomas M Stulnig
- Department of Medicine III, Division of Endocrinology and Metabolism, Medical University of Vienna, Austria; Department of Medicine III and Karl Landsteiner Institute for Metabolic Diseases and Nephrology, Clinic Hietzing, Vienna, Austria.
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Khound P, Gurumayum N, Devi R. Amelioration of atherosclerotic complications and dyslipidemia by verbascoside-enriched fraction of Clerodendrum glandulosum leaves targeting LDL-R and LXR-mediated reverse cholesterol transport. CHINESE HERBAL MEDICINES 2025; 17:352-367. [PMID: 40256711 PMCID: PMC12009097 DOI: 10.1016/j.chmed.2025.02.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2024] [Revised: 10/31/2024] [Accepted: 02/24/2025] [Indexed: 04/22/2025] Open
Abstract
Objective Clerodendrum glandulosum is widely used in traditional Chinese and Indian systems of medicine for conditions like hypertension and diabetes. While various pharmacological benefits have been reported, research on its anti-atherosclerotic properties remains limited. Atherosclerosis (AS) is a chronic cardiovascular disease linked to dyslipidemia (DLD) and inflammation. This study aims to identify the bioactive fraction from C. glandulosum extract, evaluate its potential against AS and DLD, and explore the molecular mechanisms of cholesterol metabolism. Methods Bioactivity-guided fractionation was employed to investigate the bioactivity of C. glandulosum by screening biochemical enzyme inhibitory potential. The active fraction was subjected to in vitro testing to assess the anti-inflammatory and anti-adhesion properties. The fraction was administered at 50 and 100 mg/kg per os (p.o.) to cholesterol-cholic acid-thiouracil (CCT) diet-induced atherosclerotic Wistar rats. Changes in lipid and antioxidant profiles, inflammatory markers, and cholesterol metabolism pathways were assessed using Western blotting. Histopathological analyses of the aorta, liver, heart, and kidneys were also conducted. Molecular docking was conducted for the verbascoside (VER) and the standard statin, atorvastatin (ATS), for their binding capabilities with the molecular targets considered in this study. Results Bioactivity-guided fractionation and screening revealed that ethyl acetate fraction (EAF) contained VER as the principal phytoconstituent. EAF exhibited potent enzyme inhibitory activity, with IC50 values of 1.059 mg/mL for pancreatic lipase and 22.48 µg/mL for α-glucosidase. In vitro analysis revealed that EAF significantly lowered cell-to-cell adhesion to 0.57 folds from 2.5 folds in the disease control and normalized the inflammatory cytokines. In CCT-diet-induced rats, elevated serum cholesterol and low-density lipoproteins (LDL) levels (92.1 mg/dL and 78.49 mg/dL, respectively) were reduced to 63.52 mg/dL and 58.51 mg/dL with EAF at 100 mg/kg. EAF at 100 mg/kg reduced oxidized LDL to 53.63 ng/mL compared to 157.1 ng/mL in CCT-diet-fed rats. EAF also restored antioxidant activity by increasing superoxide dismutase and catalase levels to 73.78 and 17.72 U/mg protein, respectively, compared to 42.22 and 9.62 U/mg protein in CCT-diet-fed rats. EAF restored inflammatory cytokines to normal levels. Histological analyses validated the protective benefits of EAF supplementation for the structural integrity of the aorta, liver, heart, and kidney tissues. Western blotting analysis of liver tissues revealed changes in the cholesterol metabolic pathway by upregulating peroxisome proliferator-activated receptor gamma (PPARγ)/liver X receptor alpha (LXRα)/adenosine triphosphate-binding cassette sub-family G member 1 (ABCG1) and low-density lipoprotein receptor (LDL-R) expression. Unlike ATS, molecular docking analyses indicated strong interactions between VER and molecular targets. Conclusion EAF prevented DLD and AS by reverse cholesterol transport via the PPARγ/LXRα/ABCG1 pathway, offering potential therapeutic benefits for cardiovascular health.
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Affiliation(s)
- Puspanjali Khound
- Life Sciences Division, Institute of Advanced Study in Science and Technology (IASST), Paschim Boragaon, Garchuk, Guwahati 781035, India
- Department of Zoology, Gauhati University, Jalukbari, Guwahati 781014, India
| | - Nonibala Gurumayum
- Life Sciences Division, Institute of Advanced Study in Science and Technology (IASST), Paschim Boragaon, Garchuk, Guwahati 781035, India
- Department of Zoology, Gauhati University, Jalukbari, Guwahati 781014, India
| | - Rajlakshmi Devi
- Life Sciences Division, Institute of Advanced Study in Science and Technology (IASST), Paschim Boragaon, Garchuk, Guwahati 781035, India
- Department of Zoology, Gauhati University, Jalukbari, Guwahati 781014, India
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Li R, Liu Y, Zhang Y, Yan Z, Cao Y, Li Q, Mei Y, Sun S, Cao X, Guo L, Gao J. Effects of high α-linolenic acid transgenic rapeseed oil diet on growth performance, fat deposition, flesh quality, antioxidant capacity, and immunity of juvenile largemouth bass (Micropterus salmoides). Lipids 2025; 60:25-37. [PMID: 39356000 DOI: 10.1002/lipd.12419] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2024] [Revised: 09/08/2024] [Accepted: 09/11/2024] [Indexed: 10/03/2024]
Abstract
Omega-3 long-chain polyunsaturated fatty acid (n-3 LC-PUFA) increases in aquatic products contributes to improving meat quality, thereby positively impacting human health. Different from marine fish which primarily obtain n-3 LC-PUFAs directly from zooplankton and algae, freshwater fish mainly utilize dietary linolenic acid (ALA) as a substrate to synthesize n-3 LC-PUFAs. Our team has successfully created a transgenic rapeseed oil (TRO) with high ALA content. Therefore, we here assessed the impacts of four different diets (LR, low-fat rapeseed oil (RO) diet; HR, high-fat RO diet; LTR, low-fat TRO diet; HTR, high-fat TRO diet) on growth performance, lipid accumulation, fatty acid composition, antioxidant capacity, immunity and serum biochemical indexes of juvenile largemouth bass (Micropterus salmoides), an economically valuable freshwater fish. The results showed no significant difference in survival rate among the four dietary groups. No significant differences in body weight gain and final weight were found between the LR and LTR groups, as well as between HR and HTR groups. No matter if it was a high-fat or low-fat diet, compared with the RO diet, TRO diets significantly increased the content of n-3 LC-PUFA, improved meat quality, effectively alleviated lipid accumulation in livers and muscles of juvenile largemouth bass. In addition, using high-fat diets, TRO diet improved the antioxidant capacity and immune ability of juvenile largemouth bass, thereby promoting the overall health of fish. This study provides novel insights for fish feed formulation optimization from the perspective of genetically modified feed ingredients, and high-quality aquatic products for human consumption.
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Affiliation(s)
- Rongyun Li
- College of Fisheries, Engineering Research Center of Green Development for Conventional Aquatic Biological Industry in the Yangtze River Economic Belt, Ministry of Education, Huazhong Agricultural University, Wuhan, China
- Hubei Provincial Engineering Laboratory for Pond Aquaculture, Huazhong Agricultural University, Wuhan, China
| | - Yunhao Liu
- National Key Laboratory of Crop Genetic Improvement, Huazhong Agricultural University, Wuhan, China
- Shenzhen Institute of Nutrition and Health, Huazhong Agricultural University, Wuhan, China
| | - Yunbang Zhang
- College of Fisheries, Engineering Research Center of Green Development for Conventional Aquatic Biological Industry in the Yangtze River Economic Belt, Ministry of Education, Huazhong Agricultural University, Wuhan, China
| | - Ze Yan
- College of Fisheries, Engineering Research Center of Green Development for Conventional Aquatic Biological Industry in the Yangtze River Economic Belt, Ministry of Education, Huazhong Agricultural University, Wuhan, China
| | - Yun Cao
- College of Fisheries, Engineering Research Center of Green Development for Conventional Aquatic Biological Industry in the Yangtze River Economic Belt, Ministry of Education, Huazhong Agricultural University, Wuhan, China
| | - Qingshan Li
- College of Fisheries, Engineering Research Center of Green Development for Conventional Aquatic Biological Industry in the Yangtze River Economic Belt, Ministry of Education, Huazhong Agricultural University, Wuhan, China
| | - Yihui Mei
- College of Fisheries, Engineering Research Center of Green Development for Conventional Aquatic Biological Industry in the Yangtze River Economic Belt, Ministry of Education, Huazhong Agricultural University, Wuhan, China
| | - Shouxiang Sun
- College of Fisheries, Engineering Research Center of Green Development for Conventional Aquatic Biological Industry in the Yangtze River Economic Belt, Ministry of Education, Huazhong Agricultural University, Wuhan, China
| | - Xiaojuan Cao
- College of Fisheries, Engineering Research Center of Green Development for Conventional Aquatic Biological Industry in the Yangtze River Economic Belt, Ministry of Education, Huazhong Agricultural University, Wuhan, China
- Hubei Provincial Engineering Laboratory for Pond Aquaculture, Huazhong Agricultural University, Wuhan, China
| | - Liang Guo
- National Key Laboratory of Crop Genetic Improvement, Huazhong Agricultural University, Wuhan, China
- Shenzhen Institute of Nutrition and Health, Huazhong Agricultural University, Wuhan, China
| | - Jian Gao
- College of Fisheries, Engineering Research Center of Green Development for Conventional Aquatic Biological Industry in the Yangtze River Economic Belt, Ministry of Education, Huazhong Agricultural University, Wuhan, China
- Hubei Provincial Engineering Laboratory for Pond Aquaculture, Huazhong Agricultural University, Wuhan, China
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Queathem ED, Stagg D, Nelson A, Chaves AB, Crown SB, Fulghum K, D Avignon DA, Ryder JR, Bolan PJ, Hayir A, Gillingham JR, Jannatpour S, Rome FI, Williams AS, Muoio DM, Ikramuddin S, Hughey CC, Puchalska P, Crawford PA. Ketogenesis protects against MASLD-MASH progression through mechanisms that extend beyond overall fat oxidation rate. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.10.17.618895. [PMID: 39464122 PMCID: PMC11507910 DOI: 10.1101/2024.10.17.618895] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/29/2024]
Abstract
The progression of metabolic-dysfunction-associated steatotic liver disease (MASLD) to metabolic-dysfunction-associated steatohepatitis (MASH) involves complex alterations in both liver-autonomous and systemic metabolism that influence the liver's balance of fat accretion and disposal. Here, we quantify the relative contribution of hepatic oxidative pathways to liver injury in MASLD-MASH. Using NMR spectroscopy, UHPLC-MS, and GC-MS, we performed stable-isotope tracing and formal flux modeling to quantify hepatic oxidative fluxes in humans across the spectrum of MASLD-MASH, and in mouse models of impaired ketogenesis. We found in humans with MASH, that liver injury correlated positively with ketogenesis and total fat oxidation, but not with turnover of the tricarboxylic acid cycle. The use of loss-of-function mouse models demonstrated that disruption of mitochondrial HMG-CoA synthase (HMGCS2), the rate-limiting step of ketogenesis, impairs overall hepatic fat oxidation and induces a MASLD-MASH-like phenotype. Disruption of mitochondrial β-hydroxybutyrate dehydrogenase (BDH1), the terminal step of ketogenesis, also impaired fat oxidation, but surprisingly did not exacerbate steatotic liver injury. Taken together, these findings suggest that quantifiable variations in overall hepatic fat oxidation may not be a primary determinant of MASLD-to-MASH progression, but rather, that maintenance of hepatic ketogenesis could serve a protective role through additional mechanisms that extend beyond quantified overall rates of fat oxidation.
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Kalia S, Magnuson AD, Sun T, Sun Z, Lei XG. Potential and Metabolic Impacts of Double Enrichments of Docosahexaenoic Acid and 25-Hydroxy Vitamin D 3 in Tissues of Broiler Chickens. J Nutr 2024; 154:3312-3322. [PMID: 39332774 PMCID: PMC11600121 DOI: 10.1016/j.tjnut.2024.09.022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2024] [Revised: 09/05/2024] [Accepted: 09/22/2024] [Indexed: 09/29/2024] Open
Abstract
BACKGROUND Chicken may be enriched with 25-hydroxy D3 [25(OH)D3] and docosahexaenoic acid (DHA) to enhance the dietary intake of the public. OBJECTIVES Two experiments (Expt.) were conducted to determine the potential and metabolic impacts of enriching both DHA and 25(OH)D3 in the tissues of broiler chickens. METHODS In Expt. 1, 144 chicks (6 cages/treatment and 6 birds/cage) were fed a corn-soybean meal basal diet (BD), BD + 10,000 IU 25(OH)D3/kg [BD + 25(OH)D3], BD + 1% DHA-rich Aurantiochytrium (1.2 g DHA/kg; BD + DHA), or BD + 25(OH)D3+DHA for 6 wk. In Expt. 2, 180 chicks were fed the BD, BD + DHA-rich microalgal oil (1.5-3.0 g DHA/kg, BD + DHA), BD + DHA + eicosapentaenoic acid (EPA)-rich microalgae (0.3-0.6 g EPA/kg, BD + DHA + EPA), BD + DHA + 25(OH)D3 [6000 to 12,000 IU/kg diet; BD + DHA + 25(OH)D3], and BD + DHA + EPA + 25(OH)D3 for 6 wk. RESULTS Supranutrition of these 2 nutrients resulted in 57-62 mg DHA and 1.9-3.3 μg of 25(OH)D3/100 g of breast or thigh muscles. The DHA enrichment was independent of dietary EPA or 25(OH)D3, but that of 25(OH)D3 in the liver was decreased (68%, P < 0.05) by dietary DHA in Expt. 1. Compared with BD, BD + 25(OH)D3 enhanced (P < 0.05) gene expression related to D3 absorption (scavenger receptor class B type 1 and Niemann-pick c1 like 1) in the liver and D3 degradation (cytochrome P450 24A1) in the breast, and decreased mRNA or protein concentrations of vitamin D binding protein in the adipose tissue or thigh muscle. Supranutrition of DHA decreased mRNA concentrations of lipid metabolism-related genes (fatty acid desaturase 1,2, ELOVL fatty acid elongase 5, fatty acid desaturase 2, fatty acid synthase, and sterol regulatory element-binding protein 1). CONCLUSIONS Both DHA and 25(OH)D3 were enriched in the muscles up to meeting 50%-100% of the suggested intakes of these nutrients by consuming 2 servings of 100 g of fortified chicken. The enrichments altered gene expression related to lipid biosynthesis and vitamin D transport or storage.
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Affiliation(s)
- Sahil Kalia
- Department of Animal Science, Cornell University, Ithaca, NY, United States
| | - Andrew D Magnuson
- Department of Animal Science, Cornell University, Ithaca, NY, United States
| | - Tao Sun
- Department of Animal Science, Cornell University, Ithaca, NY, United States
| | - Ziqiao Sun
- Department of Animal Science, Cornell University, Ithaca, NY, United States
| | - Xin Gen Lei
- Department of Animal Science, Cornell University, Ithaca, NY, United States.
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9
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Frankhouser DE, DeWess T, Snodgrass IF, Cole RM, Steck S, Thomas D, Kalu C, Belury MA, Clinton SK, Newman JW, Yee LD. Randomized dose-response trial of n-3 fatty acids in hormone receptor negative breast cancer survivors- impact on breast adipose oxylipin and DNA methylation patterns. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2024:2024.09.16.24313691. [PMID: 39371146 PMCID: PMC11451633 DOI: 10.1101/2024.09.16.24313691] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 10/08/2024]
Abstract
Background Increasing evidence suggests the unique susceptibility of estrogen receptor and progesterone receptor negative (ERPR-) breast cancer to dietary fat amount and type. Dietary n-3 polyunsaturated fatty acids (PUFAs), such as docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), may modulate breast adipose fatty acid profiles and downstream bioactive metabolites to counteract pro-inflammatory, pro-carcinogenic signaling in the mammary microenvironment. Objective To determine effects of ~1 to 5 g/d EPA+DHA over 12 months on breast adipose fatty acid and oxylipin profiles in women with ERPR(-) breast cancer, a high-risk molecular subtype. Methods We conducted a 12-month randomized controlled, double-blind clinical trial of ~5g/d vs ~1g/d DHA+EPA supplementation in women within 5 years of completing standard therapy for ERPR(-) breast cancer Stages 0-III. Blood and breast adipose tissue specimens were collected every 3 months for biomarker analyses including fatty acids by gas chromatography, oxylipins by LC-MS/MS, and DNA methylation by reduced-representation bisulfite sequencing (RRBS). Results A total of 51 participants completed the 12-month intervention. Study treatments were generally well-tolerated. While both doses increased n-3 PUFAs from baseline in breast adipose, erythrocytes, and plasma, the 5g/d supplement was more potent (n =51, p <0.001). The 5g/d dose also reduced plasma triglycerides from baseline (p =0.008). Breast adipose oxylipins at 0, 6, and 12 months showed dose-dependent increases in unesterified and esterified DHA and EPA metabolites (n =28). Distinct DNA methylation patterns in adipose tissue after 12 months were identified, with effects unique to the 5g/d dose group (n =17). Conclusions Over the course of 1 year, EPA+DHA dose-dependently increased concentrations of these fatty acids and their derivative oxylipin metabolites, producing differential DNA methylation profiles of gene promoters involved in metabolism-related pathways critical to ERPR(-) breast cancer development and progression. These data provide evidence of both metabolic and epigenetic effects of n-3 PUFAs in breast adipose tissue, elucidating novel mechanisms of action for high-dose EPA+DHA-mediated prevention of ERPR(-) breast cancer.
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Affiliation(s)
- David E. Frankhouser
- Department of Computational and Quantitative Medicine, City of Hope, Duarte, CA 91010
| | - Todd DeWess
- Department of Computational and Quantitative Medicine, City of Hope, Duarte, CA 91010
- Department of Surgery, City of Hope, Duarte CA 91010
| | - Isabel F. Snodgrass
- University of California Davis West Coast Metabolomics Center, Genome Center, University of California Davis, Davis CA, 95616
| | - Rachel M. Cole
- Department of Food Science and Technology, The Ohio State University, Columbus OH 43210
| | - Sarah Steck
- The Ohio State University Comprehensive Cancer Center, Columbus OH 43210
| | | | - Chidimma Kalu
- Department of Surgery, City of Hope, Duarte CA 91010
| | - Martha A. Belury
- Department of Food Science and Technology, The Ohio State University, Columbus OH 43210
- The Ohio State University Comprehensive Cancer Center, Columbus OH 43210
| | - Steven K. Clinton
- The Ohio State University Comprehensive Cancer Center, Columbus OH 43210
- Department of Internal Medicine, The Ohio State University, Columbus OH 43210
| | - John W. Newman
- University of California Davis West Coast Metabolomics Center, Genome Center, University of California Davis, Davis CA, 95616
- Department of Nutrition, University of California Davis, Davis CA, 956169
- United States Department of Agriculture Agricultural Research Service, Western Human Nutrition Research Center, Davis CA, 95616
| | - Lisa D. Yee
- Department of Surgery, City of Hope, Duarte CA 91010
- City of Hope Comprehensive Cancer Center, Duarte, CA 91010
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10
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Corporeau C, Le Foll C, Cruciani-Guglielmacci C, Le Stunff H, Mithieux G, Magnan C, Delarue J. Fish oil minimises feed intake and improves insulin sensitivity in Zucker fa/fa rats. Br J Nutr 2024; 131:749-761. [PMID: 37877265 DOI: 10.1017/s0007114523002404] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2023]
Abstract
Long-chain n-3 PUFA (LC n-3 PUFA) prevent, in rodents, insulin resistance (IR) induced by a high-fat and/or fructose diet but not IR induced by glucocorticoids. In humans, contrasting effects have also been reported. We investigated their effects on insulin sensitivity, feed intake (FI) and body weight gain in genetically insulin resistant male obese (fa/fa) Zucker (ZO) rats during the development of obesity. ZO rats were fed a diet supplemented with 7 % fish oil (FO) + 1 % corn oil (CO) (wt/wt) (ZOFO), while the control group was fed a diet containing 8 % fat from CO (wt/wt) (ZOCO). Male lean Zucker (ZL) rats fed either FO (ZLFO) or CO (ZLCO) diet were used as controls. FO was a marine-derived TAG oil containing EPA 90 mg/g + DHA 430 mg/g. During an oral glucose tolerance test, glucose tolerance remained unaltered by FO while insulin response was reduced in ZOFO only. Liver insulin sensitivity (euglycaemic-hyperinsulinaemic clamp + 2 deoxyglucose) was improved in ZOFO rats, linked to changes in phosphoenolpyruvate carboxykinase expression, activity and glucose-6-phosphatase activity. FI in response to intra-carotid insulin/glucose infusion was decreased similarly in ZOFO and ZOCO. Hypothalamic ceramides levels were lower in ZOFO than in ZOCO. Our study demonstrates that LC n-3 PUFA can minimise weight gain, possibly by alleviating hypothalamic lipotoxicity, and liver IR in genetically obese Zucker rats.
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Affiliation(s)
- Charlotte Corporeau
- Department of Nutritional Sciences, Hospital University, Faculty of Medicine, University of Brest, Plouzané, France
- Present address: Ifremer, University of Brest, CNRS, IRD, LEMAR, F-29280 Plouzané, France
| | - Christelle Le Foll
- Department of Nutritional Sciences, Hospital University, Faculty of Medicine, University of Brest, Plouzané, France
- Present address: Institute of Veterinary Physiology, University of Zurich, CH-8057, Zurich, Switzerland
| | | | - Hervé Le Stunff
- Université Paris Cité, CNRS, Unité de Biologie Fonctionnelle et Adaptative, F-75013 Paris, France
- Present address: Institut des Neurosciences Paris-Saclay-Université Paris-Saclay-CNRS UMR 9197, Gif-sur-Yvette, France
| | - Gilles Mithieux
- Inserm, U855, Lyon, F-69008, France
- University Lyon 1, Villeurbanne, F-69622, France
- University of Lyon, Lyon, F-69008, France
| | - Christophe Magnan
- Université Paris Cité, CNRS, Unité de Biologie Fonctionnelle et Adaptative, F-75013 Paris, France
| | - Jacques Delarue
- Department of Nutritional Sciences, ER7479 SPURBO, Hospital University, Faculty of Medicine University of Brest, Plouzane, France
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11
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Menzel R, Zhang X, Pietrucik T, Bathelt A, Ruess L. Omega-3 PUFA and the fitness and cognition of the nematode Caenorhabditis elegans under different environmental conditions. Comp Biochem Physiol B Biochem Mol Biol 2024; 270:110925. [PMID: 38040326 DOI: 10.1016/j.cbpb.2023.110925] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2023] [Revised: 11/21/2023] [Accepted: 11/23/2023] [Indexed: 12/03/2023]
Abstract
Many invertebrate species possess the metabolic ability to synthesize long-chain ω3 polyunsaturated fatty acids (PUFA) de novo. Due to their diverse effects on membrane architecture, neuroplasticity, growth and reproduction, PUFA have a high potential to positively influence the fitness of an organism. But how and when do these supposed advantages actually come into play? Other species, that are often closely related, pass natural selection without this special metabolic ability. The ω3-PUFA rich model organism Caenorhabditis elegans (Nematoda) and its mutant fat-1(wa9), lacking these PUFA, are a suitable test system. We analyzed potential impairments in reproduction and growth in a soil assay. Further, chemotaxis after aversive olfactory, associative learning and integration of a second sensory signal were assessed on agar plates. Moreover, we analyzed the phospholipid pattern of both C. elegans strains and further free-living nematodes species at different temperatures. While the phenotypic effects were rather small under standard conditions, lowering the temperature to 15 or even 10 °C or reducing the soil moisture, led to significant limitations, with the investigated parameters for neuroplasticity being most impaired. The ω3-PUFA free C. elegans mutant strain fat-1 did not adapt the fatty acid composition of its phospholipids to a decreasing temperature, while ω3-PUFA containing nematodes proportionally increased this PUFA group. In contrats, other ω3-PUFA free nematode species produced significantly more ω6-PUFA. Thus, the ability to synthesize long-chain ω3-PUFA de novo likely is fundamental for an increase in neuroplasticity and an efficient way for regulating membrane fluidity to maintain their functionality.
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Affiliation(s)
- Ralph Menzel
- Humboldt-Universität zu Berlin, Institute of Biology, Ecology, Philippstr. 13, 10115 Berlin, Germany.
| | - Xuchao Zhang
- Humboldt-Universität zu Berlin, Institute of Biology, Ecology, Philippstr. 13, 10115 Berlin, Germany
| | - Tamara Pietrucik
- Humboldt-Universität zu Berlin, Institute of Biology, Ecology, Philippstr. 13, 10115 Berlin, Germany
| | - Antonia Bathelt
- Humboldt-Universität zu Berlin, Institute of Biology, Ecology, Philippstr. 13, 10115 Berlin, Germany
| | - Liliane Ruess
- Humboldt-Universität zu Berlin, Institute of Biology, Ecology, Philippstr. 13, 10115 Berlin, Germany
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12
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Bae S, Moon YA. Deletion of Elovl5 leads to dyslipidemia and atherosclerosis in LDLR-deficient mice. Biochem Biophys Res Commun 2024; 690:149292. [PMID: 38000296 DOI: 10.1016/j.bbrc.2023.149292] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2023] [Accepted: 11/17/2023] [Indexed: 11/26/2023]
Abstract
Atherosclerosis is a chronic inflammatory disease for which hepatic steatosis and atherogenic dyslipidemia are significant risk factors. We investigated the effects of endogenously generated very-long-chain polyunsaturated fatty acids (VL-PUFAs) on dyslipidemia and atherosclerosis development using mice that lack ELOVL5, a PUFA elongase that is required for the synthesis of arachidonic acid, EPA, and DHA from the essential fatty acids linoleic and linolenic acids, and the LDL receptor (LDLR). Elovl5-/-;Ldlr-/- mice manifest increased liver triglyceride and cholesterol concentrations due to the activation of sterol regulatory element binding protein-1, a transcription factor that activates enzymes required for de novo lipogenesis. Plasma levels of triglycerides and cholesterol in VLDL, IDL, and LDL were markedly elevated in Elovl5-/-;Ldlr-/- mice fed a chow and the mice exhibited marked aortic atherosclerotic plaques. Bone marrow-derived monocytes from wild-type (WT) and Elovl5-/- mice were polarized to M1 and M2 macrophages, and the effects of ELOVL5 on inflammatory activity were determined. There were no differences in most of the markers tested for M1 and M2 polarized cells between WT and Elovl5-/- cells, except for a slight increase in PGE2 secretion in Elovl5-/- cells, likely due to elevated Cox-2 expression. These results suggest that the deletion of Elovl5 leads to hepatic steatosis and dyslipidemia, which are the major factors in severe atherosclerosis in Elovl5-/-;Ldlr-/- mice.
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Affiliation(s)
- Sijeong Bae
- Department of Molecular Medicine, Inha University College of Medicine, Incheon, South Korea
| | - Young-Ah Moon
- Department of Molecular Medicine, Inha University College of Medicine, Incheon, South Korea.
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13
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Michaeloudes C, Christodoulides S, Christodoulou P, Kyriakou TC, Patrikios I, Stephanou A. Variability in the Clinical Effects of the Omega-3 Polyunsaturated Fatty Acids DHA and EPA in Cardiovascular Disease-Possible Causes and Future Considerations. Nutrients 2023; 15:4830. [PMID: 38004225 PMCID: PMC10675410 DOI: 10.3390/nu15224830] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2023] [Revised: 11/08/2023] [Accepted: 11/16/2023] [Indexed: 11/26/2023] Open
Abstract
Cardiovascular disease (CVD) that includes myocardial infarction and stroke, is the leading cause of mortality worldwide. Atherosclerosis, the primary underlying cause of CVD, can be controlled by pharmacological and dietary interventions, including n-3 polyunsaturated fatty acid (PUFA) supplementation. n-3 PUFA supplementation, primarily consisting of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), has shown promise in reducing atherosclerosis by modulating risk factors, including triglyceride levels and vascular inflammation. n-3 PUFAs act by replacing pro-inflammatory fatty acid types in cell membranes and plasma lipids, by regulating transcription factor activity, and by inducing epigenetic changes. EPA and DHA regulate cellular function through shared and differential molecular mechanisms. Large clinical studies on n-3 PUFAs have reported conflicting findings, causing confusion among the public and health professionals. In this review, we discuss important factors leading to these inconsistencies, in the context of atherosclerosis, including clinical study design and the differential effects of EPA and DHA on cell function. We propose steps to improve clinical and basic experimental study design in order to improve supplement composition optimization. Finally, we propose that understanding the factors underlying the poor response to n-3 PUFAs, and the development of molecular biomarkers for predicting response may help towards a more personalized treatment.
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Affiliation(s)
- Charalambos Michaeloudes
- School of Medicine, European University Cyprus, Nicosia 2404, Cyprus; (S.C.); (P.C.); (T.-C.K.); (I.P.); (A.S.)
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14
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Pourrajab B, Sharifi-Zahabi E, Soltani S, Shahinfar H, Shidfar F. Comparison of canola oil and olive oil consumption on the serum lipid profile in adults: a systematic review and meta-analysis of randomized controlled trials. Crit Rev Food Sci Nutr 2023; 63:12270-12284. [PMID: 35866510 DOI: 10.1080/10408398.2022.2100314] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
BACKGROUND AND AIMS Several randomized clinical trials have investigated the effects of canola oil (CO) compared to olive oil (OO) on the serum lipid profiles in adults. However, the results of these studies are inconsistent. Thus, this study aimed to assess the comparison of CO and OO consumption on the serum lipid components in adults. METHODS AND RESULTS The following online databases were searched until February 4th, 2022: PubMed/Medline, Scopus, Clarivate Analytics Web of Science, Cochrane Central Register of Controlled Trials, and Google Scholar. The effect sizes were stated as the weighted mean difference (WMD) with 95% confidence intervals (CI). A total of 13 eligible trials were included in this meta-analysis. The results showed that the CO consumption, significantly reduced serum LDL-c (WMD: -6.13 mg/dl, 95%CI: -9.79, -2.46, p = 0.001), TC (WMD: -8.92 mg/dl, 95% CI: -13.52, -4.33, P < 0.001) and LDL-c/HDL-c ratio (WMD: -0.30; 95% CI, -0.53, -0.06, p = 0.01) levels compared to OO. There were no significant changes in the other components of the blood lipids. CONCLUSION The results of this review suggest that CO consumptionhas beneficial effects on LDL-c, TC, and LDL-c/HDL-c ratio compared to OO. Therefore, its replacement with OO can have cardioprotective impacts.
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Affiliation(s)
- Behnaz Pourrajab
- Department of Nutrition, School of Public Health, Iran University of Medical Sciences, Tehran, Iran
| | - Elham Sharifi-Zahabi
- Department of Nutrition, School of Public Health, Iran University of Medical Sciences, Tehran, Iran
| | - Sepideh Soltani
- Yazd Cardiovascular Research Center, Non-communicable Diseases Research Institute, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Hossein Shahinfar
- Department of Nutrition, School of Public Health, Iran University of Medical Sciences, Tehran, Iran
| | - Farzad Shidfar
- Department of Nutrition, School of Public Health, Iran University of Medical Sciences, Tehran, Iran
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15
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Østbye TKK, Gudbrandsen OA, Drotningsvik A, Ruyter B, Berge GM, Vogt G, Nilsson A. Different Dietary Ratios of Camelina Oil to Sandeel Oil Influence the Capacity to Synthesise and Deposit EPA and DHA in Zucker Fa/Fa Rats. Nutrients 2023; 15:nu15102344. [PMID: 37242227 DOI: 10.3390/nu15102344] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2023] [Revised: 05/12/2023] [Accepted: 05/15/2023] [Indexed: 05/28/2023] Open
Abstract
Plant-based food provides more ALA (α-linolenic acid) and less EPA (eicosapentaenoic acid) and DHA (docosahexanoic acid) than marine food. Earlier studies indicate that cetoleic acid (22:1n-11) stimulates the n-3 pathway from ALA to EPA and DHA. The present study aimed to investigate the dietary effects of camelina oil (CA) high in ALA and sandeel oil (SA) high in cetoleic acid on the conversion of ALA to EPA and DHA. Male Zucker fa/fa rats were fed a diet of soybean oil (Ctrl) or diets of CA, SA, or a combination of CA and SA. Significantly higher levels of DPA (docosapentaenoic acid) and DHA in blood cells from the CA group compared to the Ctrl indicate an active conversion of ALA to DPA and DHA. Increasing the uptake and deposition of EPA and DHA meant that a trend towards a decrease in the liver gene expression of Elovl5, Fads1, and Fads2 along with an increase in the dietary content of SA was observed. However, 25% of the SA could be exchanged with CA without having a significant effect on EPA, DPA, or DHA in blood cells, indicating that bioactive components in SA, such as cetoleic acid, might counteract the inhibiting effect of the high dietary content of DHA on the n-3 biosynthetic pathway.
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Affiliation(s)
| | - Oddrun Anita Gudbrandsen
- Dietary Research Group, Centre for Nutrition, Department of Clinical Medicine, University of Bergen, 5007 Bergen, Norway
| | - Aslaug Drotningsvik
- Dietary Research Group, Centre for Nutrition, Department of Clinical Medicine, University of Bergen, 5007 Bergen, Norway
- Vedde AS, 6030 Langevåg, Norway
| | - Bente Ruyter
- Nofima AS, Norwegian Institute of Food, Fisheries and Aquaculture Research, 1433 Ås, Norway
| | - Gerd Marit Berge
- Nofima AS, Norwegian Institute of Food, Fisheries and Aquaculture Research, 1433 Ås, Norway
| | - Gjermund Vogt
- Eurofins Food & Agro Testing Norway AS, 1538 Moss, Norway
| | - Astrid Nilsson
- Nofima AS, Norwegian Institute of Food, Fisheries and Aquaculture Research, 1433 Ås, Norway
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16
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Danielli M, Perne L, Jarc Jovičić E, Petan T. Lipid droplets and polyunsaturated fatty acid trafficking: Balancing life and death. Front Cell Dev Biol 2023; 11:1104725. [PMID: 36776554 PMCID: PMC9911892 DOI: 10.3389/fcell.2023.1104725] [Citation(s) in RCA: 63] [Impact Index Per Article: 31.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2022] [Accepted: 01/17/2023] [Indexed: 01/28/2023] Open
Abstract
Lipid droplets are fat storage organelles ubiquitously distributed across the eukaryotic kingdom. They have a central role in regulating lipid metabolism and undergo a dynamic turnover of biogenesis and breakdown to meet cellular requirements for fatty acids, including polyunsaturated fatty acids. Polyunsaturated fatty acids esterified in membrane phospholipids define membrane fluidity and can be released by the activity of phospholipases A2 to act as ligands for nuclear receptors or to be metabolized into a wide spectrum of lipid signaling mediators. Polyunsaturated fatty acids in membrane phospholipids are also highly susceptible to lipid peroxidation, which if left uncontrolled leads to ferroptotic cell death. On the one hand, lipid droplets act as antioxidant organelles that control polyunsaturated fatty acid storage in triglycerides in order to reduce membrane lipid peroxidation, preserve organelle function and prevent cell death, including ferroptosis. On the other hand, lipid droplet breakdown fine-tunes the delivery of polyunsaturated fatty acids into metabolic and signaling pathways, but unrestricted lipid droplet breakdown may also lead to the release of lethal levels of polyunsaturated fatty acids. Precise regulation of lipid droplet turnover is thus essential for polyunsaturated fatty acid distribution and cellular homeostasis. In this review, we focus on emerging aspects of lipid droplet-mediated regulation of polyunsaturated fatty acid trafficking, including the management of membrane lipid peroxidation, ferroptosis and lipid mediator signaling.
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Affiliation(s)
| | | | | | - Toni Petan
- Department of Molecular and Biomedical Sciences, Jožef Stefan Institute, Ljubljana, Slovenia
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17
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Wernicke C, Pohrt A, Pletsch-Borba L, Apostolopoulou K, Hornemann S, Meyer N, Machann J, Gerbracht C, Tacke F, Pfeiffer AF, Spranger J, Mai K. Effect of unsaturated fat and protein intake on liver fat in people at risk of unhealthy aging: 1-year results of a randomized controlled trial. Am J Clin Nutr 2023; 117:785-793. [PMID: 36804020 DOI: 10.1016/j.ajcnut.2023.01.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Revised: 01/08/2023] [Accepted: 01/10/2023] [Indexed: 01/15/2023] Open
Abstract
BACKGROUND Short-term trials indicate improvement of intrahepatic lipids (IHLs) and metabolism by dietary protein or unsaturated fatty acids (UFAs) beyond weight loss. OBJECTIVES We aimed to assess the effect of a dietary intervention high in protein and UFAs on IHLs and metabolic outcome after 12 mo, as long-term effects of such a combined intervention are unknown. METHODS Within a 36-mo randomized controlled trial, eligible subjects (aged 50 to 80 y, ≥1 risk factor for unhealthy aging) were randomly assigned to either intervention group (IG) with high intake of mono-/poly-UFAs [15-20 percent of total energy (%E)/10%-15%E, respectively], plant protein (15%-25%E), and fiber (≥30 g/d), or control group [CG, usual care, dietary recommendations of the German Nutrition Society (fat 30%E/carbohydrates 55%E/protein 15%E)]. Stratification criteria were sex, known cardiovascular disease, heart failure, arterial hypertension, type 2 diabetes, and cognitive or physical impairment. Nutritional counseling and supplementation of foods mirroring the intended dietary pattern were performed in the IG. Diet-induced effects on IHLs, analyzed by magnetic resonance spectroscopy, as well as on lipid and glucose metabolism were predefined secondary endpoints. RESULTS IHL content was analyzed in 346 subjects without significant alcohol consumption at baseline and in 258 subjects after 12 mo. Adjusted for weight loss, sex, and age, we observed a comparable decline of IHLs in IG and CG (-33.3%; 95% CI: -49.3, -12.3%; n = 128 compared with -21.8%; 95% CI: -39.7, 1.5%; n = 130; P = 0.179), an effect that became significant by comparing adherent IG subjects to adherent CG subjects (-42.1%; 95% CI: -58.1, -20.1%; n = 88 compared with -22.2%; 95% CI: -40.7, 2.0%; n = 121; P = 0.013). Compared with the CG, decline of LDL cholesterol (LDL-C) and total cholesterol (TC) was stronger in the IG (for LDL-C P = 0.019, for TC P = 0.010). Both groups decreased in triglycerides and insulin resistance (P for difference between groups P = 0.799 and P = 0.124, respectively). CONCLUSIONS Diets enriched with protein and UFAs have beneficial long-term effects on liver fat and lipid metabolism in adherent older subjects. This study was registered at the German Clinical Trials Register, https://www.drks.de/drks_web/setLocale_EN.do, DRKS00010049. Am J Clin Nutr 20XX;xx:xx-xx.
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Affiliation(s)
- Charlotte Wernicke
- Charité-Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Endocrinology and Metabolism, 10117 Berlin, Germany; NutriAct-Competence Cluster Nutrition Research Berlin-Potsdam, Germany
| | - Anne Pohrt
- Charité - Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institute of Biometry and Clinical Epidemiology, Germany
| | - Laura Pletsch-Borba
- Charité-Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Endocrinology and Metabolism, 10117 Berlin, Germany; NutriAct-Competence Cluster Nutrition Research Berlin-Potsdam, Germany
| | - Konstantina Apostolopoulou
- Charité-Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Endocrinology and Metabolism, 10117 Berlin, Germany; NutriAct-Competence Cluster Nutrition Research Berlin-Potsdam, Germany
| | - Silke Hornemann
- NutriAct-Competence Cluster Nutrition Research Berlin-Potsdam, Germany; Department of Clinical Nutrition, German Institute of Human Nutrition, Potsdam-Rehbruecke, Nuthetal, Germany; German Center for Diabetes Research, München-Neuherberg, Germany
| | - Nina Meyer
- Charité-Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Endocrinology and Metabolism, 10117 Berlin, Germany; NutriAct-Competence Cluster Nutrition Research Berlin-Potsdam, Germany
| | - Jürgen Machann
- German Center for Diabetes Research, München-Neuherberg, Germany; Institute for Diabetes Research and Metabolic Diseases (IDM) of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany; Section on Experimental Radiology, Department of Diagnostic and Interventional Radiology, University Hospital Tübingen, Germany
| | - Christiana Gerbracht
- NutriAct-Competence Cluster Nutrition Research Berlin-Potsdam, Germany; Department of Clinical Nutrition, German Institute of Human Nutrition, Potsdam-Rehbruecke, Nuthetal, Germany
| | - Frank Tacke
- Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Hepatology and Gastroenterology, 10117 Berlin, Germany
| | - Andreas Fh Pfeiffer
- Charité-Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Endocrinology and Metabolism, 10117 Berlin, Germany; NutriAct-Competence Cluster Nutrition Research Berlin-Potsdam, Germany; Department of Clinical Nutrition, German Institute of Human Nutrition, Potsdam-Rehbruecke, Nuthetal, Germany; German Center for Diabetes Research, München-Neuherberg, Germany
| | - Joachim Spranger
- Charité-Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Endocrinology and Metabolism, 10117 Berlin, Germany; NutriAct-Competence Cluster Nutrition Research Berlin-Potsdam, Germany; DZHK (German Centre for Cardiovascular Research), partner site Berlin, Berlin, Germany.
| | - Knut Mai
- Charité-Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Endocrinology and Metabolism, 10117 Berlin, Germany; NutriAct-Competence Cluster Nutrition Research Berlin-Potsdam, Germany; DZHK (German Centre for Cardiovascular Research), partner site Berlin, Berlin, Germany
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18
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Becker SL, Humphrey DC, Karriker LA, Brown JT, Skoland KJ, Greiner LL. The effects of dietary essential fatty acid ratios and energy level on growth performance, lipid metabolism, and inflammation in grow-finish pigs. J Anim Sci 2023; 101:skad151. [PMID: 37170903 PMCID: PMC10226270 DOI: 10.1093/jas/skad151] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Accepted: 05/09/2023] [Indexed: 05/13/2023] Open
Abstract
The objective of this study was to investigate the effects of dietary metabolizable energy (ME) level and the ratio of linoleic acid:α-linolenic acid (LA:ALA) on the growth performance, lipid metabolism, circulatory and joint inflammatory status, and synovial fluid proteome of grow-finish pigs. A total of 224 pigs (BW = 41.5 ± 6.1 kg; PIC Genus 337 × 1050, Hendersonville, TN) were randomly assigned to either a high (3.55 Mcal/kg; HE) or low (3.29 Mcal/kg; LE) ME dietary treatment with a high (23:1) or low (12:1) LA:ALA in a 2 × 2 factorial arrangement. Diets were fed across three 28-d phases. Pigs were housed either four barrows or four gilts per pen. Blood samples were collected on days 0, 21, 42, and 84. Synovial fluid was collected from the hock and carpus joints on days 0 and 84. Liver and adipose tissue samples were collected on day 84. Data were analyzed as repeated measures using PROC MIXED (SAS 9.4) with pen as the experimental unit and energy level, essential fatty acid ratio, sex, phase, and their interactions as fixed effects. Compared to LE, HE increased days 28, 56, and 84 body weight (BW; P = 0.005). For the overall period, HE increased average daily gain (ADG) compared to LE (P < 0.001) and improved feed efficiency (P = 0.001), while LE increased feed intake compared to HE (P < 0.001). Gilts receiving diets with low LA:ALA had similar final BW to barrows receiving a low LA:ALA at days 28, 56, and 84 (P = 0.024), resulting from improved overall days 0-84 ADG compared to gilts receiving the high LA:ALA (P = 0.031). In the liver, HE decreased the mRNA abundance of acetyl CoA carboxylase (ACACA; P = 0.004), cluster of differentiation 36 (P = 0.034), and tended to decrease fatty acid synthase (FASN; P = 0.056). In adipose tissue, HE decreased ACACA (P = 0.001) and FASN (P = 0.017). Plasma inflammatory markers C-reactive protein (CRP) and tumor necrosis factor-α (TNFα) were reduced on day 84 compared to day 0 (P ≤ 0.014). In the hock and carpus synovial fluid, LE tended to reduce CRP and TNFα (P ≤ 0.096). Hock and carpus synovial fluid CRP were also reduced on day 84 compared to day 0 (P = 0.001). Age of the pig impacted serum and hock synovial fluid protein abundance, but not energy level, LA:ALA, or their interactions (P < 0.05). To conclude, the high and low LA:ALA ratios utilized in this study can be fed at varying energy levels without impacting growth. Additionally, LA:ALA ratios can differentially impact the growth of barrows and gilts.
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Affiliation(s)
- Spenser L Becker
- Department of Animal Science, Iowa State University, Ames, IA 50011, USA
| | - Dalton C Humphrey
- Department of Animal Science, Iowa State University, Ames, IA 50011, USA
| | - Locke A Karriker
- Department of Veterinary Diagnostic and Production Medicine, Swine Medicine Education Center, College of Veterinary Medicine, Iowa State University, Ames, IA 50011, USA
| | - Justin T Brown
- Department of Veterinary Diagnostic and Production Medicine, Swine Medicine Education Center, College of Veterinary Medicine, Iowa State University, Ames, IA 50011, USA
| | - Kristin J Skoland
- Department of Veterinary Diagnostic and Production Medicine, Swine Medicine Education Center, College of Veterinary Medicine, Iowa State University, Ames, IA 50011, USA
| | - Laura L Greiner
- Department of Animal Science, Iowa State University, Ames, IA 50011, USA
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The Ameliorative Effect and Mechanisms of Ruditapes philippinarum Bioactive Peptides on Obesity and Hyperlipidemia Induced by a High-Fat Diet in Mice. Nutrients 2022; 14:nu14235066. [PMID: 36501096 PMCID: PMC9737393 DOI: 10.3390/nu14235066] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2022] [Revised: 11/25/2022] [Accepted: 11/25/2022] [Indexed: 11/29/2022] Open
Abstract
In this study, bioactive peptides (RBPs) from Ruditapes philippinarum were prepared by fermentation with Bacillus natto and the effect and mechanisms of RBPs on obesity and hyperlipidemia were explored in mice. We found that RBPs significantly reduced body weight, adipose tissue weight, accumulation of hepatic lipids, and serum levels of total cholesterol (CHO), triglyceride (TG), and low-density lipoprotein (LDL). Mechanistic studies showed that RBPs up-regulated the hepatic expression of genes related to lipolysis, such as hormone-sensitive lipase (HSL), phosphorylated AMP-activated protein kinase (p-AMPK), and peroxisome proliferator-activated receptors α (PPARα), and down-regulated the expression of peroxisome proliferator-activated receptors γ (PPARγ) which is related to lipid synthesis. In addition, RBPs could attenuate obesity and hyperlipidemia by regulating disordered gut microbiota composition, such as increasing the abundance of microflora related to the synthesis of short chain fatty acids (SCFAs) (Bacteroidetes, Prevotellaceas_UCG_001, norank_f_Muribaculaceae, and Odoribacter) and controlling those related to intestinal inflammation (reduced abundance of Deferribacteres and increased abundance of Alistipes and ASF356) to exert anti-obesity and lipid-lowering activities. Our findings laid the foundation for the development and utilization of RBPs as a functional food to ameliorate obesity and hyperlipidemia.
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20
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Miyake T, Furukawa S, Matsuura B, Yoshida O, Miyazaki M, Shiomi A, Kanzaki S, Nakaguchi H, Sunago K, Nakamura Y, Imai Y, Watanabe T, Yamamoto Y, Koizumi Y, Tokumoto Y, Hirooka M, Kumagi T, Abe M, Hiasa Y. Plasma Fatty Acid Composition Is Associated with Histological Findings of Nonalcoholic Steatohepatitis. Biomedicines 2022; 10:biomedicines10102540. [PMID: 36289802 PMCID: PMC9599601 DOI: 10.3390/biomedicines10102540] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2022] [Revised: 10/08/2022] [Accepted: 10/09/2022] [Indexed: 11/16/2022] Open
Abstract
The relationship between advanced nonalcoholic steatohepatitis (NASH) and plasma fatty acid composition remains unknown. We aimed to examine the plasma fatty acid composition in biopsy-confirmed nonalcoholic fatty liver disease (NAFLD) and evaluate the relationship between histological findings and fatty acid composition. Overall, 235 patients (134 women) with NAFLD were enrolled. Comprehensive blood chemistry tests and histological examinations of liver samples were conducted. Multivariate analyses adjusted for age, sex, body mass index, alanine aminotransferase, hemoglobin A1c, creatinine, total cholesterol, triglyceride, and NAFLD Activity Score values showed that lower levels of arachidic, behenic, α-linolenic, eicosatetraenoic, docosapentaenoic, and docosahexaenoic acids and higher levels of mead acid were associated with fibrosis stage 3–4. Furthermore, higher lauric acid, myristic acid, and palmitic acid levels and monounsaturated fatty acids such as palmitoleic acid and oleic acid were significantly associated with high NAS in analyses adjusted for the same factors and fibrosis stage. The plasma fatty acid composition was associated with the histological evidence of NASH. Increased synthesis of fatty acids is associated with NASH; insufficient intake of n-3 essential fatty acids and reduced elongation of fatty acids are associated with fibrosis in NASH. These features may help clinicians to understand and treat advanced NASH cases.
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Affiliation(s)
- Teruki Miyake
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, 454 Shitsukawa, Toon 791-0295, Ehime, Japan
- Correspondence:
| | - Shinya Furukawa
- Health Services Center, Ehime University, Bunkyo, Matsuyama 790-8577, Ehime, Japan
| | - Bunzo Matsuura
- Department of Lifestyle-related Medicine and Endocrinology, Ehime University Graduate School of Medicine, 454 Shitsukawa, Toon 791-0295, Ehime, Japan
| | - Osamu Yoshida
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, 454 Shitsukawa, Toon 791-0295, Ehime, Japan
| | - Masumi Miyazaki
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, 454 Shitsukawa, Toon 791-0295, Ehime, Japan
| | - Akihito Shiomi
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, 454 Shitsukawa, Toon 791-0295, Ehime, Japan
| | - Sayaka Kanzaki
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, 454 Shitsukawa, Toon 791-0295, Ehime, Japan
| | - Hironobu Nakaguchi
- Department of Lifestyle-related Medicine and Endocrinology, Ehime University Graduate School of Medicine, 454 Shitsukawa, Toon 791-0295, Ehime, Japan
| | - Kotaro Sunago
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, 454 Shitsukawa, Toon 791-0295, Ehime, Japan
| | - Yoshiko Nakamura
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, 454 Shitsukawa, Toon 791-0295, Ehime, Japan
| | - Yusuke Imai
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, 454 Shitsukawa, Toon 791-0295, Ehime, Japan
| | - Takao Watanabe
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, 454 Shitsukawa, Toon 791-0295, Ehime, Japan
| | - Yasunori Yamamoto
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, 454 Shitsukawa, Toon 791-0295, Ehime, Japan
| | - Yohei Koizumi
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, 454 Shitsukawa, Toon 791-0295, Ehime, Japan
| | - Yoshio Tokumoto
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, 454 Shitsukawa, Toon 791-0295, Ehime, Japan
| | - Masashi Hirooka
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, 454 Shitsukawa, Toon 791-0295, Ehime, Japan
| | - Teru Kumagi
- Postgraduate Medical Education Center, Ehime University Graduate School of Medicine, 454 Shitsukawa, Toon 791-0295, Ehime, Japan
| | - Masanori Abe
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, 454 Shitsukawa, Toon 791-0295, Ehime, Japan
| | - Yoichi Hiasa
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, 454 Shitsukawa, Toon 791-0295, Ehime, Japan
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Nezhadebrahimi A, Sepehri H, Jahanshahi M, Marjani M, Marjani A. The effect of simvastatin on gene expression of low-density lipoprotein receptor, sterol regulatory element-binding proteins, stearoyl-CoA desaturase 1 mRNA in rat hepatic tissues. Arch Physiol Biochem 2022; 128:1383-1390. [PMID: 32643419 DOI: 10.1080/13813455.2020.1772829] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Abstract
The study aimed to assess the effect of simvastatin on gene expression of LDLR, SREBPs, and SCD1 in rat hepatic tissues fed with high-fat diets (HFD) and its association with some biochemical parameters. Thirty-two male Wister albino rats were divided into four equal groups (three test and one control groups). The biochemical parameters were determined by using spectrophotometer techniques and the Elisa method. Low-density lipoprotein receptor, sterol regulatory element-binding proteins, stearoyl-CoA desaturase1, Beta-actin were analysed by real-time quantitative polymerase chain reaction (RT-PCR) method. At the end of study, the livers of the rats were separated and changes of hepatic tissue were determined. LDLR, SREBP2, and SCD1 expression increased significantly when compared G1 versus G4 and G2 versus G4. The expression of LDLR, SREBP2, and SCD1 also increased significantly when compared G2 versus G3, G1versus G3 and G1 versus G3 and G2 versus G3. The serum level of cholesterol, triglyceride, glucose, LDL, and HDL increased significantly when compared G1 versus G3. LDL showed significantly decreased when compared G1 versus G2. Cholesterol, glucose and HDL and triglyceride levels were increased significantly when compared G1 versus G4 and G2. Treatment of rats with HFD and simvastatin 20 mg/kg, triglyceride and LDL were almost the same as a control group and LDLR expression increased 98% in liver tissue. Gene expressions may be up-regulated in liver tissue and they showed different effects on biochemical parameters.
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Affiliation(s)
- Abbas Nezhadebrahimi
- Department of Biochemistry and Biophysics, Student Research Center, Metabolic Disorders Research Center, Gorgan Faculty of Medicine, Golestan University Medical Sciences, Gorgan, Iran
- Department of Physiology, Neuroscience Research Center, Faculty of Medicine, Golestan University of Medical Sciences, Gorgan, Iran
| | - Hamid Sepehri
- Department of Physiology, Neuroscience Research Center, Faculty of Medicine, Golestan University of Medical Sciences, Gorgan, Iran
| | - Mehrdad Jahanshahi
- Neuroscience Research Center, Department of Anatomy, Faculty of Medicine, Golestan University of Medical Sciences, Gorgan, Iran
| | - Majid Marjani
- Faculty of Pharmacy, Eastern Mediterranean University, Famagusta, North Cyprus, Turkey
| | - Abdoljalal Marjani
- Metabolic Disorders Research Center, Department of Biochemistry and Biophysics, Gorgan Faculty of Medicine, Golestan University Medical Sciences, Gorgan, Iran
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22
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de Britto Rosa MC, Ribeiro PR, de Oliveira Silva V, Selvati-Rezende DADC, da Silva TP, Souza FR, Cardoso MDG, Seixas JN, Andrade EF, Pardi V, Murata RM, Pereira LJ. Fatty acids composition and in vivo biochemical effects of Aleurites moluccana seed (Candlenut) in obese wistar rats. Diabetol Metab Syndr 2022; 14:80. [PMID: 35676689 PMCID: PMC9178887 DOI: 10.1186/s13098-022-00847-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Accepted: 05/13/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Candlenut (CN) has been used indiscriminately for weight loss. In vivo effects of CN in different doses are scarce. OBJECTIVE To evaluate the effects of CN ingestion in obese rats. DESIGN Thirty animals (obese and non-obese) received one of three different types of treatments: placebo, CN ingestion in a popular therapeutic regimen (8 days with oral administration of 0.2 mg/kg followed by 20 days with doses of 0.4 mg/kg), and ingestion of a doubled popular dose-called 2CN. Treatment was maintained for 28 days. RESULTS The fatty acid profile of CN indicated mainly linolelaidic and palmitoleic acids. Rats receiving CN and 2CN showed reduced plasmatic levels of glucose and lipoproteins (p < 0.05). A dose-dependent carcass fat reduction was observed (p < 0.05). Blood levels of aspartate aminotransferase (AST) and gamma-glutamyl transferase (GGT) reduced with CN and increased with 2CN doses (p < 0.05). Alanine aminotransferase (ALT) and the atherogenic index remained similar among all treatments (p > 0.05). Hepatic vacuolation decreased with CN, but the 2CN dose produced mononuclear leucocyte infiltrate. CONCLUSIONS Although CN presented beneficial effects on the metabolism of rats, it also caused increased risk of liver damage.
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Affiliation(s)
| | - Paula Reis Ribeiro
- Veterinary Medicine Department, Universidade Federal de Lavras, Mail Box 3037, Lavras, Minas Gerais, Brazil
| | - Viviam de Oliveira Silva
- Department of Health Sciences, Universidade Federal de Lavras (UFLA), Mailbox 3037, Lavras, Minas Gerais, 37200-900, Brazil
| | | | - Tácio Peres da Silva
- Agriculture Department, Universidade Federal de Lavras, Mail Box 3037, Lavras, Minas Gerais, Brazil
| | - Fernanda Rezende Souza
- Veterinary Medicine Department, Universidade Federal de Lavras, Mail Box 3037, Lavras, Minas Gerais, Brazil
| | - Maria das Graças Cardoso
- Chemistry Department, Universidade Federal de Lavras, Mail Box 3037, Lavras, Minas Gerais, Brazil
| | - Josilene Nascimento Seixas
- Department of Health Sciences, Universidade Federal de Lavras (UFLA), Mailbox 3037, Lavras, Minas Gerais, 37200-900, Brazil
| | - Eric Francelino Andrade
- Department of Health Sciences, Universidade Federal de Lavras (UFLA), Mailbox 3037, Lavras, Minas Gerais, 37200-900, Brazil
- Agrarian Sciences Institute, Universidade Federal dos Vales do Jequitinhonha e Mucuri, Unaí, Minas Gerais, 38610-000, Brazil
| | - Vanessa Pardi
- Department of Foundational Sciences, School of Dental Medicine, East Carolina University (ECU), Greenville, NC, 27834, USA
| | - Ramiro Mendonça Murata
- Department of Foundational Sciences, School of Dental Medicine, East Carolina University (ECU), Greenville, NC, 27834, USA
| | - Luciano José Pereira
- Veterinary Medicine Department, Universidade Federal de Lavras, Mail Box 3037, Lavras, Minas Gerais, Brazil.
- Department of Health Sciences, Universidade Federal de Lavras (UFLA), Mailbox 3037, Lavras, Minas Gerais, 37200-900, Brazil.
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23
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Park JE, Son J, Seo Y, Han JS. HM-Chromanone Ameliorates Hyperglycemia and Dyslipidemia in Type 2 Diabetic Mice. Nutrients 2022; 14:1951. [PMID: 35565920 PMCID: PMC9101766 DOI: 10.3390/nu14091951] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2022] [Revised: 04/26/2022] [Accepted: 05/05/2022] [Indexed: 02/04/2023] Open
Abstract
The effects of (E)-5-hydroxy-7-methoxy-3-(2-hydroxybenzyl)-4-chromanone (HMC) on hyperglycemia and dyslipidemia were investigated in diabetic mice. Mice were separated into three groups: db/db, rosiglitazone and HMC. Blood glucose or glycosylated hemoglobin values in HMC-treated mice were significantly lower compared to db/db mice. Total cholesterol, LDL-cholesterol, and triglyceride values were lower, and HDL-C levels were higher, in the HMC group compared to the diabetic and rosiglitazone groups. HMC markedly increased IRS-1Tyr612, AktSer473 and PI3K levels and plasma membrane GLUT4 levels in skeletal muscle, suggesting improved insulin resistance. HMC also significantly stimulated AMPKThr172 and PPARα in the liver, and ameliorated dyslipidemia by inhibiting SREBP-1c and FAS. Consequently, HMC reduced hyperglycemia by improving the expression of insulin-resistance-related genes and improved dyslipidemia by regulating fatty acid synthase and oxidation-related genes in db/db mice. Therefore, HMC could ameliorate hyperglycemia and dyslipidemia in type 2 diabetic mice.
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Affiliation(s)
- Jae Eun Park
- Department of Food Science and Nutrition, Pusan National University, Busan 46241, Korea;
| | - Jaemin Son
- Division of Marine Bioscience, Ocean Science & Technology School, Korea Maritime and Ocean University, Busan 49112, Korea; (J.S.); (Y.S.)
| | - Youngwan Seo
- Division of Marine Bioscience, Ocean Science & Technology School, Korea Maritime and Ocean University, Busan 49112, Korea; (J.S.); (Y.S.)
| | - Ji Sook Han
- Department of Food Science and Nutrition, Pusan National University, Busan 46241, Korea;
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24
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Plant and marine N3-PUFA regulation of fatty acid trafficking along the adipose tissue-liver axis varies according to nutritional state. J Nutr Biochem 2022; 102:108940. [PMID: 35017005 DOI: 10.1016/j.jnutbio.2022.108940] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2021] [Revised: 11/26/2021] [Accepted: 12/07/2021] [Indexed: 11/22/2022]
Abstract
BACKGROUND Marine sourced N3-PUFA regulate lipid metabolism in adipose tissue and liver; however, less is known about plant sourced N3-PUFA. The goal of this study was to investigate plant and marine N3-PUFA regulation of fatty acid trafficking along the adipose tissue-liver axis according to nutritional state. METHODS Mice were fed low-fat diets (7% w/w) containing either lard, flaxseed, or menhaden oils for 8 weeks, and were euthanized in either fed or fasted states. Substrate utilization and physical activity were assessed during the transition from a fed to fasted state. Plasma biomarkers (triglycerides (TAG), non-esterified fatty acids (NEFA)), as well as liver and epididymal adipose tissue (eWAT) lipogenic and lipolytic markers, were measured. RESULTS Neither plant nor marine N3-PUFA influenced substrate utilization or activity during the transition from a fed to fasted state. In the fed state, marine N3-PUFA reduced plasma TAG levels compared to the other diets, with no further reduction seen in fasted mice. Hepatic lipogenic markers (Fasn, Acc, Scd1, and Elovl6) were reduced in the fed state with marine N3-PUFA, but not plant N3-PUFA. In the fasted state, mice fed either N3-PUFA accumulated less liver TAG, had lower plasma NEFA, and suppressed eWAT HSL activity compared to lard. CONCLUSION Marine N3-PUFA are more potent regulators of lipogenesis than plant N3-PUFA in the fed state, whereas both N3-PUFA influence eWAT lipolysis and plasma NEFA in the fasted state. This work provides novel insights regarding N3-PUFA regulation of fatty acid trafficking along the adipose tissue-liver axis according to nutritional state.
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25
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Chen J, Liu Y, Huang Y, Tong A, Liu B, Zeng F. Schizochytrium
oil and its Mixture with Fish Oil and
Sacha inchi
Oil Ameliorate Gut Microbiota Composition and Lipid Metabolism via the FAS/HMGCR/SREBP Signaling Pathway. EUR J LIPID SCI TECH 2021. [DOI: 10.1002/ejlt.202100108] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Affiliation(s)
- Jie Chen
- College of Food Science Fujian Agriculture and Forestry University Fuzhou 350002 China
| | - Yilin Liu
- College of Food Science Fujian Agriculture and Forestry University Fuzhou 350002 China
| | - Ying Huang
- College of Food Science Fujian Agriculture and Forestry University Fuzhou 350002 China
| | - Aijun Tong
- College of Food Science Fujian Agriculture and Forestry University Fuzhou 350002 China
| | - Bin Liu
- College of Food Science Fujian Agriculture and Forestry University Fuzhou 350002 China
- National Engineering Research Center of JUNCAO Technology Fujian Agriculture and Forestry University Fuzhou 350002 China
| | - Feng Zeng
- College of Food Science Fujian Agriculture and Forestry University Fuzhou 350002 China
- National Engineering Research Center of JUNCAO Technology Fujian Agriculture and Forestry University Fuzhou 350002 China
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26
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Liu R, Jiang J, Fu Z, Liu C, Yao L, Quan H. Effects of Omega-3 Fatty Acid Intake in Patients Undergoing Dialysis: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. J Am Coll Nutr 2021; 41:697-712. [PMID: 34635026 DOI: 10.1080/07315724.2021.1953416] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Objective: Fish oil supplementation has been shown to be beneficial for hemodialysis (HD) patients. The aim of this study was to evaluate the efficacy and safety of omega-3 fatty acid supplementation or dietary adjustment in dialysis patients.Methods: A systematic literature search was performed to identify relevant randomized controlled trials (RCTs) to study the effects of omega-3 supplementation on dialysis patients. The variables of interest included the levels of blood lipids, inflammatory indicators, proteins, parathyroid hormone (PTH), gastrointestinal adverse reactions, and all-cause mortality. The mean differences (MDs) and 95% confidence intervals (CIs) were calculated, and heterogeneity was assessed with the I2 test. Subgroup and sensitivity analyses were performed to identify potential sources.Results: The systematic review included 49 RCTs and evaluated the efficacy and safety of omega-3 fatty acid supplementation in dialysis patients. Data synthesis showed that compared with the control group, the group receivingomega-3 supplementation exhibited significantly decreased serum triglyceride (TG) levels, decreased C-reactive protein (CRP) and TNF-alpha levels, increased hemoglobin levels, reduced serum phosphorus levels, increased PTH levels, and increased gastrointestinal adverse reactions to a certain extent. Furthermore, there was no effect on the blood total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), albumin or calcium levels and all-cause mortality.Conclusion: Omega-3 fatty acid supplementation is related to a reduction in serum TG, LDL and inflammation index levels and has few adverse reactions. Therefore, omega-3 fatty acid supplementation may be a useful nutrition therapy for dialysis patients.
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Affiliation(s)
- Rui Liu
- Department of Intensive Care Unit, Tangdu Hospital, Second Affiliated Hospital of Air Force Military Medical University, Xi'an, China
| | - Jiawei Jiang
- Department of Intensive Care Unit, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin, China
| | | | - Chao Liu
- Medical School of Chinese PLA, Beijing, China.,Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing, China
| | - Linong Yao
- Department of Intensive Care Unit, Tangdu Hospital, Second Affiliated Hospital of Air Force Military Medical University, Xi'an, China
| | - Hong Quan
- Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing, China.,Department of Nephrology, Chinese PLA General Hospital, Beijing, China
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27
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Hattori H, Mori T, Shibata T, Kita M, Mitsunaga T. 6-Paradol Acts as a Potential Anti-obesity Vanilloid from Grains of Paradise. Mol Nutr Food Res 2021; 65:e2100185. [PMID: 33793045 DOI: 10.1002/mnfr.202100185] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Indexed: 12/22/2022]
Abstract
SCOPE Grains of Paradise (GOP), the seeds of Aframomum melegueta, has anti-obesity effects. However, the mechanisms underlying the effects remain unclear. METHODS AND RESULTS This study sets up to study the anti-obesity impact and homeostatic effects of 6-paradol, a major vanilloid found in GOP, and investigates the physiological outputs and the lipometabolism-related gene in fat and liver in high-fat-induced obese mice with a comparison with structurally similar vanilloids (6-gingerol and 6-shogaol). The vanilloids are synthesized in adequate quantities for performing animal experiments and orally administered to 6-week-old male mice over 2 weeks. This study found that 6-paradol decreased body weight gain and visceral and subcutaneous fats in 2 weeks, whereas 6-gingerol and 6-shogaol have no effect. Additionally, 6-paradol suppresses the hepatic cholesterol and triglyceride and significantly decreases the gene expression related to fatty acid synthesis, lipid transportation, and adipocyte differentiation in both liver and adipose tissue. Moreover, phosphorylation of AMP-activated protein kinase (AMPK) that greatly contributes to lipometabolism is promoted by 6-gingerol but not 6-paradol. CONCLUSION These results suggest that 6-paradol regulates several obesity-related genes in an AMPK-independent manner. Therefore, it could be the principal active vanilloid in GOP giving it anti-obesity properties with a different mechanism.
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Affiliation(s)
- Hiroyuki Hattori
- Asian Satellite Campuses Institute, Nagoya University, Nagoya, 464-8601, Japan.,Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya, 464-8601, Japan
| | - Takashi Mori
- Faculty of Applied Biological Sciences, Gifu University, Gifu, 501-1193, Japan
| | - Takahiro Shibata
- Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya, 464-8601, Japan
| | - Masaki Kita
- Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya, 464-8601, Japan
| | - Tohru Mitsunaga
- Faculty of Applied Biological Sciences, Gifu University, Gifu, 501-1193, Japan
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28
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Okue S, Ishikawa E, Nakahara R, Ito T, Okura T, Sakae M, Miura A, Ozaki-Masuzawa Y, Hosono T, Seki T. Fish oil suppresses obesity more potently in lean mice than in diet-induced obese mice but ameliorates steatosis in such obese mice. Biosci Biotechnol Biochem 2021; 85:421-429. [PMID: 33604637 DOI: 10.1093/bbb/zbaa038] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Accepted: 08/18/2020] [Indexed: 11/14/2022]
Abstract
This study sought to clarify the antiobesity effects of fish oil (FO) in terms of prevention and amelioration. An isocaloric diet composed of lard or FO was given to lean C57BL/6J mice for the study of prevention and high-fat diet-induced obese (DIO) mice for the study of amelioration for 4 weeks. Body weight gain and food efficiency were potently suppressed by FO in lean mice compared to lard diet-fed mice. Uncoupling protein-1 (UCP-1) expression in inguinal white adipose tissue (WAT) was also significantly induced by FO in lean mice. FO also suppressed body weight gain and food efficiency in DIO mice but did not reduce body weight. FO ameliorated liver steatosis in DIO mice by mildly inducing UCP-1 in inguinal WAT. FO suppressed obesity more potently in lean mice than in DIO mice but ameliorated steatosis in the DIO mice.
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Affiliation(s)
- Sachiko Okue
- Department of Applied Life Sciences, Nihon University Graduate School of Bioresource Sciences, Kanagawa, Japan
| | - Eimi Ishikawa
- Department of Chemistry and Life Science, Collage of Bioresource Sciences, Nihon University, Kanagawa, Japan
| | - Ren Nakahara
- Department of Applied Life Sciences, Nihon University Graduate School of Bioresource Sciences, Kanagawa, Japan
| | - Tsubasa Ito
- Department of Chemistry and Life Science, Collage of Bioresource Sciences, Nihon University, Kanagawa, Japan
| | - Takumi Okura
- Department of Chemistry and Life Science, Collage of Bioresource Sciences, Nihon University, Kanagawa, Japan
| | - Mana Sakae
- Department of Chemistry and Life Science, Collage of Bioresource Sciences, Nihon University, Kanagawa, Japan
| | - Atsushi Miura
- Department of Chemistry and Life Science, Collage of Bioresource Sciences, Nihon University, Kanagawa, Japan
| | - Yori Ozaki-Masuzawa
- Department of Chemistry and Life Science, Collage of Bioresource Sciences, Nihon University, Kanagawa, Japan
| | - Takashi Hosono
- Department of Applied Life Sciences, Nihon University Graduate School of Bioresource Sciences, Kanagawa, Japan.,Department of Chemistry and Life Science, Collage of Bioresource Sciences, Nihon University, Kanagawa, Japan
| | - Taiichiro Seki
- Department of Applied Life Sciences, Nihon University Graduate School of Bioresource Sciences, Kanagawa, Japan.,Department of Chemistry and Life Science, Collage of Bioresource Sciences, Nihon University, Kanagawa, Japan
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29
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Xia M, Chandrasekaran P, Rong S, Fu X, Mitsche MA. Hepatic deletion of Mboat7 (LPIAT1) causes activation of SREBP-1c and fatty liver. J Lipid Res 2021; 62:100031. [PMID: 32859645 PMCID: PMC8022244 DOI: 10.1194/jlr.ra120000856] [Citation(s) in RCA: 45] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2020] [Revised: 07/30/2020] [Indexed: 12/13/2022] Open
Abstract
Genetic variants that increase the risk of fatty liver disease and cirrhosis have recently been identified in the proximity of membrane-bound O-acyltransferase domain-containing 7 (MBOAT7). To elucidate the link between these variants and fatty liver disease, we characterized Mboat7 liver-specific KO mice (Mboat7 LSKO). Chow-fed Mboat7 LSKO mice developed fatty livers and associated liver injury. Lipidomic analysis of liver using MS revealed a pronounced reduction in 20-carbon PUFA content in phosphatidylinositols (PIs) but not in other phospholipids. The change in fatty acid composition of PIs in these mice was associated with a marked increase in de novo lipogenesis because of activation of SREBP-1c, a transcription factor that coordinates the activation of genes encoding enzymes in the fatty acid biosynthesis pathway. Hepatic removal of both SREBP cleavage-activating protein (Scap) and Mboat7 normalized hepatic triglycerides relative to Scap-only hepatic KO, showing that increased SREBP-1c processing is required for Mboat7-induced steatosis. This study reveals a clear relationship between PI fatty acid composition and regulation of hepatic fat synthesis and delineates the mechanism by which mutations in MBOAT7 cause hepatic steatosis.
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Affiliation(s)
- Mingfeng Xia
- Center for Human Nutrition, University of Texas Southwestern Medical Center, Dallas, TX, USA; Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Preethi Chandrasekaran
- Center for Human Nutrition, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Shunxing Rong
- Center for Human Nutrition, University of Texas Southwestern Medical Center, Dallas, TX, USA; Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Xiaorong Fu
- Center for Human Nutrition, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Matthew A Mitsche
- Center for Human Nutrition, University of Texas Southwestern Medical Center, Dallas, TX, USA; Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX, USA.
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30
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Romano A, Friuli M, Del Coco L, Longo S, Vergara D, Del Boccio P, Valentinuzzi S, Cicalini I, Fanizzi FP, Gaetani S, Giudetti AM. Chronic Oleoylethanolamide Treatment Decreases Hepatic Triacylglycerol Level in Rat Liver by a PPARγ/SREBP-Mediated Suppression of Fatty Acid and Triacylglycerol Synthesis. Nutrients 2021; 13:394. [PMID: 33513874 PMCID: PMC7910994 DOI: 10.3390/nu13020394] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2020] [Revised: 01/18/2021] [Accepted: 01/23/2021] [Indexed: 12/14/2022] Open
Abstract
Oleoylethanolamide (OEA) is a naturally occurring bioactive lipid belonging to the family of N-acylethanolamides. A variety of beneficial effects have been attributed to OEA, although the greater interest is due to its potential role in the treatment of obesity, fatty liver, and eating-related disorders. To better clarify the mechanism of the antiadipogenic effect of OEA in the liver, using a lipidomic study performed by 1H-NMR, LC-MS/MS and thin-layer chromatography analyses we evaluated the whole lipid composition of rat liver, following a two-week daily treatment of OEA (10 mg kg-1 i.p.). We found that OEA induced a significant reduction in hepatic triacylglycerol (TAG) content and significant changes in sphingolipid composition and ceramidase activity. We associated the antiadipogenic effect of OEA to decreased activity and expression of key enzymes involved in fatty acid and TAG syntheses, such as acetyl-CoA carboxylase, fatty acid synthase, diacylglycerol acyltransferase, and stearoyl-CoA desaturase 1. Moreover, we found that both SREBP-1 and PPARγ protein expression were significantly reduced in the liver of OEA-treated rats. Our findings add significant and important insights into the molecular mechanism of OEA on hepatic adipogenesis, and suggest a possible link between the OEA-induced changes in sphingolipid metabolism and suppression of hepatic TAG level.
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Affiliation(s)
- Adele Romano
- Department of Physiology and Pharmacology “V. Erspamer”, Sapienza University of Rome, P.le Aldo Moro 5, 00185 Rome, Italy; (A.R.); (M.F.); (S.G.)
| | - Marzia Friuli
- Department of Physiology and Pharmacology “V. Erspamer”, Sapienza University of Rome, P.le Aldo Moro 5, 00185 Rome, Italy; (A.R.); (M.F.); (S.G.)
| | - Laura Del Coco
- Department of Biological and Environmental Sciences and Technologies, University of Salento, Via Prov.le Lecce-Monteroni, 73100 Lecce, Italy; (L.D.C.); (S.L.); (D.V.)
| | - Serena Longo
- Department of Biological and Environmental Sciences and Technologies, University of Salento, Via Prov.le Lecce-Monteroni, 73100 Lecce, Italy; (L.D.C.); (S.L.); (D.V.)
| | - Daniele Vergara
- Department of Biological and Environmental Sciences and Technologies, University of Salento, Via Prov.le Lecce-Monteroni, 73100 Lecce, Italy; (L.D.C.); (S.L.); (D.V.)
| | - Piero Del Boccio
- Department of Pharmacy, University “G. d’Annunzio” of Chieti-Pescara, 66100 Chieti, Italy; (P.D.B.); (S.V.)
- Center for Advanced Studies and Technology (CAST), University “G. d’Annunzio” of Chieti-Pescara, 66100 Chieti, Italy;
| | - Silvia Valentinuzzi
- Department of Pharmacy, University “G. d’Annunzio” of Chieti-Pescara, 66100 Chieti, Italy; (P.D.B.); (S.V.)
- Center for Advanced Studies and Technology (CAST), University “G. d’Annunzio” of Chieti-Pescara, 66100 Chieti, Italy;
| | - Ilaria Cicalini
- Center for Advanced Studies and Technology (CAST), University “G. d’Annunzio” of Chieti-Pescara, 66100 Chieti, Italy;
- Department of Medicine and Aging Science, University “G. d’Annunzio” of Chieti-Pescara, 66100 Chieti, Italy
| | - Francesco P. Fanizzi
- Department of Biological and Environmental Sciences and Technologies, University of Salento, Via Prov.le Lecce-Monteroni, 73100 Lecce, Italy; (L.D.C.); (S.L.); (D.V.)
| | - Silvana Gaetani
- Department of Physiology and Pharmacology “V. Erspamer”, Sapienza University of Rome, P.le Aldo Moro 5, 00185 Rome, Italy; (A.R.); (M.F.); (S.G.)
| | - Anna M. Giudetti
- Department of Biological and Environmental Sciences and Technologies, University of Salento, Via Prov.le Lecce-Monteroni, 73100 Lecce, Italy; (L.D.C.); (S.L.); (D.V.)
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Rifkin SB, Shrubsole MJ, Cai Q, Smalley WE, Ness RM, Swift LL, Milne G, Zheng W, Murff HJ. Differences in erythrocyte phospholipid membrane long-chain polyunsaturated fatty acids and the prevalence of fatty acid desaturase genotype among African Americans and European Americans. Prostaglandins Leukot Essent Fatty Acids 2021; 164:102216. [PMID: 33310680 DOI: 10.1016/j.plefa.2020.102216] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2020] [Revised: 05/31/2020] [Accepted: 11/12/2020] [Indexed: 01/02/2023]
Abstract
Numerous studies have reported an association between genetic variants in fatty acid desaturases (FADS1 and FADS2) and plasma or erythrocyte long chain polyunsaturated fatty acid (PUFA) levels. Increased levels of n-6 PUFAs have been associated with inflammation and several chronic diseases, including diabetes and cancer. We hypothesized that genetic variants of FADS that more efficiently convert precursor n-6 PUFA to arachidonic acid (AA) may explain the higher burden of chronic diseases observed in African Americans. To test this hypothesis, we measured the level of n-6 and n-3 PUFAs in erythrocyte membrane phospholipids and genotyped the rs174537 FADS variants associated with higher AA conversion among African American and European American populations. We included data from 1,733 individuals who participated in the Tennessee Colorectal Polyp Study, a large colonoscopy-based case-control study. Erythrocyte membrane PUFA percentages were measured using gas chromatography. Generalized linear models were used to estimate association of race and genotype on erythrocyte phospholipid membrane PUFA levels while controlling for self-reported dietary intake. We found that African Americans have higher levels of AA and a higher prevalence of GG allele compared to whites, 81% vs 43%, respectively. Homozygous GG genotype was negatively associated with precursor PUFAs (linoleic [LA], di-homo-γ-linolenic [DGLA]), positively associated with both product PUFA (AA, docosahexaenoic acid [DHA]), product to precursor ratio (AA to DGLA), an indirect measure of FADs efficiency and increased urinary isoprostane F2 (F2-IsoP) and isoprostane F3 (F3-IsoP), markers of oxidative stress. Increased consumption of n-6 PUFA and LA resulting in increased AA and subsequent inflammation may be fueling increased prevalence of chronic diseases especially in African descent.
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Affiliation(s)
- S B Rifkin
- Division of Gastroenterology and Hepatology, University of Michigan School of Medicine, 1150 W. Medical Center Drive, 6520 MSRB1, Ann Arbor, Michigan, United States.
| | - M J Shrubsole
- Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, United States; Division of Epidemiology, Vanderbilt University School of Medicine, United States; Geriatrics Research, Education and Clinical Center (GRECC), Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, TN, United States
| | - Q Cai
- Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, United States; Division of Epidemiology, Vanderbilt University School of Medicine, United States
| | - W E Smalley
- Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, United States; Division of Gastroenterology, Vanderbilt University School of Medicine, United States
| | - R M Ness
- Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, United States; Division of Gastroenterology, Vanderbilt University School of Medicine, United States
| | - L L Swift
- Department of Pathology, Microbiology and Immunology, Vanderbilt University, United States
| | - G Milne
- Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, United States; Division of Clinical Pharmacology, Vanderbilt University School of Medicine, United States
| | - W Zheng
- Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, United States; Division of Epidemiology, Vanderbilt University School of Medicine, United States; Geriatrics Research, Education and Clinical Center (GRECC), Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, TN, United States
| | - H J Murff
- Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, United States; Geriatrics Research, Education and Clinical Center (GRECC), Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, TN, United States; Division of General Internal Medicine and Public Health, Vanderbilt University Medical Center, United States
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Schiano E, Annunziata G, Ciampaglia R, Iannuzzo F, Maisto M, Tenore GC, Novellino E. Bioactive Compounds for the Management of Hypertriglyceridemia: Evidence From Clinical Trials and Putative Action Targets. Front Nutr 2020; 7:586178. [PMID: 33330588 PMCID: PMC7734325 DOI: 10.3389/fnut.2020.586178] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2020] [Accepted: 10/26/2020] [Indexed: 01/22/2023] Open
Abstract
Hypertriglyceridemia refers to the presence of elevated concentrations of triglycerides (TG) in the bloodstream (TG >200 mg/dL). This lipid alteration is known to be associated with an increased risk of atherosclerosis, contributing overall to the onset of atherosclerotic cardiovascular disease (CVD). Guidelines for the management of hypertriglyceridemia are based on both lifestyle intervention and pharmacological treatment, but poor adherence, medication-related costs and side effects can limit the success of these interventions. For this reason, the search for natural alternative approaches to reduce plasma TG levels currently represents a hot research field. This review article summarizes the most relevant clinical trials reporting the TG-reducing effect of different food-derived bioactive compounds. Furthermore, based on the evidence obtained from in vitro studies, we provide a description and classification of putative targets of action through which several bioactive compounds can exert a TG-lowering effect. Future research may lead to investigations of the efficacy of novel nutraceutical formulations consisting in a combination of bioactive compounds which contribute to the management of plasma TG levels through different action targets.
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Affiliation(s)
| | | | | | - Fortuna Iannuzzo
- Department of Pharmacy, University of Naples Federico II, Naples, Italy
| | - Maria Maisto
- Department of Pharmacy, University of Naples Federico II, Naples, Italy
| | - Gian Carlo Tenore
- Department of Pharmacy, University of Naples Federico II, Naples, Italy
| | - Ettore Novellino
- Department of Pharmacy, University of Naples Federico II, Naples, Italy
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Fatty Acids and Cardiovascular Risk. Evidence, Lack of Evidence, and Diligence. Nutrients 2020; 12:nu12123782. [PMID: 33317164 PMCID: PMC7764656 DOI: 10.3390/nu12123782] [Citation(s) in RCA: 61] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Revised: 12/05/2020] [Accepted: 12/08/2020] [Indexed: 12/11/2022] Open
Abstract
One of the most controversial areas of nutrition research relates to fats, particularly essential fatty acids, in the context of cardiovascular disease risk. A critical feature of dietary fatty acids is that they incorporate into the plasma membrane, modifying fluidity and key physiological functions. Importantly, they can reshape the bioavailability of eicosanoids and other lipid mediators, which direct cellular responses to external stimuli, such as inflammation and chronic stress conditions. This paper provides an overview of the most recent evidence, as well as historical controversies, linking fat consumption with human health and disease. We underscore current pitfalls in the area of fatty acid research and critically frame fatty acid intake in the larger context of diet and behavior. We conclude that fundamental research on fatty acids and lipids is appropriate in certain areas, but the rigor and reproducibility are lacking in others. The pros and cons are highlighted throughout the review, seeking to guide future research on the important area of nutrition, fat intake, and cardiovascular disease risk.
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Haubold S, Kröger-Koch C, Tuchscherer A, Kanitz E, Weitzel JM, Hoeflich A, Starke A, Tröscher A, Sauerwein H, Hammon HM. Effects of a combined essential fatty acid and conjugated linoleic acid abomasal infusion on metabolic and endocrine traits, including the somatotropic axis, in dairy cows. J Dairy Sci 2020; 103:12069-12082. [PMID: 32981718 DOI: 10.3168/jds.2020-18569] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2020] [Accepted: 07/17/2020] [Indexed: 01/04/2023]
Abstract
The objective of this study was to test the effects of essential fatty acids (EFA), particularly α-linolenic acid (ALA), and conjugated linoleic acid (CLA) supplementation on metabolic and endocrine traits related to energy metabolism, including the somatotropic axis, in mid-lactation dairy cows. Four cows (126 ± 4 d in milk) were used in a dose-escalation study design and were abomasally infused with coconut oil (CTRL; 38.3 g/d; providing saturated fatty acids), linseed and safflower oils (EFA; 39.1 and 1.6 g/d; n-6:n-3 FA ratio = 1:3), Lutalin (CLA; cis-9,trans-11 and trans-10,cis-12 CLA, 4.6 g/d of each), or EFA and CLA (EFA+CLA) for 6 wk. The initial dosage was doubled twice after 2 wk, resulting in 3 dosages (dosages 1, 2, and 3). Each cow received each fat treatment at different times. Cows were fed with a corn silage-based total mixed ration providing a low-fat content and a high n-6:n-3 fatty acid ratio. Plasma concentrations of metabolites and hormones (insulin-like growth factor-binding proteins only on wk 0 and 6) were analyzed at wk 0, 2, 4, and 6 of each treatment period. Liver biopsies were taken before starting the trial and at wk 6 of each treatment period to measure hepatic mRNA abundance of genes linked to glucose, cholesterol and lipid metabolism, and the somatotropic axis. The changes in the milk and blood fatty acid patterns and lactation performance of these cows have already been published in a companion paper. The plasma concentration of total cholesterol increased with dosage in all groups, except CLA, reaching the highest levels in EFA+CLA and CTRL compared with CLA. The high-density lipoprotein cholesterol plasma concentration increased in CTRL and was higher than that in EFA and CLA, whereas the concentration of low-density lipoprotein cholesterol increased in a dose-dependent manner in EFA and EFA+CLA, and was higher than that in CLA. Hepatic mRNA expression of 3-hydroxy-3-methyl-glutaryl-CoA synthase 1 was upregulated in all groups but was highest in EFA+CLA. Expression of sterol regulatory element-binding factor 1 tended to be lowest due to EFA treatment, whereas expression of long chain acyl-CoA-synthetase was lower in EFA than in CTRL. Hepatic mRNA expression of GHR1A tended to be higher in EFA+CLA than in CTRL. The plasma concentration of insulin-like growth factor I increased in CLA, and the plasma IGFBP-2 concentration was lower in EFA+CLA than in CTRL at wk 6. The plasma concentration of adiponectin decreased in EFA+CLA up to dosage 2. Plasma concentrations of albumin and urea were lower in CLA than in CTRL throughout the experimental period. Supplementation with EFA and CLA affected cholesterol and lipid metabolism and their regulation differently, indicating distinct stimulation after the combined EFA and CLA treatment. The decreased IGFBP-2 plasma concentration and upregulated hepatic mRNA abundance of GHR1A in EFA+CLA-supplemented cows indicated the beneficial effect of the combined EFA and CLA treatment on the somatotropic axis in mid-lactation dairy cows. Moreover, supplementation with CLA might affect protein metabolism in dairy cows.
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Affiliation(s)
- S Haubold
- Institute of Nutritional Physiology "Oskar Kellner," Leibniz Institute for Farm Animal Biology (FBN), 18196 Dummerstorf, Germany
| | - C Kröger-Koch
- Institute of Nutritional Physiology "Oskar Kellner," Leibniz Institute for Farm Animal Biology (FBN), 18196 Dummerstorf, Germany
| | - A Tuchscherer
- Institute of Genetics and Biometry, Leibniz Institute for Farm Animal Biology (FBN), 18196 Dummerstorf, Germany
| | - E Kanitz
- Institute of Behavioural Physiology, Leibniz Institute for Farm Animal Biology (FBN), 18196 Dummerstorf, Germany
| | - J M Weitzel
- Institute of Reproductive Biology, Leibniz Institute for Farm Animal Biology (FBN), 18196 Dummerstorf, Germany
| | - A Hoeflich
- Institute of Genome Biology of Leibniz Institute for Farm Animal Biology (FBN), 18196 Dummerstorf, Germany
| | - A Starke
- Clinic for Ruminants and Swine, Faculty of Veterinary Medicine, University of Leipzig, 04103 Leipzig, Germany
| | | | - H Sauerwein
- Institute of Animal Science, Physiology and Hygiene Unit, University of Bonn, 53115 Bonn, Germany
| | - H M Hammon
- Institute of Nutritional Physiology "Oskar Kellner," Leibniz Institute for Farm Animal Biology (FBN), 18196 Dummerstorf, Germany.
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Hishikawa D, Yanagida K, Nagata K, Kanatani A, Iizuka Y, Hamano F, Yasuda M, Okamura T, Shindou H, Shimizu T. Hepatic Levels of DHA-Containing Phospholipids Instruct SREBP1-Mediated Synthesis and Systemic Delivery of Polyunsaturated Fatty Acids. iScience 2020; 23:101495. [PMID: 32891885 PMCID: PMC7481256 DOI: 10.1016/j.isci.2020.101495] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2020] [Revised: 07/25/2020] [Accepted: 08/19/2020] [Indexed: 12/25/2022] Open
Abstract
Polyunsaturated fatty acids (PUFAs), such as docosahexaenoic acid (DHA) and arachidonic acid (ARA), play fundamental roles in mammalian physiology. Although PUFA imbalance causes various disorders, mechanisms of the regulation of their systemic levels are poorly understood. Here, we report that hepatic DHA-containing phospholipids (DHA-PLs) determine the systemic levels of PUFAs through the SREBP1-mediated transcriptional program. We demonstrated that liver-specific deletion of Agpat3 leads to a decrease of DHA-PLs and a compensatory increase of ARA-PLs not only in the liver but also in other tissues including the brain. Together with recent findings that plasma lysophosphatidylcholine (lysoPC) is the major source of brain DHA, our results indicate that hepatic AGPAT3 contributes to brain DHA accumulation by supplying DHA-PLs as precursors of DHA-lysoPC. Furthermore, dietary fish oil-mediated suppression of hepatic PUFA biosynthetic program was blunted in liver-specific Agpat3 deletion. Our findings highlight the central role of hepatic DHA-PLs as the molecular rheostat for systemic homeostasis of PUFAs.
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Affiliation(s)
- Daisuke Hishikawa
- Department of Lipid Signaling, National Center for Global Health and Medicine, Shinjuku-ku, Tokyo 162-8655, Japan.
| | - Keisuke Yanagida
- Department of Lipid Signaling, National Center for Global Health and Medicine, Shinjuku-ku, Tokyo 162-8655, Japan
| | - Katsuyuki Nagata
- Department of Lipid Signaling, National Center for Global Health and Medicine, Shinjuku-ku, Tokyo 162-8655, Japan
| | - Ayumi Kanatani
- Department of Lipid Signaling, National Center for Global Health and Medicine, Shinjuku-ku, Tokyo 162-8655, Japan
| | - Yoshiko Iizuka
- Department of Lipid Signaling, National Center for Global Health and Medicine, Shinjuku-ku, Tokyo 162-8655, Japan
| | - Fumie Hamano
- Department of Lipid Signaling, National Center for Global Health and Medicine, Shinjuku-ku, Tokyo 162-8655, Japan; Life Science Core Faculty, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan
| | - Megumi Yasuda
- Department of Lipid Signaling, National Center for Global Health and Medicine, Shinjuku-ku, Tokyo 162-8655, Japan
| | - Tadashi Okamura
- Laboratory Animal Medicine, National Center for Global Health and Medicine, Shinjuku-ku, Tokyo 162-8655, Japan; Section of Animal Models, Department of Infectious Diseases, National Center for Global Health and Medicine, Shinjuku-ku, Tokyo 162-8655, Japan
| | - Hideo Shindou
- Department of Lipid Signaling, National Center for Global Health and Medicine, Shinjuku-ku, Tokyo 162-8655, Japan; Department of Lipid Science, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan
| | - Takao Shimizu
- Department of Lipid Signaling, National Center for Global Health and Medicine, Shinjuku-ku, Tokyo 162-8655, Japan; Department of Lipidomics, Graduate School of Medicine, the University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan.
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Draycott SAV, Elmes MJ, Muhlhausler BS, Langley-Evans S. Omega-6:Omega-3 Fatty Acid Ratio and Total Fat Content of the Maternal Diet Alter Offspring Growth and Fat Deposition in the Rat. Nutrients 2020; 12:nu12092505. [PMID: 32825093 PMCID: PMC7551768 DOI: 10.3390/nu12092505] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Revised: 08/06/2020] [Accepted: 08/13/2020] [Indexed: 12/11/2022] Open
Abstract
Omega-3 long-chain polyunsaturated fatty acids (LCPUFA) have been shown to inhibit lipogenesis and adipogenesis in adult rats. Their possible early life effects on offspring fat deposition, however, remain to be established. To investigate this, female Wistar rats (n = 6–9 per group) were fed either a 9:1 ratio of linoleic acid (LA) to alpha-linolenic acid (ALA) or a lower 1:1.5 ratio during pregnancy and lactation. Each ratio was fed at two total fat levels (18% vs. 36% fat w/w) and offspring were weaned onto standard laboratory chow. Offspring exposed to a 36% fat diet, irrespective of maternal dietary LA:ALA ratio, were lighter (male, 27 g lighter; female 19 g lighter; p < 0.0001) than those exposed to an 18% fat diet between 3 and 8 weeks of age. Offspring exposed to a low LA (18% fat) diet had higher proportions of circulating omega-3 LCPUFA and increased gonadal fat mass at 4 weeks of age (p < 0.05). Reduced Srebf1 mRNA expression of hepatic (p < 0.01), gonadal fat (p < 0.05) and retroperitoneal fat (p < 0.05) tissue was observed at 4 weeks of age in male and female offspring exposed to a 36% fat diet, and hepatic Srebf1 mRNA was also reduced in male offspring at 8 weeks of age (p < 0.05). Thus, while offspring fat deposition appeared to be sensitive to both maternal dietary LA:ALA ratio and total fat content, offspring growth and lipogenic capacity of tissues appeared to be more sensitive to maternal dietary fat content.
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Affiliation(s)
- Sally A. V. Draycott
- Sutton Bonington Campus, School of Biosciences, University of Nottingham, Loughborough LE12 5RD, UK; (M.J.E.); (S.L.-E.)
- Food and Nutrition Research Group, Department of Food and Wine Science, School of Agriculture, Food and Wine, University of Adelaide, Adelaide, SA 5064, Australia;
- Correspondence:
| | - Matthew J. Elmes
- Sutton Bonington Campus, School of Biosciences, University of Nottingham, Loughborough LE12 5RD, UK; (M.J.E.); (S.L.-E.)
| | - Beverly S. Muhlhausler
- Food and Nutrition Research Group, Department of Food and Wine Science, School of Agriculture, Food and Wine, University of Adelaide, Adelaide, SA 5064, Australia;
- Commonwealth Scientific and Industrial Research Organisation, Adelaide, SA 5000, Australia
| | - Simon Langley-Evans
- Sutton Bonington Campus, School of Biosciences, University of Nottingham, Loughborough LE12 5RD, UK; (M.J.E.); (S.L.-E.)
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Froyen E, Burns-Whitmore B. The Effects of Linoleic Acid Consumption on Lipid Risk Markers for Cardiovascular Disease in Healthy Individuals: A Review of Human Intervention Trials. Nutrients 2020; 12:E2329. [PMID: 32759714 PMCID: PMC7469037 DOI: 10.3390/nu12082329] [Citation(s) in RCA: 48] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2020] [Revised: 07/30/2020] [Accepted: 08/01/2020] [Indexed: 02/07/2023] Open
Abstract
Cardiovascular disease (CVD) is the leading cause of death worldwide. Risk factors for developing this disease include high serum concentrations of total cholesterol, triglycerides, low-density lipoproteins, very-low density lipoproteins, and low concentrations of high-density lipoproteins. One proposed dietary strategy for decreasing risk factors involves replacing a portion of dietary saturated fatty acids with mono- and polyunsaturated fatty acids (PUFAs). The essential omega-6 PUFA, linoleic acid (LA), is suggested to decrease the risk for CVD by affecting these lipid risk markers. Reviewing human intervention trials will provide further evidence of the effects of LA consumption on risk factors for CVD. PubMed was used to search for peer-reviewed articles. The purpose of this review was: (1) To summarize human intervention trials that studied the effects of LA consumption on lipid risk markers for CVD in healthy individuals, (2) to provide mechanistic details, and (3) to provide recommendations regarding the consumption of LA to decrease the lipid risk markers for CVD. The results from this review provided evidence that LA consumption decreases CVD lipid risk markers in healthy individuals.
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Affiliation(s)
- Erik Froyen
- Department of Nutrition and Food Science, Huntley College of Agriculture, California State Polytechnic University, Pomona, CA 91768, USA;
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fat-1 transgenic zebrafish are protected from abnormal lipid deposition induced by high-vegetable oil feeding. Appl Microbiol Biotechnol 2020; 104:7355-7365. [PMID: 32676712 DOI: 10.1007/s00253-020-10774-x] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2020] [Revised: 06/28/2020] [Accepted: 07/05/2020] [Indexed: 12/27/2022]
Abstract
High dietary concentration of vegetable oil, particularly those rich in n-6 polyunsaturated fatty acids (PUFAs), can induce negative physiological effects including excessive lipid deposition in teleost fish. Omega-3 desaturase (Fat-1) of Caenorhabditis elegans is able to convert n-6 PUFAs to n-3 PUFAs and thus induces a low n-6/n-3 PUFAs ratio alleviating lipid deposition. In this study, we investigated the effects of dietary n-6 PUFAs on lipid metabolism of fat-1 transgenic zebrafish (Tg:fat-1), to explore the role of fat-1 in fish lipid metabolism. We first generated Tg:fat-1 zebrafish and assayed the effects of a low-fat diet (LFD) and a high-fat diet (HFD) prepared from soybean oil. Wild type zebrafish (WT) fed with HFD (HFD-WT) exhibited increased obesity and lipid deposition, especially in the abdominal cavity and liver. These defects were absent from HFD-Tg:fat-1. For each diet group, Tg:fat-1 exhibited significantly decreased levels of almost all hepatic lipid classes compared with WT. Expression levels of lipid synthesis-related genes and lipid deposition-related genes were markedly lower in the liver of HFD-Tg:fat-1 compared with HFD-WT. In contrast, the steatolysis-related genes significantly upregulated in HFD-Tg:fat-1. Then expression profiles of mitochondrial energy metabolism-related genes and ATP contents in the livers from LFD-WT, LFD-Tg:fat-1, HFD-WT, and HFD-Tg:fat-1 were determined. Our findings suggest that fat-1 protects fish from abnormal lipid deposition induced by high-vegetable oil feeding, through endogenously converting n-6 PUFAs to n-3 PUFAs. KEY POINTS: • fat-1 transgenic zebrafish (Tg:fat-1) can endogenously convert n-6 PUFAs to n-3 PUFAs. • Tg:fat-1 avoid serious abnormal lipid deposition induced by high-vegetable oil feeding. • fat-1 transgenosis effectively improved lipid metabolism and mitochondrial energy metabolism in zebrafish.
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Tanaka Y, Ikeda T, Ogawa H, Kamisako T. Ezetimibe Markedly Reduces Hepatic Triglycerides and Cholesterol in Rats Fed on Fish Oil by Increasing the Expression of Cholesterol Efflux Transporters. J Pharmacol Exp Ther 2020; 374:175-183. [PMID: 32366600 DOI: 10.1124/jpet.120.265660] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2019] [Accepted: 04/30/2020] [Indexed: 03/08/2025] Open
Abstract
Besides diet therapy, hypolipidemic pharmacological therapy may be a crucial component of nonalcoholic fatty liver disease (NAFLD) treatment. Ezetimibe may be a promising drug for treatment of NAFLD. n-3 polyunsaturated fatty acids, which are abundant in fish oil, reduce serum and hepatic cholesterol and triglycerides in rodents. The aim of this study was to examine the combined effects of dietary fish oil and ezetimibe on lipid metabolism in rats. Seven-week-old male Sprague-Dawley rats were allocated to four different diets containing 1) 10% soybean oil (C), 2) 10% fish oil (F), 3) 10% soybean oil + 0.005% ezetimibe, and 4) 10% fish oil + 0.005% ezetimibe (F+E) for 4 weeks, when the liver, jejunum, blood, and fecal samples were collected. Compared with the C group, the F+E diet decreased hepatic triglycerides and cholesterol 84% and 86%, but it did not increase fecal cholesterol. In liver, the expression of lipogenic enzymes was decreased in the F+E diet, whereas β-oxidation-related genes were not increased. Abcg5/g8 mRNA expression was increased 1380%/442% when ezetimibe was added to the F diet. These gene expression changes are related to the decrease in hepatic lipids. In jejunum, Abcg5/g8 mRNA was increased 244%/841% when ezetimibe was added to the F diet. Hepatic induction of Abcg5/8 rather than intestinal induction correlates with the marked decrease in liver cholesterol when ezetimibe was added to the F diet. These data suggest that fish oil diet and ezetimibe in combination may be a beneficial therapy for NAFLD by increasing hepatic Abcg5/g8 and decreasing lipogenic genes. SIGNIFICANCE STATEMENT: There is currently no single treatment for NAFLD. Thus, lifestyle modifications including dietary regulation and physical activity are also important options. In this study, ezetimibe, a cholesterol absorption inhibitor, was evaluated for the treatment of liver steatosis in rats fed on the different diets. We found that ezetimibe and fish oil in combination markedly improved fatty liver by increasing cholesterol efflux transporters. The combination therapy of fish oil agents and ezetimibe may be effective for NAFLD.
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Affiliation(s)
- Yuji Tanaka
- Department of Clinical Laboratory Medicine, Kindai University Faculty of Medicine, Osakasayama, Osaka, Japan (Y.T., T.K.), and Faculty of Human Sciences, Tezukayama Gakuin University, Sakai, Osaka, Japan (T.I., H.O.)
| | - Takanori Ikeda
- Department of Clinical Laboratory Medicine, Kindai University Faculty of Medicine, Osakasayama, Osaka, Japan (Y.T., T.K.), and Faculty of Human Sciences, Tezukayama Gakuin University, Sakai, Osaka, Japan (T.I., H.O.)
| | - Hiroshi Ogawa
- Department of Clinical Laboratory Medicine, Kindai University Faculty of Medicine, Osakasayama, Osaka, Japan (Y.T., T.K.), and Faculty of Human Sciences, Tezukayama Gakuin University, Sakai, Osaka, Japan (T.I., H.O.)
| | - Toshinori Kamisako
- Department of Clinical Laboratory Medicine, Kindai University Faculty of Medicine, Osakasayama, Osaka, Japan (Y.T., T.K.), and Faculty of Human Sciences, Tezukayama Gakuin University, Sakai, Osaka, Japan (T.I., H.O.)
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Matilainen J, Mustonen AM, Rilla K, Käkelä R, Sihvo SP, Nieminen P. Orotic acid-treated hepatocellular carcinoma cells resist steatosis by modification of fatty acid metabolism. Lipids Health Dis 2020; 19:70. [PMID: 32284043 PMCID: PMC7155272 DOI: 10.1186/s12944-020-01243-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2019] [Accepted: 03/18/2020] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND Orotic acid (OA) has been intensively utilized to induce fatty liver in rats. Although the capacity of OA to cause steatosis is species-specific, previous in vitro studies indicate that humans could also be susceptible to OA-induced fatty liver. The aim of the present study was to re-elucidate the potential of OA exposure to modulate the cellular mechanisms involved in both non-alcoholic fatty liver disease pathogenesis and cellular protection from lipid accumulation. In addition, alterations in detailed fatty acid (FA) profiles of cells and culture media were analyzed to assess the significance of lipid metabolism in these phenomena. METHODS In our experiments, human hepatocellular carcinoma HepG2 cells were exposed to OA. Bacterial endotoxin, lipopolysaccharide (LPS), was used to mimic hepatic inflammation. The lipogenic and inflammatory effects of OA and/or LPS on cells were assessed by labeling cellular lipids with Nile red stain and by performing image quantifications. The expression levels of key enzymes involved in de novo lipogenesis (DNL) and of inflammatory markers related to the disease development were studied by qRT-PCR. FA profiles of cells and culture media were determined from total lipids with gas chromatography-mass spectrometry. RESULTS Our data indicate that although OA possibly promotes the first stage of DNL, it does not cause a definite lipogenic transformation in HepG2 cells. Reduced proportions of 16:0, increased stearoyl-Coenzyme A desaturase 1 mRNA expression and relatively high proportions of 16:1n-7 suggest that active delta9-desaturation may limit lipogenesis and the accumulation of toxic 16:0. Inflammatory signaling could be reduced by the increased production of long-chain n-3 polyunsaturated FA (PUFA) and the active incorporation of certain FA, including 18:1n-9, into cells. In addition, increased proportions of 20:4n-6 and 22:6n-3, total PUFA and dimethyl acetal 18:0 suggest that OA exposure may cause increased secretion of lipoproteins and extracellular vesicles. CONCLUSIONS The present data suggest that, apart from the transcription-level events reported by previous studies, modifications of FA metabolism may also be involved in the prevention of OA-mediated steatosis. Increased delta9-desaturation and secretion of lipoproteins and extracellular vesicles could offer potential mechanisms for further studies to unravel how OA-treated cells alleviate lipidosis.
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Affiliation(s)
- Johanna Matilainen
- Faculty of Health Sciences, School of Medicine, Institute of Biomedicine, University of Eastern Finland, P.O. Box 1627, FI-70211, Kuopio, Finland.
| | - Anne-Mari Mustonen
- Faculty of Health Sciences, School of Medicine, Institute of Biomedicine, University of Eastern Finland, P.O. Box 1627, FI-70211, Kuopio, Finland
- Faculty of Science and Forestry, Department of Environmental and Biological Sciences, University of Eastern Finland, P.O. Box 111, FI-80101, Joensuu, Finland
| | - Kirsi Rilla
- Faculty of Health Sciences, School of Medicine, Institute of Biomedicine, University of Eastern Finland, P.O. Box 1627, FI-70211, Kuopio, Finland
| | - Reijo Käkelä
- Faculty of Biological and Environmental Sciences, Molecular and Integrative Biosciences Research Programme, University of Helsinki, P.O. Box 65, FI-00014, Helsinki, Finland
- Helsinki Institute for Life Science (HiLIFE), Helsinki University Lipidomics Unit (HiLIPID), University of Helsinki, P.O. Box 65, FI-00014, Helsinki, Finland
| | - Sanna P Sihvo
- Faculty of Biological and Environmental Sciences, Molecular and Integrative Biosciences Research Programme, University of Helsinki, P.O. Box 65, FI-00014, Helsinki, Finland
- Helsinki Institute for Life Science (HiLIFE), Helsinki University Lipidomics Unit (HiLIPID), University of Helsinki, P.O. Box 65, FI-00014, Helsinki, Finland
| | - Petteri Nieminen
- Faculty of Health Sciences, School of Medicine, Institute of Biomedicine, University of Eastern Finland, P.O. Box 1627, FI-70211, Kuopio, Finland
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Chen J, Li Y, Tang Z, Sun Z. Regulatory Functions of Fatty Acids with Different Chain Lengths on the Intestinal Health in Pigs and Relative Signaling Pathways. Curr Protein Pept Sci 2019; 20:674-682. [PMID: 31084590 DOI: 10.2174/1389203720666190514120023] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2018] [Revised: 12/30/2018] [Accepted: 01/12/2019] [Indexed: 01/04/2023]
Abstract
Intestines are not only major organs for nutrient digestion and absorption, but are also the largest immune organ in pigs. They are essential for maintaining the health and growth of piglets. Fatty acids, including short-chain fatty acids, medium-chain fatty acids, and long-chain polyunsaturated fatty acids, are important nutrients; they are a major energy source, important components of the cell membrane, metabolic substrates in many biochemical pathways, cell-signaling molecules, and play role as immune modulators. Research has shown that fatty acids exert beneficial effects on intestinal health in animal models and clinical trials. The objective of this review is to give a clear understanding of the regulatory effects of fatty acids of different chain lengths on intestinal health in pigs and their signaling pathways, providing scientific reference for developing a feeding technique to apply fatty acids to piglet diets.
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Affiliation(s)
- Jinchao Chen
- Laboratory for Bio-feed and Molecular Nutrition, College of Animal Science and Technology, Southwest University, Chongqing 400715, China
| | - Yunxia Li
- Institute of Animal Nutrition, Sichuan Agricultural University, Chengdu 611130, China
| | - Zhiru Tang
- Laboratory for Bio-feed and Molecular Nutrition, College of Animal Science and Technology, Southwest University, Chongqing 400715, China
| | - Zhihong Sun
- Laboratory for Bio-feed and Molecular Nutrition, College of Animal Science and Technology, Southwest University, Chongqing 400715, China
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42
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Xie C, Duan X, Long C, Wu X. Hepatic lipid metabolism is affected by a daily 3-meal pattern with varying dietary crude protein with a pig model. ACTA ACUST UNITED AC 2019; 6:16-23. [PMID: 32211524 PMCID: PMC7082684 DOI: 10.1016/j.aninu.2019.11.001] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2019] [Revised: 10/09/2019] [Accepted: 11/04/2019] [Indexed: 02/08/2023]
Abstract
The present study was conducted to evaluate the effects of 3 meals administered daily with varying dietary crude protein (CP) contents on hepatic lipid metabolism with a pig model. Pigs were divided into 3 groups according to the following feeding patterns: feeding a basal CP diet 3 times daily (3C); feeding a high CP diet for breakfast, the basal CP diet for lunch, and a low CP diet for dinner (HCL); and feeding the low CP diet for breakfast, the basal CP diet for lunch, and the high protein diet for dinner (LCH). Three groups took equivalent diet per meal ensuring that every pig was fed with similar dietary formulae daily. Results showed that HCL feeding pattern reduced the relative kidney weight (P < 0.05), and LCH feeding pattern increased the relative liver weight of pigs (P < 0.05) when compared with those in the 3C group. Plasma urea nitrogen (P < 0.01) and lipase (P < 0.05) decreased in the HCL group but increased in the LCH group. Both HCL and LCH feeding patterns reduced plasma triglycerides (P < 0.01), non-esterified fatty acids (NEFA) (P < 0.01), and hepatic crude fat (0.05 < P < 0.10) of pigs. Real-time quantitative PCR (RT-qPCR) results showed that dynamic feeding patterns down-regulated (P < 0.05) the mRNA level of lipid metabolism related genes, including adipose triglyceride lipase (ATGL), acetyl-CoA carboxylase (ACCα), liver X receptor (LXRα) in the liver, and negatively regulate elements of circadian clock, including period 1 (Per1), period 2 (Per2), cryptochrome (Cry2), which in turn, upregulated (P < 0.05) the protein expression of positive regulate element brain and muscle Arnt-like 1 (BMAL1) when compared with 3C group. Overall, our findings suggested that dynamic feeding patterns may affect hepatic lipid metabolism via regulation of the circadian clock.
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Affiliation(s)
- Chunyan Xie
- College of Bioscience and Biotechnology, Hunan Agricultural University, Changsha 410128, China.,Institute of Biological Resources, Jiangxi Academy of Sciences, Nanchang 330096, China
| | - Xinyi Duan
- College of Bioscience and Biotechnology, Hunan Agricultural University, Changsha 410128, China.,Key Laboratory of Agro-ecological Processes in Subtropical Region, Institute of Subtropical Agriculture, Chinese Academy of Sciences, National Engineering Laboratory for Pollution Control and Waste Utilization in Livestock and Poultry Production, Hunan Provincial Engineering Research Center for Healthy Livestock and Poultry Production, Changsha 410125, China
| | - Cimin Long
- Key Laboratory of Agro-ecological Processes in Subtropical Region, Institute of Subtropical Agriculture, Chinese Academy of Sciences, National Engineering Laboratory for Pollution Control and Waste Utilization in Livestock and Poultry Production, Hunan Provincial Engineering Research Center for Healthy Livestock and Poultry Production, Changsha 410125, China
| | - Xin Wu
- Institute of Biological Resources, Jiangxi Academy of Sciences, Nanchang 330096, China.,Key Laboratory of Agro-ecological Processes in Subtropical Region, Institute of Subtropical Agriculture, Chinese Academy of Sciences, National Engineering Laboratory for Pollution Control and Waste Utilization in Livestock and Poultry Production, Hunan Provincial Engineering Research Center for Healthy Livestock and Poultry Production, Changsha 410125, China
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43
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Zhang Y, Zheng X, Huang F, Zhao A, Ge K, Zhao Q, Jia W. Ursodeoxycholic Acid Alters Bile Acid and Fatty Acid Profiles in a Mouse Model of Diet-Induced Obesity. Front Pharmacol 2019; 10:842. [PMID: 31402868 PMCID: PMC6669341 DOI: 10.3389/fphar.2019.00842] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2019] [Accepted: 07/01/2019] [Indexed: 12/19/2022] Open
Abstract
Ursodeoxycholic acid (UDCA) is a bile acid (BA) approved by the U.S. Food and Drug Administration for the treatment of primary biliary cholangitis. It is also the major active component of bear bile used in traditional Chinese medicine to reduce fever, remove toxins, and treat liver and eye ailments. In addition, UDCA and its conjugated form have been evaluated for their potential to improve symptoms of metabolic diseases, but the results have been inconclusive. To address this issue, in this study, we investigated the effects of orally administered UDCA on mice with diet-induced obesity, including the BA and free fatty acid (FFA) profiles of serum, liver, and epididymis and brown adipose tissues. We found that UDCA treatment significantly improved most metabolic indices; tauroursodeoxycholic acid (TUDCA) and taurolithocholic acid (TLCA) contents were increased in all examined tissues, whereas saturated FA levels were decreased, and n-3 polyunsaturated fatty acid (n-3 PUFA) levels were increased in most tissues. A correlation analysis showed that the concentrations of UDCA and its derivatives were positively correlated with that of n-3 PUFA. To clarify the mechanism by which UDCA alters FFA profiles, we analyzed the expression levels of genes involved in FFA biosynthesis, uptake, and oxidation and found that FFA biosynthesis and uptake were inhibited while FFA oxidation was stimulated by UDCA treatment. Additionally, amino acid-conjugated derivatives of UDCA, such as TUDCA and TLCA, altered FFA profiles by modulating FFA biosynthesis, uptake, and oxidation. These findings provide evidence that UDCA can alleviate metabolic dysfunction and could therefore be effective in the treatment of obesity.
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Affiliation(s)
- Yunjing Zhang
- School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China.,Shanghai Key Laboratory of Diabetes Mellitus and Center for Translational Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Xiaojiao Zheng
- Shanghai Key Laboratory of Diabetes Mellitus and Center for Translational Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Fengjie Huang
- Shanghai Key Laboratory of Diabetes Mellitus and Center for Translational Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Aihua Zhao
- Shanghai Key Laboratory of Diabetes Mellitus and Center for Translational Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Kun Ge
- Shanghai Key Laboratory of Diabetes Mellitus and Center for Translational Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Qing Zhao
- Shanghai Key Laboratory of Diabetes Mellitus and Center for Translational Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Wei Jia
- School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China.,Shanghai Key Laboratory of Diabetes Mellitus and Center for Translational Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.,Cancer Biology Program, The University of Hawaii Cancer Center, Honolulu, HI, United States
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SREBP1-dependent de novo fatty acid synthesis gene expression is elevated in malignant melanoma and represents a cellular survival trait. Sci Rep 2019; 9:10369. [PMID: 31316083 PMCID: PMC6637239 DOI: 10.1038/s41598-019-46594-x] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2018] [Accepted: 07/01/2019] [Indexed: 02/07/2023] Open
Abstract
de novo fatty acid biosynthesis (DNFA) is a hallmark adaptation of many cancers that supports survival, proliferation, and metastasis. Here we elucidate previously unexplored aspects of transcription regulation and clinical relevance of DNFA in cancers. We show that elevated expression of DNFA genes is characteristic of many tumor types and correlates with poor prognosis, especially in melanomas. Elevated DNFA gene expression depends on the SREBP1 transcription factor in multiple melanoma cell lines. SREBP1 predominantly binds to the transcription start sites of DNFA genes, regulating their expression by recruiting RNA polymerase II to promoters for productive transcription elongation. We find that SREBP1-regulated DNFA represents a survival trait in melanoma cells, regardless of proliferative state and oncogenic mutation status. Indeed, malignant melanoma cells exhibit elevated DNFA gene expression after the BRAF/MEK signaling pathway is blocked (e.g. by BRAF inhibitors), and DNFA expression remains higher in melanoma cells resistant to vemurafenib treatment than in untreated cells. Accordingly, DNFA pathway inhibition, whether by direct targeting of SREBP1 with antisense oligonucleotides, or through combinatorial effects of multiple DNFA enzyme inhibitors, exerts potent cytotoxic effects on both BRAFi-sensitive and -resistant melanoma cells. Altogether, these results implicate SREBP1 and DNFA enzymes as enticing therapeutic targets in melanomas.
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Wu S, Näär AM. A lipid-free and insulin-supplemented medium supports De Novo fatty acid synthesis gene activation in melanoma cells. PLoS One 2019; 14:e0215022. [PMID: 30970006 PMCID: PMC6457551 DOI: 10.1371/journal.pone.0215022] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2018] [Accepted: 03/25/2019] [Indexed: 12/23/2022] Open
Abstract
While investigating the role played by de novo lipid (DNL) biosynthesis in cancer cells, we sought a medium condition that would support cell proliferation without providing any serum lipids. Here we report that a defined serum free cell culture medium condition containing insulin, transferrin and selenium (ITS) supports controlled study of transcriptional regulation of de novo fatty acid (DNFA) production and de novo cholesterol synthesis (DNCS) in melanoma cell lines. This lipid-free ITS medium is able to support continuous proliferation of several melanoma cell lines that utilize DNL to support their lipid requirements. We show that the ITS medium stimulates gene transcription in support of both DNFA and DNCS, specifically mediated by SREBP1/2 in melanoma cells. We further found that the ITS medium promoted SREBP1 nuclear localization and occupancy on DNFA gene promoters. Our data show clear utility of this serum and lipid-free medium for melanoma cancer cell culture and lipid-related areas of investigation.
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Affiliation(s)
- Su Wu
- Massachusetts General Hospital Center for Cancer Research, Charlestown, Massachusetts, United States of America
- Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, United States of America
- * E-mail: (SW); (AMN)
| | - Anders M. Näär
- Massachusetts General Hospital Center for Cancer Research, Charlestown, Massachusetts, United States of America
- Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, United States of America
- * E-mail: (SW); (AMN)
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Macronutrients and the Adipose-Liver Axis in Obesity and Fatty Liver. Cell Mol Gastroenterol Hepatol 2019; 7:749-761. [PMID: 30763771 PMCID: PMC6463203 DOI: 10.1016/j.jcmgh.2019.02.001] [Citation(s) in RCA: 74] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2018] [Revised: 01/30/2019] [Accepted: 02/01/2019] [Indexed: 02/06/2023]
Abstract
Macronutrient metabolism is a highly orchestrated process, with adipose tissue and liver each playing central roles in nutrient uptake, processing, transport, and storage. These 2 tissues form an important metabolic circuit, particularly as it relates to lipids as the primary storage form of excess energy. The function of the circuit is influenced by many factors, including the quantity and type of nutrients consumed and their impact on the overall health of the tissues. In this review we begin with a brief summary of the homeostatic disposition of lipids between adipose tissue and liver and how these processes can become dysregulated in obesity. We then explore how specific dietary nutrients and nutrient combinations can exert unique influences on the liver-adipose tissue axis.
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miR-146a is involved in the regulation of vertebrate LC-PUFA biosynthesis by targeting elovl5 as demonstrated in rabbitfish Siganus canaliculatus. Gene 2018; 676:306-314. [DOI: 10.1016/j.gene.2018.08.063] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2018] [Revised: 08/13/2018] [Accepted: 08/21/2018] [Indexed: 01/26/2023]
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Zhang S, Lu C, Das AK, Pasupulati AK, Menon RK. Abrogation of GH action in Kupffer cells results in increased hepatic CD36 expression and exaggerated nonalcoholic fatty liver disease. Growth Horm IGF Res 2018; 42-43:74-79. [PMID: 30321786 PMCID: PMC6286732 DOI: 10.1016/j.ghir.2018.10.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2018] [Revised: 09/09/2018] [Accepted: 10/02/2018] [Indexed: 02/07/2023]
Abstract
OBJECTIVE To investigate the effects of GH signaling on Kupffer cells and the resulting changes in lipid homeostasis and their underlying mechanism(s) in the livers of diet-induced obese (DIO) mice. DESIGN Male macrophage specific-growth hormone receptor knockout mice (MacGHR KO) and their litter mate controls were fed a high fat diet containing 60% calories from fat for 26 weeks. Lipid content and lipid profiles in the liver and circulation were analyzed. Expression levels of CD36 in the liver were quantified by RT-PCR and Western Blot. RESULTS Increased hepatic lipid content and abundance of long-chain unsaturated fatty acids were observed in the liver of MacGHR KO mice. These findings were associated with increased steady state levels of CD36 mRNA and protein in MacGHR KO mice when compared with their litter mate controls. CONCLUSION GH action in Kupffer cells is required for maintaining hepatic lipid homeostasis, in part via regulation of hepatic CD36 expression.
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Affiliation(s)
- Sherry Zhang
- Departments of Pediatrics & Communicable Diseases, University of Michigan, United States
| | - Chunxia Lu
- Departments of Pediatrics & Communicable Diseases, University of Michigan, United States
| | - Arun K Das
- Department of Internal Medicine, University of Michigan, United States
| | - Anil K Pasupulati
- Department of Biochemistry, University of Hyderabad, Hyderabad, India
| | - Ram K Menon
- Departments of Pediatrics & Communicable Diseases, University of Michigan, United States; Department of Molecular & Integrative Physiology, University of Michigan, United States.
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Dziedzic B, Bewicz-Binkowska D, Zgorzynska E, Stulczewski D, Wieteska L, Kaza B, Walczewska A. DHA upregulates FADS2 expression in primary cortical astrocytes exposed to vitamin A. Physiol Res 2018; 67:663-668. [PMID: 29750879 DOI: 10.33549/physiolres.933708] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023] Open
Abstract
The fads2 gene encoding delta6-desaturase, the rate-limiting enzyme of the LCPUFA biosynthesis is expressed in astrocytes. Dietary fatty acids, which cross the blood-brain barrier, may regulate the transcription of lipogenic enzymes through activation of transcription factors such as peroxisome proliferator-activated receptors (PPARs). The PPARs form the transcription complex with retinoid X receptors (RXRs) that are activated by 9-cis retinoic acid, a metabolite of vitamin A (VA). The study examines whether challenge of astrocytes with VA, prior 24-h treatment with palmitic acid (PA), alpha-linolenic acid (ALA) or docosahexaenoic acid (DHA) has the effect on the FADS2 expression. RT-qPCR showed that in astrocytes not challenged with VA, PA increased fads2 gene expression and DHA decreased it. However, in VA-primed astrocytes, PA doubled the FADS2 mRNA levels, while DHA increased fads2 gene expression, oppositely to non-primed cells. Furthermore, similar changes were seen in VA-primed astrocytes with regard to delta6-desaturase protein levels following PA and DHA treatment. ALA did not have any effect on the FADS2 mRNA and protein levels in either VA-primed or non-primed astrocytes. These findings indicate that in the presence of vitamin A, DHA upregulates fads2 gene expression in astrocytes.
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Affiliation(s)
- B Dziedzic
- Department of Cell-to-Cell Communication, Medical University of Lodz, Lodz, Poland.
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Lei L, Chen J, Liu Y, Wang L, Zhao G, Chen ZY. Dietary Wheat Bran Oil Is Equally as Effective as Rice Bran Oil in Reducing Plasma Cholesterol. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2018; 66:2765-2774. [PMID: 29502409 DOI: 10.1021/acs.jafc.7b06093] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/21/2023]
Abstract
Rice bran oil (RBO) possesses a plasma cholesterol-lowering activity, while effect of wheat bran oil (WBO) on plasma cholesterol remains unknown. The present study compared the cholesterol-lowering activity of WBO with that of RBO in hamsters. Fifty-four male hamsters were divided into seven groups fed either a noncholesterol diet (NCD) or one of six high-cholesterol diets, namely HCD diet (0.2% cholesterol +9.5% lard), HCD+C diet (0.2% cholesterol +9.5% lard +0.5% cholestyramine), WL diet (0.2% cholesterol +4.8% Lard +4.8% WBO), WH diet (0.2% cholesterol +9.5% WBO), RL diet (0.2% cholesterol +4.8% Lard +4.8% RBO), and RH diet (0.2% cholesterol +9.5% RBO). Plasma total cholesterol (TC) in HCD group was 327.4 ± 31.8 mg/dL, while plasma TC in two WBO and two RBO groups was 242.2 ± 20.8, 243.1 ± 31.7, 257.1 ± 16.3, and 243.4 ± 46.0 mg/dL, respectively, leading to a decrease in plasma TC by 22-26% ( P < 0.01). No significant difference in cholesterol-lowering potency was seen between WBO and RBO. Plasma cholesterol-lowering activity of WBO and RBO was accompanied by down-regulation of hepatic 3-hydroxy-3-methylglutaryl-CoA reductase and fatty acid synthase, while up-regulation of cholesterol-7α-hydroxylase. WL, WH, RL, and RH diets increased the fecal excretion of total neutral sterols by 72.8%, 106.9%, 5.4%, and 36.8% ( P < 0.01) respectively. Results indicated WBO and RBO could inhibit cholesterol absorption via down-regulation of intestinal Niemann-Pick C1 like 1 protein, acyl CoA:cholesterol acyltransferase 2, and ATP binding cassette transporter 5. In summary, WBO was equally effective as RBO in decreasing plasma cholesterol in hypercholesterolemia hamsters.
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Affiliation(s)
- Lin Lei
- College of Food Science , Southwest University , Chongqing 400715 , China
- School of Life Sciences , The Chinese University of Hong Kong , Hong, Kong , China
| | - Jingnan Chen
- Provincial Key Laboratory for Transformation and Utilization of Cereal Resource , Henan University of Technology , Zhengzhou , Henan 450001 , China
| | - Yuwei Liu
- School of Public Health , Fudan University , Shanghai 200032 , China
| | - Lijun Wang
- Shenzhen Institute for Drug Control, Shenzhen , China
| | - Guohua Zhao
- College of Food Science , Southwest University , Chongqing 400715 , China
| | - Zhen-Yu Chen
- School of Life Sciences , The Chinese University of Hong Kong , Hong, Kong , China
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