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Zhou B, Zhang B, Han J, Zhang J, Li J, Dong W, Zhao X, Zhang Y, Zhang Q. Role of Acyl-CoA Thioesterase 7 in Regulating Fatty Acid Metabolism and Its Contribution to the Onset and Progression of Bovine Clinical Mastitis. Int J Mol Sci 2024; 25:13046. [PMID: 39684757 DOI: 10.3390/ijms252313046] [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: 11/02/2024] [Revised: 12/02/2024] [Accepted: 12/02/2024] [Indexed: 12/18/2024] Open
Abstract
Clinical mastitis (CM) is a prevalent and severe inflammatory disease in dairy cows affecting the mammary glands. Fatty acid (FA) metabolism and associated enzymes are crucial for many physiological and pathological processes in dairy cows. However, the relationships among FA metabolism, FA-associated enzymes, and CM, as well as the mechanisms underlying their interactions, in dairy cows are not fully understood. The aim of this study was to characterize biological process (BP) terms, pathways, and differentially expressed proteins (DEPs) related to FA metabolism from our previous data-independent acquisition proteomic study. Six BPs involving 14 downregulated and 20 upregulated DEPs, and four pathways involving 10 downregulated and 11 upregulated DEPs related to FA synthesis and metabolism were systematically identified. Associated analysis suggested that 12 candidate DEPs obtained from BPs and pathways, especially acyl-CoA thioesterase 7 (ACOT7), regulate long-chain FA (LCFA) elongation and the biosynthesis of unsaturated FAs. Immunohistochemical and immunofluorescence staining results showed that ACOT7 was present mainly in the cytoplasm of mammary epithelial cells. The qRT-PCR and Western blotting results showed that ACOT7 mRNA and protein levels in the mammary glands of the CM group were significantly upregulated compared to those in the healthy group. This evidence indicates that ACOT7 is positively correlated with CM onset and progression in Holstein cows. These findings offer novel insights into the role of FA metabolism and related enzymes in CM and offer potential targets for the development of therapeutic strategies and biomarkers for the prevention and treatment of CM in dairy cows.
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Affiliation(s)
- Bin Zhou
- College of Life Sciences and Biotechnology, Gansu Agricultural University, Lanzhou 730030, China
- Gansu Key Laboratory of Animal Generational Physiology and Reproductive Regulation, Lanzhou 730070, China
| | - Bohao Zhang
- Gansu Key Laboratory of Animal Generational Physiology and Reproductive Regulation, Lanzhou 730070, China
- College of Veterinary Medicine, Gansu Agricultural University, Lanzhou 730070, China
| | - Jiangyuan Han
- College of Life Sciences and Biotechnology, Gansu Agricultural University, Lanzhou 730030, China
| | - Junjun Zhang
- College of Life Sciences and Biotechnology, Gansu Agricultural University, Lanzhou 730030, China
- Gansu Key Laboratory of Animal Generational Physiology and Reproductive Regulation, Lanzhou 730070, China
| | - Jianfu Li
- College of Life Sciences and Biotechnology, Gansu Agricultural University, Lanzhou 730030, China
- Gansu Key Laboratory of Animal Generational Physiology and Reproductive Regulation, Lanzhou 730070, China
| | - Weitao Dong
- Gansu Key Laboratory of Animal Generational Physiology and Reproductive Regulation, Lanzhou 730070, China
- College of Veterinary Medicine, Gansu Agricultural University, Lanzhou 730070, China
| | - Xingxu Zhao
- College of Life Sciences and Biotechnology, Gansu Agricultural University, Lanzhou 730030, China
- Gansu Key Laboratory of Animal Generational Physiology and Reproductive Regulation, Lanzhou 730070, China
- College of Veterinary Medicine, Gansu Agricultural University, Lanzhou 730070, China
| | - Yong Zhang
- College of Life Sciences and Biotechnology, Gansu Agricultural University, Lanzhou 730030, China
- Gansu Key Laboratory of Animal Generational Physiology and Reproductive Regulation, Lanzhou 730070, China
- College of Veterinary Medicine, Gansu Agricultural University, Lanzhou 730070, China
| | - Quanwei Zhang
- College of Life Sciences and Biotechnology, Gansu Agricultural University, Lanzhou 730030, China
- Gansu Key Laboratory of Animal Generational Physiology and Reproductive Regulation, Lanzhou 730070, China
- College of Veterinary Medicine, Gansu Agricultural University, Lanzhou 730070, China
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Tang Y, Chen Z, Zuo Q, Kang Y. Regulation of CD8+ T cells by lipid metabolism in cancer progression. Cell Mol Immunol 2024; 21:1215-1230. [PMID: 39402302 PMCID: PMC11527989 DOI: 10.1038/s41423-024-01224-z] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2024] [Accepted: 09/22/2024] [Indexed: 11/02/2024] Open
Abstract
Dysregulation of lipid metabolism is a key characteristic of the tumor microenvironment, where tumor cells utilize lipids for proliferation, survival, metastasis, and evasion of immune surveillance. Lipid metabolism has become a critical regulator of CD8+ T-cell-mediated antitumor immunity, with excess lipids in the tumor microenvironment impeding CD8+ T-cell activities. Considering the limited efficacy of immunotherapy in many solid tumors, targeting lipid metabolism to enhance CD8+ T-cell effector functions could significantly improve immunotherapy outcomes. In this review, we examine recent findings on how lipid metabolic processes, including lipid uptake, synthesis, and oxidation, regulate CD8+ T cells within tumors. We also assessed the impact of different lipids on CD8+ T-cell-mediated antitumor immunity, with a particular focus on how lipid metabolism affects mitochondrial function in tumor-infiltrating CD8+ T cells. Furthermore, as cancer is a systemic disease, we examined systemic factors linking lipid metabolism to CD8+ T-cell effector function. Finally, we summarize current therapeutic approaches that target lipid metabolism to increase antitumor immunity and enhance immunotherapy. Understanding the molecular and functional interplay between lipid metabolism and CD8+ T cells offers promising therapeutic opportunities for cancer treatment.
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Affiliation(s)
- Yong Tang
- Department of Molecular Biology, Princeton University, Princeton, NJ, 08544, USA
- Ludwig Institute for Cancer Research Princeton Branch, Princeton, NJ, 08544, USA
| | - Ziqing Chen
- Department of Molecular Biology, Princeton University, Princeton, NJ, 08544, USA
- Ludwig Institute for Cancer Research Princeton Branch, Princeton, NJ, 08544, USA
| | - Qianying Zuo
- Department of Molecular Biology, Princeton University, Princeton, NJ, 08544, USA
- Ludwig Institute for Cancer Research Princeton Branch, Princeton, NJ, 08544, USA
| | - Yibin Kang
- Department of Molecular Biology, Princeton University, Princeton, NJ, 08544, USA.
- Ludwig Institute for Cancer Research Princeton Branch, Princeton, NJ, 08544, USA.
- Cancer Metabolism and Growth Program, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, 08903, USA.
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Zhong W, Chen C, Tan S, He X, Wen X, Wang S, Tocher DR, Waiho K, Chen C. Identification and Functional Characterization of the FATP1 Gene from Mud Crab, Scylla paramamosain. Animals (Basel) 2024; 14:2969. [PMID: 39457899 PMCID: PMC11506284 DOI: 10.3390/ani14202969] [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: 09/02/2024] [Revised: 10/04/2024] [Accepted: 10/10/2024] [Indexed: 10/28/2024] Open
Abstract
In mammals, fatty acid transport protein 1 (FATP1) plays important roles in cellular uptake and activation of long-chain fatty acid (LCFA), especially in processes of transportation, oxidation and triacylglycerol synthesis. However, the role of FATP1 in invertebrates, especially decapod crustaceans, is still poorly understood. In this study, the cDNA of a FATP1 gene from a decapod crustacean, mud crab Scylla paramamosain, was cloned and functionally characterized. The FATP1 gene encoded a polypeptide consisting of 643 amino acids that exhibits all the typical features of the FATP family and shares high homology with the other FATP orthologs of crustaceans. The relative mRNA expression levels of FATP1 were observed to be higher in metabolically active tissues such as hepatopancreas, stomach and gill than in other crab parts. Knockdown of the FATP1 mRNA in vivo significantly reduced triacylglycerols and total lipid levels in the hepatopancreas, accompanied by an increase in the expression of genes related to fatty acid transportation, allocation and hydrolysis, including long-chain acyl-CoA synthetase 3/4 (ACSL3/4) and carnitine palmitoyl transferase 1 (CPT1), and a decrease in the expression of genes related to fatty acid synthesis such as acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS) in the hepatopancreas. Furthermore, increased dietary n-3 long-chain polyunsaturated fatty acid (LC-PUFA) levels resulted in the up-regulation of the FATP1 expression in the hepatopancreas, accompanied by an increase in LC-PUFA content, especially eicosapentaenoic acid (EPA, 20:5n-3) and docosahexaenoic acid (DHA, 22:6n-3), in both polar (PLs) and neutral lipids (NLs) in the hepatopancreas and muscles of crabs. These findings suggested that the FATP1 gene identified in S. paramamosain might play important roles in regulating long-chain fatty acid metabolism and deposition in crustaceans.
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Affiliation(s)
- Wenjie Zhong
- Guangdong Provincial Key Laboratory of Marine Biotechnology, Institute of Marine Sciences, Shantou University, Shantou 515063, China; (W.Z.); (C.C.); (S.T.); (X.H.); (S.W.); (D.R.T.)
| | - Chuangsi Chen
- Guangdong Provincial Key Laboratory of Marine Biotechnology, Institute of Marine Sciences, Shantou University, Shantou 515063, China; (W.Z.); (C.C.); (S.T.); (X.H.); (S.W.); (D.R.T.)
| | - Senyue Tan
- Guangdong Provincial Key Laboratory of Marine Biotechnology, Institute of Marine Sciences, Shantou University, Shantou 515063, China; (W.Z.); (C.C.); (S.T.); (X.H.); (S.W.); (D.R.T.)
| | - Xianda He
- Guangdong Provincial Key Laboratory of Marine Biotechnology, Institute of Marine Sciences, Shantou University, Shantou 515063, China; (W.Z.); (C.C.); (S.T.); (X.H.); (S.W.); (D.R.T.)
| | - Xiaobo Wen
- College of Marine Sciences, South China Agricultural University, Guangzhou 510642, China;
| | - Shuqi Wang
- Guangdong Provincial Key Laboratory of Marine Biotechnology, Institute of Marine Sciences, Shantou University, Shantou 515063, China; (W.Z.); (C.C.); (S.T.); (X.H.); (S.W.); (D.R.T.)
| | - Douglas R. Tocher
- Guangdong Provincial Key Laboratory of Marine Biotechnology, Institute of Marine Sciences, Shantou University, Shantou 515063, China; (W.Z.); (C.C.); (S.T.); (X.H.); (S.W.); (D.R.T.)
- Institute of Aquaculture, Faculty of Natural Sciences, University of Stirling, Stirling FK9 4LA, UK
| | - Khor Waiho
- Higher Institution Centre of Excellence (HICoE), Institute of Tropical Aquaculture and Fisheries, University Malaysia Terengganu, Kuala Terengganu 21300, Malaysia;
| | - Cuiying Chen
- Guangdong Provincial Key Laboratory of Marine Biotechnology, Institute of Marine Sciences, Shantou University, Shantou 515063, China; (W.Z.); (C.C.); (S.T.); (X.H.); (S.W.); (D.R.T.)
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Porter NH, Clark KL, Rebelo LR, Copelin JE, Kwon IH, Lee C. Effects of saturated fatty acids with lysophospholipids on production and nutrient digestibility in lactating cows. J Dairy Sci 2024; 107:4524-4536. [PMID: 38395396 DOI: 10.3168/jds.2023-24457] [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: 11/21/2023] [Accepted: 01/19/2024] [Indexed: 02/25/2024]
Abstract
The objective of the experiment was to determine the effects of supplemental SFA sources, lysophospholipids (LPL), and their interaction on production and nutrient digestibility in lactating dairy cows. The experiment was conducted with 48 cows in a randomized complete block design. Cows were blocked (12 blocks total) by parity and days in milk and randomly assigned to 4 dietary treatments in each block (2 × 2 factorial arrangement), i.e., 2 sources of fat supplements, C16:0 (PA)- or C18:0 (SA)-enriched fat, and with or without LPL. The experiment was conducted for 6 wk to measure daily dry matter intake, milk yield, and weekly milk composition. During the last week of the experiment, spot fecal and urine samples were collected to determine total-tract nutrient digestibility. Milk samples in the last week were also collected to analyze the milk fatty acid (FA) profile. All data were analyzed using the MIXED procedure of SAS, where block was used as a random effect and FA, LPL, and the interaction of FA by LPL were used as fixed effects. Week and interactions of week by FA or LPL were included for production measures. Different sources of SFA did not affect dry matter intake and milk yield. However, the PA treatment increased (39.7 vs. 36.8 kg) energy-corrected milk compared with SA due to increased milk fat yield. No effect of LPL on production measures was observed. Total-tract digestibilities of dry matter, organic matter, crude protein, and total FA were not different between the PA and SA groups, but PA increased (41.4% vs. 38.8%) neutral detergent fiber digestibility compared with SA. Supplementation of LPL increased (64.7% vs. 60.5%) total FA digestibility, especially 18-carbon FA (74.1% vs. 68.2%). An interaction of SFA by LPL was found for 16-carbon FA digestibility. The PA diet increased the concentration of 16-carbon FA in milk fat and SA increased the concentration of preformed FA (≥18 carbons). Supplementation of LPL decreased the concentration of trans-10 C18:1. No difference in N utilization and excretion among treatments was observed. In conclusion, the PA diet was more effective in improving milk fat yield of lactating cows compared with SA. Supplementation of LPL increased digestibility of total FA, especially 18-carbon FA but did not affect production.
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Affiliation(s)
- N H Porter
- Department of Animal Sciences, The Ohio State University, Wooster, OH 44691
| | - K L Clark
- Department of Animal Sciences, The Ohio State University, Wooster, OH 44691
| | - L R Rebelo
- Department of Animal Sciences, The Ohio State University, Wooster, OH 44691
| | - J E Copelin
- Department of Animal Sciences, The Ohio State University, Wooster, OH 44691
| | - I H Kwon
- Easy Bio Inc., Seoul 06253, South Korea
| | - C Lee
- Department of Animal Sciences, The Ohio State University, Wooster, OH 44691.
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Li L, Xia M, Yang L, He Y, Liu H, Xie M, Yu M. The decreased interface tension increased the transmembrane transport of soy hull polysaccharide-derived SCFAs in the Caco-2 cells. Int J Biol Macromol 2024; 266:131261. [PMID: 38556231 DOI: 10.1016/j.ijbiomac.2024.131261] [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: 01/11/2024] [Revised: 03/17/2024] [Accepted: 03/28/2024] [Indexed: 04/02/2024]
Abstract
Polysaccharides impact intestinal fermentation and regulate interfacial properties which affect absorption and transportation. Short-chain fatty acids (SCFAs), the main metabolites of soy hull polysaccharide lysate, are readily absorbed by the body and perform various physiological functions. We analysed the interfacial properties and transport of soy hull polysaccharide-derived SCFAs in the Caco-2 cell model to clarify the transmembrane transport mechanism. The results showed that the interfacial properties of the co-culture system were influenced by both transit time and concentration of SCFAs, the uptake and transit rates of SCFAs at 1-3 h increased significantly with time (P < 0.05). With increasing transit time and concentration, the transit rates of SCFAs on the apical side (AP) → basolateral side (BL) and BL → AP sides increased and then stabilised, the transit rate of the AP → BL side was higher than that of the BL → AP side. Proteomic analysis showed that soy hull polysaccharide-derived SCFAs resulted in the differential expression of 285 upregulated and 501 downregulated after translocation across Caco-2 cells. The differentially expressed proteins were mainly enriched in ribosomes, oxidative phosphorylation, nuclear transport, and SNARE vesicular transport. This study lays the theoretical foundation for understanding the structure-activity relationship of soy hull polysaccharides in the intestine.
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Affiliation(s)
- Li Li
- College of Food Science and Engineering, Bohai University. Jinzhou, Liaoning 121013, China; Grain and Cereal Food Bio-efficient Transformation Engineering Research Center of Liaoning Province, Jinzhou 121013, China
| | - Mingjie Xia
- College of Food Science and Engineering, Bohai University. Jinzhou, Liaoning 121013, China; Grain and Cereal Food Bio-efficient Transformation Engineering Research Center of Liaoning Province, Jinzhou 121013, China
| | - Lina Yang
- College of Food Science and Engineering, Bohai University. Jinzhou, Liaoning 121013, China; Grain and Cereal Food Bio-efficient Transformation Engineering Research Center of Liaoning Province, Jinzhou 121013, China.
| | - Yutang He
- College of Food Science and Engineering, Bohai University. Jinzhou, Liaoning 121013, China; Grain and Cereal Food Bio-efficient Transformation Engineering Research Center of Liaoning Province, Jinzhou 121013, China
| | - He Liu
- College of Food Science and Engineering, Bohai University. Jinzhou, Liaoning 121013, China; Grain and Cereal Food Bio-efficient Transformation Engineering Research Center of Liaoning Province, Jinzhou 121013, China
| | - Mengxi Xie
- Food and Processing Research Institute, Liaoning Academy of Agricultural Sciences, Shenyang, Liaoning 110161, China
| | - Miao Yu
- Food and Processing Research Institute, Liaoning Academy of Agricultural Sciences, Shenyang, Liaoning 110161, China
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Amekyeh H, Sabra R, Billa N. A Window for Enhanced Oral Delivery of Therapeutics via Lipid Nanoparticles. Drug Des Devel Ther 2024; 18:613-630. [PMID: 38476206 PMCID: PMC10927375 DOI: 10.2147/dddt.s439975] [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] [Subscribe] [Scholar Register] [Received: 09/12/2023] [Accepted: 11/25/2023] [Indexed: 03/14/2024] Open
Abstract
Oral administration of dosage forms is convenient and beneficial in several respects. Lipid nanoparticulate dosage forms have emerged as a useful carrier system in deploying low solubility drugs systemically, particularly class II, III, and IV drugs of the Biopharmaceutics Classification System. Like other nanoparticulate delivery systems, their low size-to-volume ratio facilitates uptake by phagocytosis. Lipid nanoparticles also provide scope for high drug loading and extended-release capability, ensuring diminished systemic side effects and improved pharmacokinetics. However, rapid gastrointestinal (GI) clearance of particulate delivery systems impedes efficient uptake across the mucosa. Mucoadhesion of dosage forms to the GI mucosa results in longer transit times due to interactions between the former and mucus. Delayed transit times facilitate transfer of the dosage form across the mucosa. In this regard, a balance between mucoadhesion and mucopenetration guarantees optimal systemic transfer. Furthermore, the interplay between GI anatomy and physiology is key to ensuring efficient systemic uptake. This review captures salient anatomical and physiological features of the GI tract and how these can be exploited for maximal systemic delivery of lipid nanoparticles. Materials used to impart mucoadhesion and examples of successful mucoadhesive lipid nanoformulations are highlighted in this review.
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Affiliation(s)
- Hilda Amekyeh
- Department of Pharmaceutics, School of Pharmacy, University of Health and Allied Sciences, Ho, Ghana
| | - Rayan Sabra
- Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT, USA
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Zhang Y, Yang J, Wang S, Chen Y, Zhang G. TMT-Based Proteomic Analysis Reveals the Molecular Mechanisms of Sodium Pheophorbide A against Black Spot Needle Blight Caused by Pestalotiopsis neglecta in Pinus sylvestris var. mongolica. J Fungi (Basel) 2024; 10:102. [PMID: 38392774 PMCID: PMC10889695 DOI: 10.3390/jof10020102] [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: 12/28/2023] [Revised: 01/23/2024] [Accepted: 01/25/2024] [Indexed: 02/24/2024] Open
Abstract
Black spot needle blight is a minor disease in Mongolian Scots pine (Pinus sylvestris var. mongolica) caused by Pestalotiopsis neglecta, but it can cause economic losses in severe cases. Sodium pheophorbide a (SPA), an intermediate product of the chlorophyll metabolism pathway, is a compound with photoactivated antifungal activity, which has been previously shown to inhibit the growth of P. neglecta. In this study, SPA significantly reduced the incidence and disease index and enhanced the chlorophyll content and antioxidant enzyme activities of P. sylvestris var. mongolica. To further study the molecular mechanism of the inhibition, we conducted a comparative proteomic analysis of P. neglecta mycelia with and without SPA treatment. The cellular proteins were obtained from P. neglecta mycelial samples and subjected to a tandem mass tag (TMT)-labelling LC-MS/MS analysis. Based on the results of de novo transcriptome assembly, 613 differentially expressed proteins (DEPs) (p < 0.05) were identified, of which 360 were upregulated and 253 downregulated. The 527 annotated DEPs were classified into 50 functional groups according to Gene Ontology and linked to 256 different pathways using the Kyoto Encyclopedia of Genes and Genomes database as a reference. A joint analysis of the transcriptome and proteomics results showed that the top three pathways were Amino acid metabolism, Carbohydrate metabolism, and Lipid metabolism. These results provide new viewpoints into the molecular mechanism of the inhibition of P. neglecta by SPA at the protein level and a theoretical basis for evaluating SPA as an antifungal agent to protect forests.
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Affiliation(s)
- Yundi Zhang
- Heilongjiang Province Key Laboratory of Forest Protection, School of Forest, Northeast Forestry University, Harbin 150040, China
| | - Jing Yang
- Heilongjiang Province Key Laboratory of Forest Protection, School of Forest, Northeast Forestry University, Harbin 150040, China
- College of Forestry, Guizhou University, Guiyang 550025, China
| | - Shuren Wang
- Heilongjiang Province Key Laboratory of Forest Protection, School of Forest, Northeast Forestry University, Harbin 150040, China
| | - Yunze Chen
- Heilongjiang Province Key Laboratory of Forest Protection, School of Forest, Northeast Forestry University, Harbin 150040, China
- School of Biological Sciences, Guizhou Education University, Guiyang 550018, China
| | - Guocai Zhang
- Heilongjiang Province Key Laboratory of Forest Protection, School of Forest, Northeast Forestry University, Harbin 150040, China
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Engin AB, Engin A. The Checkpoints of Intestinal Fat Absorption in Obesity. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2024; 1460:73-95. [PMID: 39287849 DOI: 10.1007/978-3-031-63657-8_3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/19/2024]
Abstract
In this chapter, intestinal lipid transport, which plays a central role in fat homeostasis and the development of obesity in addition to the mechanisms of fatty acids and monoacylglycerol absorption in the intestinal lumen and reassembly of these within the enterocyte was described. A part of the resynthesized triglycerides (triacylglycerols; TAG) is repackaged in the intestine to form the hydrophobic core of chylomicrons (CMs). These are delivered as metabolic fuels, essential fatty acids, and other lipid-soluble nutrients, from enterocytes to the peripheral tissues following detachment from the endoplasmic reticulum membrane. Moreover, the attitudes of multiple receptor functions in dietary lipid uptake, synthesis, and transport are highlighted. Additionally, intestinal fatty acid binding proteins (FABPs), which increase the cytosolic flux of fatty acids via intermembrane transfer in enterocytes, and the functions of checkpoints for receptor-mediated fatty acid signaling are debated. The importance of the balance between storage and secretion of dietary fat by enterocytes in determining the physiological fate of dietary fat, including regulation of blood lipid concentrations and energy balance, is mentioned. Consequently, promising checkpoints regarding how intestinal fat processing affects lipid homeostatic mechanisms and lipid stores in the body and the prevention of obesity-lipotoxicity due to excessive intestinal lipid absorption are evaluated. In this context, dietary TAG digestion, pharmacological inhibition of TAG hydrolysis, the regulation of long-chain fatty acid uptake traffic into adipocytes, intracellular TAG resynthesis, the enlargement of cytoplasmic lipid droplets in enterocytes and constitutional alteration of their proteome, CD36-mediated conversion of diet-derived fatty acid into cellular lipid messengers and their functions are discussed.
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Affiliation(s)
- Ayse Basak Engin
- Faculty of Pharmacy, Department of Toxicology, Gazi University, Hipodrom, Ankara, Turkey.
| | - Atilla Engin
- Faculty of Medicine, Department of General Surgery, Gazi University, Besevler, Ankara, Turkey
- Mustafa Kemal Mah. 2137. Sok. 8/14, 06520, Cankaya, Ankara, Turkey
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Wang Q, Liu J, Chen Z, Zheng J, Wang Y, Dong J. Targeting metabolic reprogramming in hepatocellular carcinoma to overcome therapeutic resistance: A comprehensive review. Biomed Pharmacother 2024; 170:116021. [PMID: 38128187 DOI: 10.1016/j.biopha.2023.116021] [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: 09/18/2023] [Revised: 11/23/2023] [Accepted: 12/14/2023] [Indexed: 12/23/2023] Open
Abstract
Hepatocellular carcinoma (HCC) poses a heavy burden on human health with high morbidity and mortality rates. Systematic therapy is crucial for advanced and mid-term HCC, but faces a significant challenge from therapeutic resistance, weakening drug effectiveness. Metabolic reprogramming has gained attention as a key contributor to therapeutic resistance. Cells change their metabolism to meet energy demands, adapt to growth needs, or resist environmental pressures. Understanding key enzyme expression patterns and metabolic pathway interactions is vital to comprehend HCC occurrence, development, and treatment resistance. Exploring metabolic enzyme reprogramming and pathways is essential to identify breakthrough points for HCC treatment. Targeting metabolic enzymes with inhibitors is key to addressing these points. Inhibitors, combined with systemic therapeutic drugs, can alleviate resistance, prolong overall survival for advanced HCC, and offer mid-term HCC patients a chance for radical resection. Advances in metabolic research methods, from genomics to metabolomics and cells to organoids, help build the HCC metabolic reprogramming network. Recent progress in biomaterials and nanotechnology impacts drug targeting and effectiveness, providing new solutions for systemic therapeutic drug resistance. This review focuses on metabolic enzyme changes, pathway interactions, enzyme inhibitors, research methods, and drug delivery targeting metabolic reprogramming, offering valuable references for metabolic approaches to HCC treatment.
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Affiliation(s)
- Qi Wang
- Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of Jilin University, Jilin University, Changchun 130021, China
| | - Juan Liu
- Research Unit of Precision Hepatobiliary Surgery Paradigm, Chinese Academy of Medical Sciences, Beijing 100021, China; Hepato-Pancreato-Biliary Center, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing 102218, China; Institute for Organ Transplant and Bionic Medicine, Tsinghua University, Beijing 102218, China; Key Laboratory of Digital Intelligence Hepatology (Ministry of Education/Beijing), School of Clinical Medicine, Tsinghua University, Beijing, China.
| | - Ziye Chen
- Clinical Translational Science Center, Beijing Tsinghua Changgung Hospital, Tsinghua University, Beijing 102218, China
| | - Jingjing Zheng
- Hepato-Pancreato-Biliary Center, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing 102218, China
| | - Yunfang Wang
- Research Unit of Precision Hepatobiliary Surgery Paradigm, Chinese Academy of Medical Sciences, Beijing 100021, China; Hepato-Pancreato-Biliary Center, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing 102218, China; Institute for Organ Transplant and Bionic Medicine, Tsinghua University, Beijing 102218, China; Clinical Translational Science Center, Beijing Tsinghua Changgung Hospital, Tsinghua University, Beijing 102218, China; Key Laboratory of Digital Intelligence Hepatology (Ministry of Education/Beijing), School of Clinical Medicine, Tsinghua University, Beijing, China.
| | - Jiahong Dong
- Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of Jilin University, Jilin University, Changchun 130021, China; Research Unit of Precision Hepatobiliary Surgery Paradigm, Chinese Academy of Medical Sciences, Beijing 100021, China; Hepato-Pancreato-Biliary Center, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing 102218, China; Institute for Organ Transplant and Bionic Medicine, Tsinghua University, Beijing 102218, China; Key Laboratory of Digital Intelligence Hepatology (Ministry of Education/Beijing), School of Clinical Medicine, Tsinghua University, Beijing, China.
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Zakaria Z, Othman ZA, Nna VU, Mohamed M. The promising roles of medicinal plants and bioactive compounds on hepatic lipid metabolism in the treatment of non-alcoholic fatty liver disease in animal models: molecular targets. Arch Physiol Biochem 2023; 129:1262-1278. [PMID: 34153200 DOI: 10.1080/13813455.2021.1939387] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2020] [Accepted: 06/01/2021] [Indexed: 12/13/2022]
Abstract
Imbalance in hepatic lipid metabolism can lead to an abnormal triglycerides deposition in the hepatocytes which can cause non-alcoholic fatty liver disease (NAFLD). Four main mechanisms responsible for regulating hepatic lipid metabolism are fatty acid uptake, de novo lipogenesis, lipolysis and fatty acid oxidation. Controlling the expression of transcription factors at molecular level plays a crucial role in NAFLD management. This paper reviews various medicinal plants and their bioactive compounds emphasising mechanisms involved in hepatic lipid metabolism, other important NAFLD pathological features, and their promising roles in managing NAFLD through regulating key transcription factors. Although there are many medicinal plants popularly investigated for NAFLD treatment, there is still little information and scientific evidence available and there has been no research on clinical trials scrutinised on this matter. This review also aims to provide molecular information of medicinal plants in NALFD treatment that might have potentials for future scientifically controlled studies.
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Affiliation(s)
- Zaida Zakaria
- Department of Physiology, School of Medical Sciences, Health Campus, Universiti Sains Malaysia, Kelantan, Malaysia
| | - Zaidatul Akmal Othman
- Department of Physiology, School of Medical Sciences, Health Campus, Universiti Sains Malaysia, Kelantan, Malaysia
- Unit of Physiology, Faculty of Medicine, Universiti Sultan Zainal Abidin, Kuala Terengganu, Malaysia
| | - Victor Udo Nna
- Department of Physiology, Faculty of Basic Medical Sciences, College of Medical Sciences, University of Calabar, Calabar, Nigeria
| | - Mahaneem Mohamed
- Department of Physiology, School of Medical Sciences, Health Campus, Universiti Sains Malaysia, Kelantan, Malaysia
- Unit of Integrative Medicine, School of Medical Sciences, Health Campus, Universiti Sains Malaysia, Kelantan, Malaysia
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11
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Abstract
The steatotic diseases of metabolic dysfunction-associated steatotic liver disease (MASLD), alcohol-associated liver disease (ALD), and chronic hepatitis C (HCV) account for the majority of liver disease prevalence, morbidity, and mortality worldwide. While these diseases have distinct pathogenic and clinical features, dysregulated lipid droplet (LD) organelle biology represents a convergence of pathogenesis in all three. With increasing understanding of hepatocyte LD biology, we now understand the roles of LD proteins involved in these diseases but also how genetics modulate LD biology to either exacerbate or protect against the phenotypes associated with steatotic liver diseases. Here, we review the history of the LD organelle and its biogenesis and catabolism. We also review how this organelle is critical not only for the steatotic phenotype of liver diseases but also for their advanced phenotypes. Finally, we summarize the latest attempts and challenges of leveraging LD biology for therapeutic gain in steatotic diseases. In conclusion, the study of dysregulated LD biology may lead to novel therapeutics for the prevention of disease progression in the highly prevalent steatotic liver diseases of MASLD, ALD, and HCV.
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Affiliation(s)
- Joseph L Dempsey
- Division of Gastroenterology, Department of Medicine, School of Medicine, University of Washington, Seattle, Washington
| | - George N Ioannou
- Division of Gastroenterology, Department of Medicine, School of Medicine, University of Washington, Seattle, Washington
- Division of Gastroenterology, Veterans Affairs Puget Sound Healthcare System Seattle, Washington
| | - Rotonya M Carr
- Division of Gastroenterology, Department of Medicine, School of Medicine, University of Washington, Seattle, Washington
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12
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Zhang Y, Cao Z, Wang L, Dong B, Qi S, Xu X, Bao Q, Zhang Y, Xu Q, Chang G, Chen G. Effects of linseed oil supplementation duration on fatty acid profile and fatty acid metabolism-related genes in the muscles of Chinese crested white ducks. Poult Sci 2023; 102:102896. [PMID: 37473521 PMCID: PMC10371819 DOI: 10.1016/j.psj.2023.102896] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2023] [Revised: 05/05/2023] [Accepted: 06/24/2023] [Indexed: 07/22/2023] Open
Abstract
Meat rich in polyunsaturated fatty acids is considered beneficial to health. Supplementing the diet with linseed oil promotes the deposition of polyunsaturated fatty acids (PUFAs) in poultry, a conclusion that has been confirmed multiple times in chicken meat. However, fewer studies have focused on the effects of dietary fatty acids on duck meat. Therefore, this study aims to evaluate the effects of the feeding time of a linseed oil diet on duck meat performance and gene expression, including meat quality performance, plasma biochemical indicators, fatty acid profile, and gene expression. For this study, we selected 168 Chinese crested ducks at 28 days old and divided them into three groups, with 56 birds in each group. The linseed oil content in the different treatment groups was as follows: the control group (0% flaxseed oil), the 14d group (2% linseed oil), and the 28d group (2% linseed oil). Ducks in the two experimental groups were fed a linseed oil diet for 28 and 14 days at 28 and 42 days of age, respectively. The results showed that linseed oil had no negative effect on duck performance (slaughter rate, breast muscle weight, and leg muscle weight) or meat quality performance (pH, meat color, drip loss, and shear force) (P > 0.05). The addition of linseed oil in the diet increased plasma total cholesterol and high-density lipoprotein cholesterol levels (P < 0.05), while decreasing triglyceride content (P < 0.05). Furthermore, the supplementation of linseed oil for four weeks affected the composition of muscle fatty acids. Specifically, levels of α-linolenic acid, eicosapentaenoic acid, and docosahexaenoic acid were increased (P < 0.05), while eicosatetraenoic acid content was negatively correlated with flaxseed oil intake (P < 0.05). qRT-PCR analysis further revealed that the expression of FATP1, FABP5, and ELOVL5 genes in the breast muscle, as well as FABP3 and FADS2 genes in the thigh muscle, increased after four weeks of linseed oil supplementation (P < 0.05). However, after two weeks of feeding, CPT1A gene expression inhibited fatty acid deposition, suggesting an increase in fatty acid oxidation (P < 0.05). Overall, the four-week feeding time may be a key factor in promoting the deposition of n-3 PUFAs in duck meat. However, the limitation of this study is that it remains unknown whether longer supplementation time will continue to affect the deposition of n-3 PUFAs. Further experiments are needed to explain how prolonged feeding of linseed oil will affect the meat quality traits and fatty acid profile of duck meat.
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Affiliation(s)
- Yang Zhang
- Key Laboratory of Animal Genetics and Breeding and Molecular Design of Jiangsu Province, College of Animal Science and Technology, Yangzhou University, Yangzhou, Jiangsu Province 225009, China
| | - Zhi Cao
- Key Laboratory of Animal Genetics and Breeding and Molecular Design of Jiangsu Province, College of Animal Science and Technology, Yangzhou University, Yangzhou, Jiangsu Province 225009, China
| | - Laidi Wang
- Key Laboratory of Animal Genetics and Breeding and Molecular Design of Jiangsu Province, College of Animal Science and Technology, Yangzhou University, Yangzhou, Jiangsu Province 225009, China
| | - Bingqiang Dong
- Key Laboratory of Animal Genetics and Breeding and Molecular Design of Jiangsu Province, College of Animal Science and Technology, Yangzhou University, Yangzhou, Jiangsu Province 225009, China
| | - Shangzong Qi
- Key Laboratory of Animal Genetics and Breeding and Molecular Design of Jiangsu Province, College of Animal Science and Technology, Yangzhou University, Yangzhou, Jiangsu Province 225009, China
| | - Xinlei Xu
- Key Laboratory of Animal Genetics and Breeding and Molecular Design of Jiangsu Province, College of Animal Science and Technology, Yangzhou University, Yangzhou, Jiangsu Province 225009, China
| | - Qiang Bao
- Key Laboratory of Animal Genetics and Breeding and Molecular Design of Jiangsu Province, College of Animal Science and Technology, Yangzhou University, Yangzhou, Jiangsu Province 225009, China
| | - Yu Zhang
- Key Laboratory of Animal Genetics and Breeding and Molecular Design of Jiangsu Province, College of Animal Science and Technology, Yangzhou University, Yangzhou, Jiangsu Province 225009, China
| | - Qi Xu
- Key Laboratory of Animal Genetics and Breeding and Molecular Design of Jiangsu Province, College of Animal Science and Technology, Yangzhou University, Yangzhou, Jiangsu Province 225009, China
| | - Guobin Chang
- Key Laboratory of Animal Genetics and Breeding and Molecular Design of Jiangsu Province, College of Animal Science and Technology, Yangzhou University, Yangzhou, Jiangsu Province 225009, China
| | - Guohong Chen
- Key Laboratory of Animal Genetics and Breeding and Molecular Design of Jiangsu Province, College of Animal Science and Technology, Yangzhou University, Yangzhou, Jiangsu Province 225009, China; Joint International Research Laboratory of Agriculture and Agri-Product Safety, the Ministry of Education of China, Yangzhou University, Yangzhou, Jiangsu Province, 225009, China.
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13
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Gao Y, Hua R, Peng K, Yin Y, Zeng C, Guo Y, Wang Y, Li L, Li X, Qiu Y, Wang Z. High-starchy carbohydrate diet aggravates NAFLD by increasing fatty acids influx mediated by NOX2. FOOD SCIENCE AND HUMAN WELLNESS 2023. [DOI: 10.1016/j.fshw.2022.10.026] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
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14
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Zeng X, Li S, Liu L, Cai S, Ye Q, Xue B, Wang X, Zhang S, Chen F, Cai C, Wang F, Zeng X. Role of functional fatty acids in modulation of reproductive potential in livestock. J Anim Sci Biotechnol 2023; 14:24. [PMID: 36788613 PMCID: PMC9926833 DOI: 10.1186/s40104-022-00818-9] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2022] [Accepted: 12/04/2022] [Indexed: 02/16/2023] Open
Abstract
Fatty acids are not only widely known as energy sources, but also play important roles in many metabolic pathways. The significance of fatty acids in modulating the reproductive potential of livestock has received greater recognition in recent years. Functional fatty acids and their metabolites improve follicular development, oocyte maturation and embryo development, as well as endometrial receptivity and placental vascular development, through enhancing energy supply and precursors for the synthesis of their productive hormones, such as steroid hormones and prostaglandins. However, many studies are focused on the impacts of individual functional fatty acids in the reproductive cycle, lacking studies involved in deeper mechanisms and optimal fatty acid requirements for specific physiological stages. Therefore, an overall consideration of the combination and synergy of functional fatty acids and the establishment of optimal fatty acid requirement for specific stages is needed to improve reproductive potential in livestock.
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Affiliation(s)
- Xiangzhou Zeng
- grid.22935.3f0000 0004 0530 8290State Key Laboratory of Animal Nutrition, Ministry of Agriculture Feed Industry Center, China Agricultural University, 100193 Beijing, P. R. China ,Beijing Key Laboratory of Bio feed Additives, 100193 Beijing, P. R. China
| | - Siyu Li
- grid.22935.3f0000 0004 0530 8290State Key Laboratory of Animal Nutrition, Ministry of Agriculture Feed Industry Center, China Agricultural University, 100193 Beijing, P. R. China ,Beijing Key Laboratory of Bio feed Additives, 100193 Beijing, P. R. China
| | - Lu Liu
- grid.22935.3f0000 0004 0530 8290State Key Laboratory of Animal Nutrition, Ministry of Agriculture Feed Industry Center, China Agricultural University, 100193 Beijing, P. R. China ,Beijing Key Laboratory of Bio feed Additives, 100193 Beijing, P. R. China
| | - Shuang Cai
- grid.22935.3f0000 0004 0530 8290State Key Laboratory of Animal Nutrition, Ministry of Agriculture Feed Industry Center, China Agricultural University, 100193 Beijing, P. R. China ,Beijing Key Laboratory of Bio feed Additives, 100193 Beijing, P. R. China
| | - Qianhong Ye
- grid.35155.370000 0004 1790 4137State Key Laboratory of Agricultural Microbiology, College of Animal Sciences and Technology, Huazhong Agricultural University, 430070 Wuhan, Hubei China
| | - Bangxin Xue
- grid.22935.3f0000 0004 0530 8290State Key Laboratory of Animal Nutrition, Ministry of Agriculture Feed Industry Center, China Agricultural University, 100193 Beijing, P. R. China ,Beijing Key Laboratory of Bio feed Additives, 100193 Beijing, P. R. China
| | - Xinyu Wang
- grid.22935.3f0000 0004 0530 8290State Key Laboratory of Animal Nutrition, Ministry of Agriculture Feed Industry Center, China Agricultural University, 100193 Beijing, P. R. China ,Beijing Key Laboratory of Bio feed Additives, 100193 Beijing, P. R. China
| | - Shihai Zhang
- grid.20561.300000 0000 9546 5767Guangdong Provincial Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, 510642 Guangzhou, China
| | - Fang Chen
- grid.20561.300000 0000 9546 5767Guangdong Provincial Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, 510642 Guangzhou, China
| | - Chuanjiang Cai
- grid.144022.10000 0004 1760 4150College of Animal Science and Technology, Northwest A&F University, 712100 Yangling, Shaanxi China
| | - Fenglai Wang
- grid.22935.3f0000 0004 0530 8290State Key Laboratory of Animal Nutrition, Ministry of Agriculture Feed Industry Center, China Agricultural University, 100193 Beijing, P. R. China ,Beijing Key Laboratory of Bio feed Additives, 100193 Beijing, P. R. China
| | - Xiangfang Zeng
- State Key Laboratory of Animal Nutrition, Ministry of Agriculture Feed Industry Center, China Agricultural University, 100193, Beijing, P. R. China. .,Beijing Key Laboratory of Bio feed Additives, 100193, Beijing, P. R. China.
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15
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Fatty acid transport proteins (FATPs) in cancer. Chem Phys Lipids 2023; 250:105269. [PMID: 36462545 DOI: 10.1016/j.chemphyslip.2022.105269] [Citation(s) in RCA: 25] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2022] [Revised: 11/12/2022] [Accepted: 11/27/2022] [Indexed: 12/03/2022]
Abstract
Lipids play pivotal roles in cancer biology. Lipids have a wide range of biological roles, especially in cell membrane synthesis, serve as energetic molecules in regulating energy-demanding processes; and they play a significant role as signalling molecules and modulators of numerous cellular functions. Lipids may participate in the development of cancer through the fatty acid signalling pathway. Lipids consumed in the diet act as a key source of extracellular pools of fatty acids transported into the cellular system. Increased availability of lipids to cancer cells is due to increased uptake of fatty acids from adipose tissues. Lipids serve as a source of energy for rapidly dividing cancerous cells. Surviving requires the swift synthesis of biomass and membrane matrix to perform exclusive functions such as cell proliferation, growth, invasion, and angiogenesis. FATPs (fatty acid transport proteins) are a group of proteins involved in fatty acid uptake, mainly localized within cells and the cellular membrane, and have a key role in long-chain fatty acid transport. FATPs are composed of six isoforms that are tissue-specific and encoded by a specific gene. Previous studies have reported that FATPs can alter fatty acid metabolism, cell growth, and cell proliferation and are involved in the development of various cancers. They have shown increased expression in most cancers, such as melanoma, breast cancer, prostate cancer, renal cell carcinoma, hepatocellular carcinoma, bladder cancer, and lung cancer. This review introduces a variety of FATP isoforms and summarises their functions and their possible roles in the development of cancer.
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16
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Abstract
Postprandial hyperlipidaemia is an important feature of diabetic dyslipidaemia and plays an important role in the development of cardiovascular disease in individuals with type 2 diabetes. Postprandial hyperlipidaemia in type 2 diabetes is secondary to increased chylomicron production by the enterocytes and delayed catabolism of chylomicrons and chylomicron remnants. Insulin and some intestinal hormones (e.g. glucagon-like peptide-1 [GLP-1]) influence intestinal lipid metabolism. In individuals with type 2 diabetes, insulin resistance and possibly reduced GLP-1 secretion are involved in the pathophysiology of postprandial hyperlipidaemia. Several factors are involved in the overproduction of chylomicrons: (1) increased expression of microsomal triglyceride transfer protein, which is a key enzyme in chylomicron synthesis; (2) higher stability and availability of apolipoprotein B-48; and (3) increased de novo lipogenesis. Individuals with type 2 diabetes present with disorders of cholesterol metabolism in the enterocytes with reduced absorption and increased synthesis. The increased production of chylomicrons in type 2 diabetes is also associated with a reduction in their catabolism, mostly because of a reduction in activity of lipoprotein lipase. Modification of the microbiota, which is observed in type 2 diabetes, may also generate disorders of intestinal lipid metabolism, but human data remain limited. Some glucose-lowering treatments significantly influence intestinal lipid absorption and transport. Postprandial hyperlipidaemia is reduced by metformin, pioglitazone, alpha-glucosidase inhibitors, dipeptidyl peptidase 4 inhibitors and GLP-1 agonists. The most pronounced effect is observed with GLP-1 agonists, which reduce chylomicron production significantly in individuals with type 2 diabetes and have a direct effect on the intestine by reducing the expression of genes involved in intestinal lipoprotein metabolism. The effect of sodium-glucose cotransporter 2 inhibitors on intestinal lipid metabolism needs to be clarified.
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Affiliation(s)
- Bruno Vergès
- Endocrinology-Diabetology Department, University-Hospital, Dijon, France.
- Inserm UMR 1231, Medical School, University of Burgundy-Franche Comté, Dijon, France.
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17
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Mater V, Eisner S, Seidel C, Schneider D. The peripherally membrane-attached protein MbFACL6 of Mycobacterium tuberculosis activates a broad spectrum of substrates. J Mol Biol 2022; 434:167842. [PMID: 36179886 DOI: 10.1016/j.jmb.2022.167842] [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: 06/10/2022] [Revised: 09/12/2022] [Accepted: 09/20/2022] [Indexed: 11/25/2022]
Abstract
The infectious disease tuberculosis is one of the fifteen most common causes of death worldwide (according to the WHO). About every fourth person is infected with the main causative agent Mycobacterium tuberculosis (Mb). A characteristic of the pathogen is its entrance into a dormant state in which a phenotypic antibiotic resistance is achieved. To target resistant strains, novel dormancy-specific targets are very promising. Such a possible target is the Mb "fatty acid-CoA ligase 6" (MbFACL6), which activates fatty acids and thereby modulates the accumulation of triacylglycerol-containing lipid droplets that are used by Mb as an energy source during dormancy. We investigated the membrane association of MbFACL6 in E. coli and its specific activity towards different substrates after establishing a novel MbFACL6 activity assay. Despite a high homology to the mammalian family of fatty acid transport proteins, which are typically transmembrane proteins, our results indicate that MbFACL6 is a peripheral membrane-attached protein. Furthermore, MbFACL6 tolerates a broad spectrum of substrates including saturated and unsaturated fatty acids (C12-C20), some cholic acid derivatives, and even synthetic fatty acids, such as 9(E)-nitrooleicacid. Therefore, the substrate selectivity of MbFACL6 appears to be much broader than previously assumed.
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Affiliation(s)
- Veronika Mater
- Department of Chemistry, Biochemistry, Johannes Gutenberg University Mainz, Hanns-Dieter-Hüsch-Weg 17, 55128 Mainz, Germany.
| | - Sabine Eisner
- Department of Chemistry, Biochemistry, Johannes Gutenberg University Mainz, Hanns-Dieter-Hüsch-Weg 17, 55128 Mainz, Germany.
| | - Cornelia Seidel
- Department of Chemistry, Biochemistry, Johannes Gutenberg University Mainz, Hanns-Dieter-Hüsch-Weg 17, 55128 Mainz, Germany.
| | - Dirk Schneider
- Department of Chemistry, Biochemistry, Johannes Gutenberg University Mainz, Hanns-Dieter-Hüsch-Weg 17, 55128 Mainz, Germany; Institute of Molecular Physiology, Johannes Gutenberg University Mainz, Hanns-Dieter-Hüsch-Weg 17, 55128 Mainz, Germany.
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18
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Ferdouse A, Clugston RD. Pathogenesis of Alcohol-Associated Fatty Liver: Lessons From Transgenic Mice. Front Physiol 2022; 13:940974. [PMID: 35864895 PMCID: PMC9294393 DOI: 10.3389/fphys.2022.940974] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Accepted: 06/15/2022] [Indexed: 12/18/2022] Open
Abstract
Alcohol-associated liver disease (ALD) is a major public health issue that significantly contributes to human morbidity and mortality, with no FDA-approved therapeutic intervention available. The health burden of ALD has worsened during the COVID-19 pandemic, which has been associated with a spike in alcohol abuse, and a subsequent increase in hospitalization rates for ALD. A key knowledge gap that underlies the lack of novel therapies for ALD is a need to better understand the pathogenic mechanisms that contribute to ALD initiation, particularly with respect to hepatic lipid accumulation and the development of fatty liver, which is the first step in the ALD spectrum. The goal of this review is to evaluate the existing literature to gain insight into the pathogenesis of alcohol-associated fatty liver, and to synthesize alcohol’s known effects on hepatic lipid metabolism. To achieve this goal, we specifically focus on studies from transgenic mouse models of ALD, allowing for a genetic dissection of alcohol’s effects, and integrate these findings with our current understanding of ALD pathogenesis. Existing studies using transgenic mouse models of ALD have revealed roles for specific genes involved in hepatic lipid metabolic pathways including fatty acid uptake, mitochondrial β-oxidation, de novo lipogenesis, triglyceride metabolism, and lipid droplet formation. In addition to reviewing this literature, we conclude by identifying current gaps in our understanding of how alcohol abuse impairs hepatic lipid metabolism and identify future directions to address these gaps. In summary, transgenic mice provide a powerful tool to understand alcohol’s effect on hepatic lipid metabolism and highlight that alcohol abuse has diverse effects that contribute to the development of alcohol-associated fatty liver disease.
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Li H, Herrmann T, Seeßle J, Liebisch G, Merle U, Stremmel W, Chamulitrat W. Role of fatty acid transport protein 4 in metabolic tissues: insights into obesity and fatty liver disease. Biosci Rep 2022; 42:BSR20211854. [PMID: 35583196 PMCID: PMC9160530 DOI: 10.1042/bsr20211854] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2021] [Revised: 05/16/2022] [Accepted: 05/17/2022] [Indexed: 11/28/2022] Open
Abstract
Fatty acid (FA) metabolism is a series of processes that provide structural substances, signalling molecules and energy. Ample evidence has shown that FA uptake is mediated by plasma membrane transporters including FA transport proteins (FATPs), caveolin-1, fatty-acid translocase (FAT)/CD36, and fatty-acid binding proteins. Unlike other FA transporters, the functions of FATPs have been controversial because they contain both motifs of FA transport and fatty acyl-CoA synthetase (ACS). The widely distributed FATP4 is not a direct FA transporter but plays a predominant function as an ACS. FATP4 deficiency causes ichthyosis premature syndrome in mice and humans associated with suppression of polar lipids but an increase in neutral lipids including triglycerides (TGs). Such a shift has been extensively characterized in enterocyte-, hepatocyte-, and adipocyte-specific Fatp4-deficient mice. The mutants under obese and non-obese fatty livers induced by different diets persistently show an increase in blood non-esterified free fatty acids and glycerol indicating the lipolysis of TGs. This review also focuses on FATP4 role on regulatory networks and factors that modulate FATP4 expression in metabolic tissues including intestine, liver, muscle, and adipose tissues. Metabolic disorders especially regarding blood lipids by FATP4 deficiency in different cell types are herein discussed. Our results may be applicable to not only patients with FATP4 mutations but also represent a model of dysregulated lipid homeostasis, thus providing mechanistic insights into obesity and development of fatty liver disease.
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Affiliation(s)
- Huili Li
- Department of Internal Medicine IV, University of Heidelberg Hospital, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Thomas Herrmann
- Westkuesten Hospital, Esmarchstraße 50, 25746 Heide, Germany
| | - Jessica Seeßle
- Department of Internal Medicine IV, University of Heidelberg Hospital, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany
| | - Gerhard Liebisch
- Institute of Clinical Chemistry and Laboratory Medicine, University Regensburg, Franz-Josef-Strauss-Allee 11, 93053 Regensburg, Germany
| | - Uta Merle
- Department of Internal Medicine IV, University of Heidelberg Hospital, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany
| | - Wolfgang Stremmel
- Department of Internal Medicine IV, University of Heidelberg Hospital, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany
| | - Walee Chamulitrat
- Department of Internal Medicine IV, University of Heidelberg Hospital, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany
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20
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Wu Y, Tang J, Wen Z, Zhang B, Cao J, Zhao L, Guo Z, Xie M, Zhou Z, Hou S. Dietary methionine deficiency stunts growth and increases fat deposition via suppression of fatty acids transportation and hepatic catabolism in Pekin ducks. J Anim Sci Biotechnol 2022; 13:61. [PMID: 35581591 PMCID: PMC9115956 DOI: 10.1186/s40104-022-00709-z] [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: 12/05/2021] [Accepted: 03/13/2022] [Indexed: 11/10/2022] Open
Abstract
Background Although methionine (Met), the first-limiting dietary amino acid, has crucial roles in growth and regulation of lipid metabolism in ducks, mechanisms underlying are not well understood. Therefore, the objective was to use dietary Met deficiency to investigate the involvement of Met in lipid metabolism and fat accumulation of Pekin ducks. Methods A total of 150 male Pekin ducks (15-d-old, 558.5 ± 4.4 g) were allocated into 5 groups (6 replicates with 5 birds each) and fed corn and soybean meal-based diets containing 0.28%, 0.35%, 0.43%, 0.50%, and 0.58% Met, respectively, for 4 weeks. Met-deficient (Met-D, 0.28% Met) and Met-adequate (Met-A, 0.43% Met) groups were selected for subsequent molecular studies. Serum, liver, and abdominal fat samples were collected to assess the genes and proteins involved in lipid metabolism of Pekin ducks and hepatocytes were cultured in vivo for verification. Results Dietary Met deficiency caused growth depression and excess fat deposition that were ameliorated by feeding diets with adequate Met. Serum triglyceride and non-esterified fatty acid concentrations increased (P < 0.05), whereas serum concentrations of total cholesterol, low density lipoprotein cholesterol, total protein, and albumin decreased (P < 0.05) in Met-D ducks compared to those in Met-A ducks. Based on hepatic proteomics analyses, dietary Met deficiency suppressed expression of key proteins related to fatty acid transport, fatty acid oxidation, tricarboxylic acid cycle, glycolysis/gluconeogenesis, ketogenesis, and electron transport chain; selected key proteins had similar expression patterns verified by qRT-PCR and Western blotting, which indicated these processes were likely impaired. In vitro verification with hepatocyte models confirmed albumin expression was diminished by Met deficiency. Additionally, in abdominal fat, dietary Met deficiency increased adipocyte diameter and area (P < 0.05), and down-regulated (P < 0.05) of lipolytic genes and proteins, suggesting Met deficiency may suppress lipolysis in adipocyte. Conclusion Taken together, these data demonstrated that dietary Met deficiency in Pekin ducks resulted in stunted growth and excess fat deposition, which may be related to suppression of fatty acids transportation and hepatic catabolism. Supplementary Information The online version contains supplementary material available at 10.1186/s40104-022-00709-z.
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Affiliation(s)
- Yongbao Wu
- State Key Laboratory of Animal Nutrition, Key Laboratory of Animal (Poultry) Genetics Breeding and Reproduction, Ministry of Agriculture and Rural Affairs, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing, 100193, China.,Key Laboratory of Feed Biotechnology of Ministry of Agriculture and Rural Affairs, Institute of Feed Research, Chinese Academy of Agricultural Sciences, Beijing, 100081, China
| | - Jing Tang
- State Key Laboratory of Animal Nutrition, Key Laboratory of Animal (Poultry) Genetics Breeding and Reproduction, Ministry of Agriculture and Rural Affairs, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing, 100193, China
| | - Zhiguo Wen
- Key Laboratory of Feed Biotechnology of Ministry of Agriculture and Rural Affairs, Institute of Feed Research, Chinese Academy of Agricultural Sciences, Beijing, 100081, China.
| | - Bo Zhang
- State Key Laboratory of Animal Nutrition, Key Laboratory of Animal (Poultry) Genetics Breeding and Reproduction, Ministry of Agriculture and Rural Affairs, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing, 100193, China
| | - Junting Cao
- State Key Laboratory of Animal Nutrition, Key Laboratory of Animal (Poultry) Genetics Breeding and Reproduction, Ministry of Agriculture and Rural Affairs, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing, 100193, China.,Key Laboratory of Feed Biotechnology of Ministry of Agriculture and Rural Affairs, Institute of Feed Research, Chinese Academy of Agricultural Sciences, Beijing, 100081, China
| | - Lulu Zhao
- Key Laboratory of Feed Biotechnology of Ministry of Agriculture and Rural Affairs, Institute of Feed Research, Chinese Academy of Agricultural Sciences, Beijing, 100081, China
| | - Zhanbao Guo
- State Key Laboratory of Animal Nutrition, Key Laboratory of Animal (Poultry) Genetics Breeding and Reproduction, Ministry of Agriculture and Rural Affairs, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing, 100193, China
| | - Ming Xie
- State Key Laboratory of Animal Nutrition, Key Laboratory of Animal (Poultry) Genetics Breeding and Reproduction, Ministry of Agriculture and Rural Affairs, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing, 100193, China
| | - Zhengkui Zhou
- State Key Laboratory of Animal Nutrition, Key Laboratory of Animal (Poultry) Genetics Breeding and Reproduction, Ministry of Agriculture and Rural Affairs, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing, 100193, China
| | - Shuisheng Hou
- State Key Laboratory of Animal Nutrition, Key Laboratory of Animal (Poultry) Genetics Breeding and Reproduction, Ministry of Agriculture and Rural Affairs, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing, 100193, China.
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Malila Y, Sanpinit P, Thongda W, Jandamook A, Srimarut Y, Phasuk Y, Kunhareang S. Influences of Thermal Stress During Three Weeks Before Market Age on Histology and Expression of Genes Associated With Adipose Infiltration and Inflammation in Commercial Broilers, Native Chickens, and Crossbreeds. Front Physiol 2022; 13:858735. [PMID: 35492598 PMCID: PMC9039046 DOI: 10.3389/fphys.2022.858735] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2022] [Accepted: 03/15/2022] [Indexed: 11/13/2022] Open
Abstract
The objectives of this study were to examine the effects of cyclic thermal stress on histological characteristics of breast muscle and gene expression regarding adipose infiltration and inflammation in breast muscles collected from different breeds of chickens. The birds, from commercial broilers (CB, Ross 308, 3 weeks), native (NT, 100% Thai native Chee, 9 weeks), H75 (crossbred; 75% broiler and 25% NT, 5 weeks), and H50 (crossbred; 50% broiler and 50% NT, 7 weeks), were equally assigned into control or treatment groups. The control samples were reared under a constant temperature of 26 ± 1°C, while the treatment groups were exposed to 35 ± 1°C (6 h per day). After a 20-day thermal challenge, 12 male birds per treatment group were randomly collected for determination of live body weight, breast weight, numbers of growth-related myopathies, and breast meat chemical composition. Histological lesions were evaluated in the pectoralis major muscle immediately collected within 20 min postmortem based on hematoxylin and eosin staining. The results indicated that despite interaction between thermal stress and breed effects, thermal challenge significantly reduced feed intake, live body weight, and breast weight of the birds and increased moisture content in breast meat (p < 0.05). An interaction between the two main factors was found for protein content (p < 0.05) for which control CB showed less protein than the other groups. Heat stress decreased histological scores for adipose infiltration in CB (p < 0.05), but it did not significantly influence such scores in the other groups. CB received histological scores for adipose tissue at greater extent than those for the other groups. Differential absolute abundance of CD36, FABP4, LITAF, PDGFRA, PLIN1, PPARG, POSTN, SCD1, and TGFB1 in the muscle samples well-agreed with the trend of histological scores, suggesting potential involvement of dysregulated fibro-adipogenic progenitors together with imbalanced lipid storage and utilization in the breast muscle. The findings demonstrated that the cyclic thermal challenge restricted growth performance and breast mass of the birds, but such effects attenuated infiltration of adipose tissue and inflammatory cells in the CB breast muscle.
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Affiliation(s)
- Yuwares Malila
- National Center for Genetic Engineering and Biotechnology (BIOTEC), Thailand Science Park, Pathum Thani, Thailand
- *Correspondence: Yuwares Malila,
| | - Pornnicha Sanpinit
- National Center for Genetic Engineering and Biotechnology (BIOTEC), Thailand Science Park, Pathum Thani, Thailand
| | - Wilawan Thongda
- National Center for Genetic Engineering and Biotechnology (BIOTEC), Thailand Science Park, Pathum Thani, Thailand
- Center of Excellence for Shrimp Molecular Biology and Biotechnology (CENTEX Shrimp), Faculty of Science, Mahidol University, Bangkok, Thailand
| | - Anuwat Jandamook
- Department of Animal Science, Faculty of Agriculture, Khon Kaen University, Khon Kaen, Thailand
| | - Yanee Srimarut
- National Center for Genetic Engineering and Biotechnology (BIOTEC), Thailand Science Park, Pathum Thani, Thailand
| | - Yupin Phasuk
- Department of Animal Science, Faculty of Agriculture, Khon Kaen University, Khon Kaen, Thailand
| | - Sajee Kunhareang
- Department of Animal Science, Faculty of Agriculture, Khon Kaen University, Khon Kaen, Thailand
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22
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Li F, Hu G, Long X, Cao Y, Li Q, Guo W, Wang J, Liu J, Fu S. Stearic Acid Activates the PI3K-mTOR-4EBP1/S6K and mTOR-SREBP-1 Signaling Axes through FATP4-CDK1 To Promote Milk Synthesis in Primary Bovine Mammary Epithelial Cells. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2022; 70:4007-4018. [PMID: 35333520 DOI: 10.1021/acs.jafc.2c00208] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/14/2023]
Abstract
Stearic acid (SA), an 18-carbon long-chain saturated fatty acid, has great potential for promoting lactation. Therefore, this study investigates the effects and mechanism of SA on milk synthesis in primary bovine mammary epithelial cells (BMECs). In our study, we found that SA significantly increased β-casein and triglycerides, and the effect was most significant at 100 μM. Signaling pathway studies have found that SA affects milk synthesis by upregulating cyclin-dependent kinase 1 (CDK1) to activate PI3K-mTOR-4EBP1/S6K and mTOR-SREBP-1 pathways. Furthermore, we detected fatty acid transport proteins (FATPs) when BMECs were treated with SA; the mRNA levels of FATP3 (3.713 ± 0.583) and FATP4 (40.815 ± 8.959) were significantly upregulated at 100 μM. Subsequently, we constructed FATP4-siRNA and found that SA was transported by FATP4 into BMECs, promoting milk synthesis. Collectively, these results revealed that SA activated PI3K-mTOR-4EBP1/S6K and mTOR-SREBP-1 signaling axes through FATP4-CDK1 to promote milk synthesis in BMECs.
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Affiliation(s)
- Feng Li
- College of Veterinary Medicine, Jilin University, Changchun 130062, China
| | - Guiqiu Hu
- College of Veterinary Medicine, Jilin University, Changchun 130062, China
| | - Xiaoyu Long
- College of Veterinary Medicine, Jilin University, Changchun 130062, China
| | - Yu Cao
- College of Veterinary Medicine, Jilin University, Changchun 130062, China
| | - Qianqian Li
- College of Veterinary Medicine, Jilin University, Changchun 130062, China
| | - Wenjin Guo
- College of Veterinary Medicine, Jilin University, Changchun 130062, China
| | - Jiaxin Wang
- College of Veterinary Medicine, Jilin University, Changchun 130062, China
| | - Juxiong Liu
- College of Veterinary Medicine, Jilin University, Changchun 130062, China
| | - Shoupeng Fu
- College of Veterinary Medicine, Jilin University, Changchun 130062, China
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23
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Ibeagha-Awemu EM, Bissonnette N, Bhattarai S, Wang M, Dudemaine PL, McKay S, Zhao X. Whole Genome Methylation Analysis Reveals Role of DNA Methylation in Cow's Ileal and Ileal Lymph Node Responses to Mycobacterium avium subsp. paratuberculosis Infection. Front Genet 2021; 12:797490. [PMID: 34992636 PMCID: PMC8724574 DOI: 10.3389/fgene.2021.797490] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Accepted: 11/22/2021] [Indexed: 12/27/2022] Open
Abstract
Johne's Disease (JD), caused by Mycobacterium avium subsp paratuberculosis (MAP), is an incurable disease of ruminants and other animal species and is characterized by an imbalance of gut immunity. The role of MAP infection on the epigenetic modeling of gut immunity during the progression of JD is still unknown. This study investigated the DNA methylation patterns in ileal (IL) and ileal lymph node (ILLN) tissues from cows diagnosed with persistent subclinical MAP infection over a one to 4 years period. DNA samples from IL and ILLN tissues from cows negative (MAPneg) (n = 3) or positive for MAP infection (MAPinf) (n = 4) were subjected to whole genome bisulfite sequencing. A total of 11,263 and 62,459 differentially methylated cytosines (DMCs), and 1259 and 8086 differentially methylated regions (DMRs) (FDR<0.1) were found between MAPinf and MAPneg IL and ILLN tissues, respectively. The DMRs were found on 394 genes (denoted DMR genes) in the IL and on 1305 genes in the ILLN. DMR genes with hypermethylated promoters/5'UTR [3 (IL) and 88 (ILLN)] or hypomethylated promoters/5'UTR [10 (IL) and 25 (ILLN)] and having multiple functions including response to stimulus/immune response (BLK, BTC, CCL21, AVPR1A, CHRNG, GABRA4, TDGF1), cellular processes (H2AC20, TEX101, GLA, NCKAP5L, RBM27, SLC18A1, H2AC20BARHL2, NLGN3, SUV39H1, GABRA4, PPA1, UBE2D2) and metabolic processes (GSTO2, H2AC20, SUV39H1, PPA1, UBE2D2) are potential DNA methylation candidate genes of MAP infection. The ILLN DMR genes were enriched for more biological process (BP) gene ontology (GO) terms (n = 374), most of which were related to cellular processes (27.6%), biological regulation (16.6%), metabolic processes (15.4%) and response to stimulus/immune response (8.2%) compared to 75 BP GO terms (related to cellular processes, metabolic processes and transport, and system development) enriched for IL DMR genes. ILLN DMR genes were enriched for more pathways (n = 47) including 13 disease pathways compared with 36 enriched pathways, including 7 disease/immune pathways for IL DMR genes. In conclusion, the results show tissue specific responses to MAP infection with more epigenetic changes (DMCs and DMRs) in the ILLN than in the IL tissue, suggesting that the ILLN and immune processes were more responsive to regulation by methylation of DNA relative to IL tissue. Our data is the first to demonstrate a potential role for DNA methylation in the pathogenesis of MAP infection in dairy cattle.
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Affiliation(s)
- Eveline M. Ibeagha-Awemu
- Sherbrooke Research and Development Centre, Agriculture and Agri-Food Canada, Sherbrooke, QC, Canada
| | - Nathalie Bissonnette
- Sherbrooke Research and Development Centre, Agriculture and Agri-Food Canada, Sherbrooke, QC, Canada
| | - Suraj Bhattarai
- Department of Animal and Veterinary Sciences, University of Vermont, Burlington, VT, United States
| | - Mengqi Wang
- Sherbrooke Research and Development Centre, Agriculture and Agri-Food Canada, Sherbrooke, QC, Canada
| | - Pier-Luc Dudemaine
- Sherbrooke Research and Development Centre, Agriculture and Agri-Food Canada, Sherbrooke, QC, Canada
| | - Stephanie McKay
- Department of Animal and Veterinary Sciences, University of Vermont, Burlington, VT, United States
| | - Xin Zhao
- Department of Animal Science, McGill University, Ste-Anne-Be-Bellevue, QC, Canada
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24
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Xu E, Chen C, Fu J, Zhu L, Shu J, Jin M, Wang Y, Zong X. Dietary fatty acids in gut health: Absorption, metabolism and function. ANIMAL NUTRITION (ZHONGGUO XU MU SHOU YI XUE HUI) 2021; 7:1337-1344. [PMID: 34786506 PMCID: PMC8570925 DOI: 10.1016/j.aninu.2021.09.010] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/08/2020] [Revised: 09/17/2021] [Accepted: 09/26/2021] [Indexed: 12/23/2022]
Abstract
In biological responses, fatty acids (FA) are absorbed and metabolized in the form of substrates for energy production. The molecular structures (number of double bonds and chain length) and composition of dietary FA impact digestion, absorption and metabolism, and the biological roles of FA. Recently, increasing evidence indicates that FA are essentially utilized as an energy source and are signaling molecules that exert physiological activity of gut microbiota and immune responses. In addition, FA could serve as natural ligands for orphan G protein-coupled receptors (GPCR), also called free fatty acid receptors (FFAR), which intertwine metabolic and immune systems via multiple mechanisms. The present review explores the recent findings on FA absorption and its impact on gut health, particularly addressing the mechanism by which dietary FA potentially influences intestinal microbiota and epithelial functions. Also, this work attempts to uncover research ideas for devising future strategies for manipulating the composition of dietary FA to regulate gut health and support a normal immune system for metabolic and immune disorders.
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Affiliation(s)
- E. Xu
- Key Laboratory of Animal Genetics, Breeding and Reproduction in the Plateau Mountainous Region, Ministry of Education, College of Aniaml Science, Guizhou University, 550025 Guiyang, China
| | - Chao Chen
- Key Laboratory of Animal Genetics, Breeding and Reproduction in the Plateau Mountainous Region, Ministry of Education, College of Aniaml Science, Guizhou University, 550025 Guiyang, China
| | - Jie Fu
- Key Laboratory of Molecular Animal Nutrition, Ministry of Education, College of Animal Sciences, Zhejiang University, 310058 Hangzhou, China
| | - Luoyi Zhu
- Key Laboratory of Molecular Animal Nutrition, Ministry of Education, College of Animal Sciences, Zhejiang University, 310058 Hangzhou, China
| | - Junlan Shu
- Key Laboratory of Animal Genetics, Breeding and Reproduction in the Plateau Mountainous Region, Ministry of Education, College of Aniaml Science, Guizhou University, 550025 Guiyang, China
| | - Mingliang Jin
- Key Laboratory of Molecular Animal Nutrition, Ministry of Education, College of Animal Sciences, Zhejiang University, 310058 Hangzhou, China
- Key Laboratory of Animal Nutrition and Feed Science in Eastern China, Ministry of Agriculture, College of Animal Sciences, Zhejiang University, 310058 Hangzhou, China
| | - Yizhen Wang
- Key Laboratory of Molecular Animal Nutrition, Ministry of Education, College of Animal Sciences, Zhejiang University, 310058 Hangzhou, China
- Key Laboratory of Animal Nutrition and Feed Science in Eastern China, Ministry of Agriculture, College of Animal Sciences, Zhejiang University, 310058 Hangzhou, China
| | - Xin Zong
- Key Laboratory of Molecular Animal Nutrition, Ministry of Education, College of Animal Sciences, Zhejiang University, 310058 Hangzhou, China
- Key Laboratory of Animal Nutrition and Feed Science in Eastern China, Ministry of Agriculture, College of Animal Sciences, Zhejiang University, 310058 Hangzhou, China
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25
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Roles of IκB kinases and TANK-binding kinase 1 in hepatic lipid metabolism and nonalcoholic fatty liver disease. Exp Mol Med 2021; 53:1697-1705. [PMID: 34848839 PMCID: PMC8639992 DOI: 10.1038/s12276-021-00712-w] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Revised: 08/31/2021] [Accepted: 09/07/2021] [Indexed: 02/06/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease and is strongly associated with obesity-related ectopic fat accumulation in the liver. Hepatic lipid accumulation encompasses a histological spectrum ranging from simple steatosis to nonalcoholic steatohepatitis (NASH), which can progress to cirrhosis and hepatocellular carcinoma. Given that dysregulated hepatic lipid metabolism may be an onset factor in NAFLD, understanding how hepatic lipid metabolism is modulated in healthy subjects and which steps are dysregulated in NAFLD subjects is crucial to identify effective therapeutic targets. Additionally, hepatic inflammation is involved in chronic hepatocyte damage during NAFLD progression. As a key immune signaling hub that mediates NF-κB activation, the IκB kinase (IKK) complex, including IKKα, IKKβ, and IKKγ (NEMO), has been studied as a crucial regulator of the hepatic inflammatory response and hepatocyte survival. Notably, TANK-binding kinase 1 (TBK1), an IKK-related kinase, has recently been revealed as a potential link between hepatic inflammation and energy metabolism. Here, we review (1) the biochemical steps of hepatic lipid metabolism; (2) dysregulated lipid metabolism in obesity and NAFLD; and (3) the roles of IKKs and TBK1 in obesity and NAFLD.
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26
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Wang MD, Wang NY, Zhang HL, Sun LY, Xu QR, Liang L, Li C, Huang DS, Zhu H, Yang T. Fatty acid transport protein-5 (FATP5) deficiency enhances hepatocellular carcinoma progression and metastasis by reprogramming cellular energy metabolism and regulating the AMPK-mTOR signaling pathway. Oncogenesis 2021; 10:74. [PMID: 34772914 PMCID: PMC8589992 DOI: 10.1038/s41389-021-00364-5] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2021] [Revised: 09/22/2021] [Accepted: 10/11/2021] [Indexed: 12/11/2022] Open
Abstract
Aberrant lipid metabolism is an essential feature of hepatocellular carcinoma (HCC). Fatty acid transport protein-5 (FATP5) is highly expressed in the liver and is involved in the fatty acid transport pathway. However, the potential role of FATP5 in the pathogenesis of HCC remains largely unknown. Herein, we showed that FATP5 was downregulated in HCC tissues and even much lower in vascular tumor thrombi. Low expression of FATP5 was correlated with multiple aggressive and invasive clinicopathological characteristics and contributed to tumor metastasis and a poor prognosis in HCC patients. FATP5 inhibited the epithelial-mesenchymal transition (EMT) process and suppressed HCC cell migration and invasion, while silencing FATP5 had the opposite effects. Mechanistically, knockdown of FATP5 promoted cellular glycolytic flux and ATP production, thus suppressing AMP-activated protein kinase (AMPK) and activating its downstream signaling mammalian target of rapamycin (mTOR) to support HCC progression and metastasis. Activation of AMPK using metformin reversed the EMT program and impaired the metastatic capacity of FATP5-depleted HCC cells. Collectively, FATP5 served as a novel suppressor of HCC progression and metastasis partly by regulating the AMPK/mTOR pathway in HCC, and targeting the FATP5-AMPK axis may be a promising therapeutic strategy for personalized HCC treatment.
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Affiliation(s)
- Ming-Da Wang
- Department of Hepatobiliary Pancreatic and Minimal Invasive Surgery, Zhejiang Provincial People's Hospital (People's Hospital of Hangzhou Medical College), Hangzhou, Zhejiang, China
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University (Navy Medical University), Shanghai, China
| | - Nan-Ya Wang
- The Cancer Center, the First Hospital of Jilin University, Changchun, Jilin, China
| | - Hui-Lu Zhang
- Department of Digestive Diseases, Huashan Hospital, Fudan University, Shanghai, China
| | - Li-Yang Sun
- Department of Hepatobiliary Pancreatic and Minimal Invasive Surgery, Zhejiang Provincial People's Hospital (People's Hospital of Hangzhou Medical College), Hangzhou, Zhejiang, China
| | - Qiu-Ran Xu
- Department of Hepatobiliary Pancreatic and Minimal Invasive Surgery, Zhejiang Provincial People's Hospital (People's Hospital of Hangzhou Medical College), Hangzhou, Zhejiang, China
- School of Clinical Medicine, Hangzhou Medical College, Hangzhou, China
| | - Lei Liang
- Department of Hepatobiliary Pancreatic and Minimal Invasive Surgery, Zhejiang Provincial People's Hospital (People's Hospital of Hangzhou Medical College), Hangzhou, Zhejiang, China
| | - Chao Li
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University (Navy Medical University), Shanghai, China
| | - Dong-Sheng Huang
- Department of Hepatobiliary Pancreatic and Minimal Invasive Surgery, Zhejiang Provincial People's Hospital (People's Hospital of Hangzhou Medical College), Hangzhou, Zhejiang, China.
- School of Clinical Medicine, Hangzhou Medical College, Hangzhou, China.
| | - Hong Zhu
- Department of Medical Oncology, the First Affiliated Hospital of Soochow University, Suzhou, China.
| | - Tian Yang
- Department of Hepatobiliary Pancreatic and Minimal Invasive Surgery, Zhejiang Provincial People's Hospital (People's Hospital of Hangzhou Medical College), Hangzhou, Zhejiang, China.
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University (Navy Medical University), Shanghai, China.
- School of Clinical Medicine, Hangzhou Medical College, Hangzhou, China.
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27
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Dietary Nano-ZnO Is Absorbed via Endocytosis and ZIP Pathways, Upregulates Lipogenesis, and Induces Lipotoxicity in the Intestine of Yellow Catfish. Int J Mol Sci 2021; 22:ijms222112047. [PMID: 34769475 PMCID: PMC8584588 DOI: 10.3390/ijms222112047] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2021] [Revised: 10/25/2021] [Accepted: 11/03/2021] [Indexed: 12/14/2022] Open
Abstract
Nano-sized zinc oxide (nano-ZnO) affects lipid deposition, but its absorption patterns and mechanisms affecting lipid metabolism are still unclear. This study was undertaken to investigate the molecular mechanism of nano-ZnO absorption and its effects on lipid metabolism in the intestinal tissues of a widely distributed freshwater teleost yellow catfish Pelteobagrus fulvidraco. We found that 100 mg/kg dietary nano-ZnO (H-Zn group) significantly increased intestinal Zn contents. The zip6 and zip10 mRNA expression levels were higher in the H-Zn group than those in the control (0 mg/kg nano-ZnO), and zip4 mRNA abundances were higher in the control than those in the L-Zn (50 mg/kg nano-ZnO) and H-Zn groups. Eps15, dynamin1, dynamin2, caveolin1, and caveolin2 mRNA expression levels tended to reduce with dietary nano-ZnO addition. Dietary nano-ZnO increased triglyceride (TG) content and the activities of the lipogenic enzymes glucose 6-phosphate dehydrogenase (G6PD), 6-phosphogluconate dehydrogenase (6PGD), and isocitrate dehydrogenase (ICDH), upregulated the mRNA abundances of lipogenic genes 6pgd, fatty acid synthase (fas), and sterol regulatory element binding protein 1 (srebp1), and reduced the mRNA expression of farnesoid X receptor (fxr) and small heterodimer partner (shp). The SHP protein level in the H-Zn group was lower than that in the control and the L-Zn group markedly. Our in vitro study indicated that the intestinal epithelial cells (IECs) absorbed nano-ZnO via endocytosis, and nano-Zn-induced TG deposition and lipogenesis were partially attributable to the endocytosis of nano-ZnO in IECs. Mechanistically, nano-ZnO-induced TG deposition was closely related to the metal responsive transcription factor 1 (MTF-1)-SHP pathway. Thus, for the first time, we found that the lipogenesis effects of nano-ZnO probably depended on the key gene shp, which is potentially regulated by MTF1 and/or FXR. This novel signaling pathway of MTF-1 through SHP may be relevant to explain the toxic effects and lipotoxicity ascribed to dietary nano-ZnO addition.
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28
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George J, Zhang Y, Sloan J, Sims JM, Imig JD, Zhao X. Tim-1 Deficiency Aggravates High-Fat Diet-Induced Steatohepatitis in Mice. Front Immunol 2021; 12:747794. [PMID: 34675931 PMCID: PMC8523998 DOI: 10.3389/fimmu.2021.747794] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Accepted: 09/16/2021] [Indexed: 11/08/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH) is commonly associated with obesity and characterized by excessive lipid accumulation and liver inflammation. The T cell immunoglobulin and mucin domain 1 (Tim-1), also known as hepatitis A virus cellular receptor 1 (Havcr-1) and kidney injury molecule 1 (Kim-1), has been shown to affect innate immunity-driven proinflammatory cascade in liver ischemia-reperfusion injury. However, its contribution to obesity-related NAFLD/NASH remains unknown. Thus, this study was designed to evaluate the role of Tim-1 in obesity-related liver inflammation and injury in wild-type (WT) and Tim-1-deficient (Tim-1-/-) C57BL/6J mice fed a high-fat diet (HFD) for 5-6 months. HFD feeding induced steatosis and upregulated Tim-1 gene expression in the liver of WT mice. Surprisingly, Tim-1-/- mice on HFD diet exhibited an exacerbation of hepatic steatosis, accompanied with an elevation of protein levels of fatty acid translocase CD36 and sterol regulatory element binding protein 1 (SREBP1). Tim-1 deficiency also enhanced HFD-induced liver inflammation and injury, as evidenced by augmented increase in hepatic expression of pro-inflammatory factor lipocalin 2 and elevated serum alanine transaminase (ALT). In addition, gene expression of type I, III and IV collagens and liver fibrosis were greatly enhanced in HFD Tim-1-/- mice compared with HFD WT mice. HFD-induced hepatic expression of YM-1, a specific mouse M2 macrophage marker, was further upregulated by deletion of Tim-1. Together, these results show that Tim-1 deficiency aggravates the effects of HFD diet on lipid accumulation and liver fibrosis, most likely through enhanced infiltration and activation of inflammatory cells.
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Affiliation(s)
- Jasmine George
- Department of Physiology, Morehouse School of Medicine, Atlanta, GA, United States
| | - Yuanyuan Zhang
- Department of Physiology, Morehouse School of Medicine, Atlanta, GA, United States
| | - Jacob Sloan
- Department of Physiology, Morehouse School of Medicine, Atlanta, GA, United States
| | - Joya M Sims
- Department of Physiology, Morehouse School of Medicine, Atlanta, GA, United States
| | - John D Imig
- Drug Discovery Center, Medical College of Wisconsin, Milwaukee, WI, United States
| | - Xueying Zhao
- Department of Physiology, Morehouse School of Medicine, Atlanta, GA, United States
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29
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Lu W, Xiao W, Xie W, Fu X, Pan L, Jin H, Yu Y, Zhang Y, Li Y. The Role of Osteokines in Sarcopenia: Therapeutic Directions and Application Prospects. Front Cell Dev Biol 2021; 9:735374. [PMID: 34650980 PMCID: PMC8505767 DOI: 10.3389/fcell.2021.735374] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Accepted: 09/07/2021] [Indexed: 12/14/2022] Open
Abstract
Sarcopenia is an age-related disease in which muscle mass, strength and function may decline with age or can be secondary to cachexia or malnutrition and can lead to weakness, falls and even death. With the increase in life expectancy, sarcopenia has become a major threat to the health of the elderly. Currently, our understanding of bone-muscle interactions is not limited to their mechanical coupling. Bone and muscle have been identified as secretory endocrine organs, and their interaction may affect the function of each. Both muscle-derived factors and osteokines can play a role in regulating muscle and bone metabolism via autocrine, paracrine and endocrine mechanisms. Herein, we comprehensively summarize the latest research progress on the effects of the osteokines FGF-23, IGF-1, RANKL and osteocalcin on muscle to explore whether these cytokines can be utilized to treat and prevent sarcopenia.
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Affiliation(s)
- Wenhao Lu
- Department of Orthopaedics, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Wenfeng Xiao
- Department of Orthopaedics, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Wenqing Xie
- Department of Orthopaedics, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Xin Fu
- Xiangya School of Medicine, Central South University, Changsha, China
| | - Linyuan Pan
- Department of Orthopaedics, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Hongfu Jin
- Department of Orthopaedics, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Yongle Yu
- Xiangya School of Medicine, Central South University, Changsha, China
| | - Yi Zhang
- Department of Orthopaedics, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Yusheng Li
- Department of Orthopaedics, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
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30
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Yoon H, Shaw JL, Haigis MC, Greka A. Lipid metabolism in sickness and in health: Emerging regulators of lipotoxicity. Mol Cell 2021; 81:3708-3730. [PMID: 34547235 PMCID: PMC8620413 DOI: 10.1016/j.molcel.2021.08.027] [Citation(s) in RCA: 238] [Impact Index Per Article: 59.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Revised: 08/10/2021] [Accepted: 08/19/2021] [Indexed: 12/12/2022]
Abstract
Lipids play crucial roles in signal transduction, contribute to the structural integrity of cellular membranes, and regulate energy metabolism. Questions remain as to which lipid species maintain metabolic homeostasis and which disrupt essential cellular functions, leading to metabolic disorders. Here, we discuss recent advances in understanding lipid metabolism with a focus on catabolism, synthesis, and signaling. Technical advances, including functional genomics, metabolomics, lipidomics, lipid-protein interaction maps, and advances in mass spectrometry, have uncovered new ways to prioritize molecular mechanisms mediating lipid function. By reviewing what is known about the distinct effects of specific lipid species in physiological pathways, we provide a framework for understanding newly identified targets regulating lipid homeostasis with implications for ameliorating metabolic diseases.
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Affiliation(s)
- Haejin Yoon
- Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA; Ludwig Center for Cancer Research at Harvard, Boston, MA 02115, USA
| | - Jillian L Shaw
- Kidney Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
| | - Marcia C Haigis
- Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA; Ludwig Center for Cancer Research at Harvard, Boston, MA 02115, USA.
| | - Anna Greka
- Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA; Kidney Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
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Lv X, Gao F, Li TP, Xue P, Wang X, Wan M, Hu B, Chen H, Jain A, Shao Z, Cao X. Skeleton interoception regulates bone and fat metabolism through hypothalamic neuroendocrine NPY. eLife 2021; 10:e70324. [PMID: 34468315 PMCID: PMC8439655 DOI: 10.7554/elife.70324] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2021] [Accepted: 05/21/2021] [Indexed: 01/04/2023] Open
Abstract
The central nervous system regulates activity of peripheral organs through interoception. In our previous study, we have demonstrated that PGE2/EP4 skeleton interception regulate bone homeostasis. Here, we show that ascending skeleton interoceptive signaling downregulates expression of hypothalamic neuropeptide Y (NPY) and induce lipolysis of adipose tissue for osteoblastic bone formation. Specifically, the ascending skeleton interoceptive signaling induces expression of small heterodimer partner-interacting leucine zipper protein (SMILE) in the hypothalamus. SMILE binds to pCREB as a transcriptional heterodimer on Npy promoters to inhibit NPY expression. Knockout of EP4 in sensory nerve increases expression of NPY causing bone catabolism and fat anabolism. Importantly, inhibition of NPY Y1 receptor (Y1R) accelerated oxidation of free fatty acids in osteoblasts and rescued bone loss in AvilCre:Ptger4fl/fl mice. Thus, downregulation of hypothalamic NPY expression lipolyzes free fatty acids for anabolic bone formation through a neuroendocrine descending interoceptive regulation.
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Affiliation(s)
- Xiao Lv
- Department of Orthopaedic Surgery, Institute of Cell Engineering, and Department of Biomedical Engineering, The Johns Hopkins UniversityBaltimoreUnited States
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyWuhanChina
| | - Feng Gao
- Department of Orthopaedic Surgery, Institute of Cell Engineering, and Department of Biomedical Engineering, The Johns Hopkins UniversityBaltimoreUnited States
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyWuhanChina
| | - Tuo Peter Li
- Department of Orthopaedic Surgery, Institute of Cell Engineering, and Department of Biomedical Engineering, The Johns Hopkins UniversityBaltimoreUnited States
| | - Peng Xue
- Department of Orthopaedic Surgery, Institute of Cell Engineering, and Department of Biomedical Engineering, The Johns Hopkins UniversityBaltimoreUnited States
| | - Xiao Wang
- Department of Orthopaedic Surgery, Institute of Cell Engineering, and Department of Biomedical Engineering, The Johns Hopkins UniversityBaltimoreUnited States
| | - Mei Wan
- Department of Orthopaedic Surgery, Institute of Cell Engineering, and Department of Biomedical Engineering, The Johns Hopkins UniversityBaltimoreUnited States
| | - Bo Hu
- Department of Orthopaedic Surgery, Institute of Cell Engineering, and Department of Biomedical Engineering, The Johns Hopkins UniversityBaltimoreUnited States
| | - Hao Chen
- Department of Orthopaedic Surgery, Institute of Cell Engineering, and Department of Biomedical Engineering, The Johns Hopkins UniversityBaltimoreUnited States
| | - Amit Jain
- Department of Orthopaedic Surgery, Institute of Cell Engineering, and Department of Biomedical Engineering, The Johns Hopkins UniversityBaltimoreUnited States
| | - Zengwu Shao
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyWuhanChina
| | - Xu Cao
- Department of Orthopaedic Surgery, Institute of Cell Engineering, and Department of Biomedical Engineering, The Johns Hopkins UniversityBaltimoreUnited States
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Fatty acids and evolving roles of their proteins in neurological, cardiovascular disorders and cancers. Prog Lipid Res 2021; 83:101116. [PMID: 34293403 DOI: 10.1016/j.plipres.2021.101116] [Citation(s) in RCA: 57] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2021] [Revised: 07/04/2021] [Accepted: 07/14/2021] [Indexed: 01/03/2023]
Abstract
The dysregulation of fat metabolism is involved in various disorders, including neurodegenerative, cardiovascular, and cancers. The uptake of long-chain fatty acids (LCFAs) with 14 or more carbons plays a pivotal role in cellular metabolic homeostasis. Therefore, the uptake and metabolism of LCFAs must constantly be in tune with the cellular, metabolic, and structural requirements of cells. Many metabolic diseases are thought to be driven by the abnormal flow of fatty acids either from the dietary origin and/or released from adipose stores. Cellular uptake and intracellular trafficking of fatty acids are facilitated ubiquitously with unique combinations of fatty acid transport proteins and cytoplasmic fatty acid-binding proteins in every tissue. Extensive data are emerging on the defective transporters and metabolism of LCFAs and their clinical implications. Uptake and metabolism of LCFAs are crucial for the brain's functional development and cardiovascular health and maintenance. In addition, data suggest fatty acid metabolic transporter can normalize activated inflammatory response by reprogramming lipid metabolism in cancers. Here we review the current understanding of how LCFAs and their proteins contribute to the pathophysiology of three crucial diseases and the mechanisms involved in the processes.
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Alves Castilho P, Bracht L, Barros L, Albuquerque BR, Dias MI, Ferreira ICFR, Comar JF, Barlati Vieira da Silva T, Peralta RM, Sá-Nakanishi ABD, Bracht A. Effects of a Myrciaria jaboticaba peel extract on starch and triglyceride absorption and the role of cyanidin-3-O-glucoside. Food Funct 2021; 12:2644-2659. [PMID: 33645616 DOI: 10.1039/d0fo02927k] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
The purpose of this study was to perform a parallel and comparative investigation of the effects of a Myrciaria jaboticaba (common name jabuticaba) peel extract and of its constituent cyanidin-3-O-glucoside on the overall process of starch and triglyceride intestinal absorption. The peel extract inhibited both the porcine pancreactic α-amylase and the pancreatic lipase but was 13.6 times more potent on the latter (IC50 values of 1963 and 143.9 μg mL-1, respectively). Cyanidin-3-O-glucoside did not contribute significantly to these inhibitions. The jabuticaba peel extract inhibited starch absorption in mice at doses that were compatible with its inhibitory action on the α-amylase. No inhibition of starch absorption was found with cyanidin-3-O-glucoside doses compatible with its content in the extract. The extract also inhibited triglyceride absorption, but at doses that were considerably smaller than those predicted by its strength in inhibiting the pancreatic lipase (ID50 = 3.65 mg kg-1). In this case, cyanidin-3-O-glucoside was also strongly inhibitory, with 72% inhibition at the dose of 2 mg kg-1. When oleate + glycerol were given to mice, both the peel extract and cyanidin-3-O-glucoside strongly inhibited the appearance of triglycerides in the plasma. The main mechanism seems, thus, not to be the lipase inhibition but rather the inhibition of one or more steps (e.g., transport) in the events that lead to the transformation of free fatty acids in the intestinal tract into triglycerides. Due to the low active doses, the jabuticaba peel extract presents many favourable perspectives as an inhibitor of fat absorption and cyanidin-3-O-glucoside seems to play a decisive role.
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Affiliation(s)
- Pamela Alves Castilho
- Post-Graduate Program in Food Sciences, State University of Maringa, 87020-900 Maringá, Paraná, Brazil
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Chowdhury S, Schulz L, Palmisano B, Singh P, Berger JM, Yadav VK, Mera P, Ellingsgaard H, Hidalgo J, Brüning J, Karsenty G. Muscle-derived interleukin 6 increases exercise capacity by signaling in osteoblasts. J Clin Invest 2021; 130:2888-2902. [PMID: 32078586 DOI: 10.1172/jci133572] [Citation(s) in RCA: 94] [Impact Index Per Article: 23.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2019] [Accepted: 02/11/2020] [Indexed: 12/11/2022] Open
Abstract
Given the numerous health benefits of exercise, understanding how exercise capacity is regulated is a question of paramount importance. Circulating interleukin 6 (IL-6) levels surge during exercise and IL-6 favors exercise capacity. However, neither the cellular origin of circulating IL-6 during exercise nor the means by which this cytokine enhances exercise capacity has been formally established yet. Here we show through genetic means that the majority of circulating IL-6 detectable during exercise originates from muscle and that to increase exercise capacity, IL-6 must signal in osteoblasts to favor osteoclast differentiation and the release of bioactive osteocalcin in the general circulation. This explains why mice lacking the IL-6 receptor only in osteoblasts exhibit a deficit in exercise capacity of similar severity to the one seen in mice lacking muscle-derived IL-6 (mIL-6), and why this deficit is correctable by osteocalcin but not by IL-6. Furthermore, in agreement with the notion that IL-6 acts through osteocalcin, we demonstrate that mIL-6 promotes nutrient uptake and catabolism into myofibers during exercise in an osteocalcin-dependent manner. Finally, we show that the crosstalk between osteocalcin and IL-6 is conserved between rodents and humans. This study provides evidence that a muscle-bone-muscle endocrine axis is necessary to increase muscle function during exercise in rodents and humans.
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Affiliation(s)
- Subrata Chowdhury
- Department of Genetics and Development, Vagelos College of Physicians and Surgeons, Columbia University, New York, New York, USA
| | - Logan Schulz
- Department of Genetics and Development, Vagelos College of Physicians and Surgeons, Columbia University, New York, New York, USA
| | - Biagio Palmisano
- Department of Genetics and Development, Vagelos College of Physicians and Surgeons, Columbia University, New York, New York, USA
| | | | - Julian M Berger
- Department of Genetics and Development, Vagelos College of Physicians and Surgeons, Columbia University, New York, New York, USA
| | - Vijay K Yadav
- Department of Genetics and Development, Vagelos College of Physicians and Surgeons, Columbia University, New York, New York, USA.,National Institute of Immunology, New Delhi, India
| | - Paula Mera
- Department of Genetics and Development, Vagelos College of Physicians and Surgeons, Columbia University, New York, New York, USA.,Department of Biochemistry and Physiology, School of Pharmacy and Food Sciences.,Institut de Biomedicina de la Universitat de Barcelona (IBUB), Universitat de Barcelona, Barcelona, Spain.,Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y la Nutrición (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain
| | - Helga Ellingsgaard
- Centre of Inflammation and Metabolism and.,Centre for Physical Activity Research, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Juan Hidalgo
- Department of Cellular Biology, Physiology and Immunology, Faculty of Biosciences, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Jens Brüning
- Max Planck Institute for Metabolism Research, Cologne, Germany
| | - Gerard Karsenty
- Department of Genetics and Development, Vagelos College of Physicians and Surgeons, Columbia University, New York, New York, USA
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Cheng L, Zhang S, Shang F, Ning Y, Huang Z, He R, Sun J, Dong S. Emodin Improves Glucose and Lipid Metabolism Disorders in Obese Mice via Activating Brown Adipose Tissue and Inducing Browning of White Adipose Tissue. Front Endocrinol (Lausanne) 2021; 12:618037. [PMID: 34040579 PMCID: PMC8143048 DOI: 10.3389/fendo.2021.618037] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2020] [Accepted: 04/06/2021] [Indexed: 11/23/2022] Open
Abstract
BACKGROUND Adipose tissue (e.g. white, brown and brite) plays a critical role in modulating energy metabolism. Activating brown adipose tissue (BAT) and inducing browning in white adipose tissue (WAT) has been proposed to be a potential molecular target for obesity treatment. Emodin is a natural anthraquinone derivative that exhibits variety of pharmacologic effects including lowering lipids and regulating glucose utilization. However, the underlying mechanism of action is still unclear. In the present study, we investigated whether emodin could alleviate obesity via promoting browning process in adipose tissue. METHODS C57BL/6J mice were fed with high fat diet to induce obesity. Emodin at the doses of 40 and 80 mg/kg were orally given to obesity mice for consecutive 6 weeks. Parameters including fasting blood glucose, oral glucose tolerance, blood lipids, and the ratios of subcutaneous white adipose tissue (scWAT) or BAT mass to body weight, and morphology of adipose tissue were observed. Besides, the protein expression of uncoupling protein 1 (UCP1) and prohibitin in BAT and scWAT was determined by immunohistochemistry method. Relative mRNA expression of Cd137, transmembrane protein 26 (Tmem26) and Tbx1 in scWAT was analyzed using qRT-PCR. And the protein expression of UCP1, CD36, fatty acid transporter 4 (FATP4), peroxisome proliferator-activated receptor alpha (PPARα) and prohibitin of scWAT and BAT were analyzed using western blotting. In addition, ultra-high-performance liquid chromatography with electrospray ionization tandem mass spectrometry was utilized to detect the small lipid metabolites of scWAT and BAT. RESULTS Emodin decreased the body weight and food intake in HFD-induced obesity mice, and it also improved the glucose tolerance and reduced the blood lipids. Emodin treatment induced beiging of WAT, and more multilocular lipid droplets were found in scWAT. Also, emodin significantly increased markers of beige adipocytes, e.g. Cd137, Tmem26 and Tbx1 mRNA in scWAT, and UCP1, CD36, FATP4, PPARα and prohibitin protein expression in scWAT and BAT. Furthermore, emodin perturbed the lipidomic profiles in scWAT and BAT of obese mice. Emodin increased total ceramides (Cers), lysophosphatidylcholines (LPCs), lyso-phosphatidylcholines oxygen (LPCs-O), and phosphatidylethanolamines oxygen (PEs-O) species concentration in scWAT. Specifically, emodin significantly up-regulated levels of Cer (34:1), LPC (18:2), LPC-(O-20:2), PC (O-40:7), PE (O-36:3), PE (O-38:6), PE (O-40:6), and sphingolipid (41:0) [SM (41:0)], and down-regulated PC (O-38:0), PE (O-40:4), PE (O-40:5) in scWAT of obesity mice. In terms of lipid matabolites of BAT, the emodin remarkably increased the total PCs levels, which was driven by significant increase of PC (30:0), PC (32:1), PC (32:2), PC (33:4) and PC (38:0) species. In addition, it also increased species of LPCs, e.g. LPC (20:0), LPC (20:1), LPC (22:0), LPC (22:1), LPC (24:0), and LPC (24:1). Especially, emodin treatment could reverse the ratio of PC/PE in HFD-induced obese mice. CONCLUSIONS These results indicated that emodin could ameliorate adiposity and improve metabolic disorders in obese mice. Also, emodin could promote browning in scWAT and activate the BAT activities. In addition, emodin treatment-induced changes to the scWAT and BAT lipidome were highly specific to certain molecular lipid species, indicating that changes in tissue lipid content reflects selective remodeling in scWAT and BAT of both glycerophospholipids and sphingolipids in response to emodin treatment.
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Affiliation(s)
- Long Cheng
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Shuofeng Zhang
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Fei Shang
- Analytical and Testing Center, Beijing University of Chemical Technology, Beijing, China
| | - Yibo Ning
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Zhiqi Huang
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Runcheng He
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Jianning Sun
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Shifen Dong
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
- *Correspondence: Shifen Dong,
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Liu D, Pan Y, Li K, Li D, Li P, Gao Z. Proteomics Reveals the Mechanism Underlying the Inhibition of Phytophthora sojae by Propyl Gallate. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2020; 68:8151-8162. [PMID: 32633954 DOI: 10.1021/acs.jafc.0c02371] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/11/2023]
Abstract
Phytophthora sojae is a serious soil-borne pathogen, and the major control measures undertaken include the induction of soybean-resistance genes, fungicides, and scientific and reasonable planting management. Owing to the safety and resistance of fungicides, it is of great importance to screen new control alternatives. In a preliminary study, we observed that propyl gallate (PG) exerts a considerable inhibitory effect on P. sojae and can effectively prevent and cure soybean diseases, although the underlying mechanism remains unclear. To explore the inhibitory mechanism of PG on P. sojae, we analyzed the differences in the protein profile of P. sojae before and after treatment with PG using tandem mass tag (TMT) proteomics. Proteomic analysis revealed that the number of differentially expressed proteins (DEPs) was 285, of which 75 were upregulated and 210 were downregulated, and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways primarily comprised glycolysis, tricarboxylic acid cycle, fatty acid metabolism, secondary metabolite generation, and other pathways. Among the DEPs involved in PG inhibition of P. sojae are two closely related uncharacterized proteins encoded by PHYSODRAFT_522340 and PHYSODRAFT_344464, denoted PsFACL and PsCPT herein. The CRISPR/Cas9 knockout technique revealed that PsFACL and PsCPT were involved in the growth rate and pathogenicity. In addition, the results of gas chromatography-mass spectrometry (GC-MS) showed that there were differences in fatty acid levels between wild-type (WT) and CRISPR/Cas9 knockout transformants. Knocking out PsFACL and PsCPT resulted in the restriction of the synthesis and β-oxidation of long-chain fatty acids, respectively. These suggest that PsFACL and PsCPT were also involved in the regulation of the fatty acid metabolism. Our results aid in understanding the mechanism underlying the inhibition of P. sojae growth by PG.
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Affiliation(s)
- Dong Liu
- College of Plant Protection, Anhui Agricultural University, 130 West of Changjiang Road, Hefei 230036, Anhui, China
- Department of Horticulture and Landscape, Anqing Vocational and Technical College, 99 North of Tianzhushan Road, Anqing 246003, Anhui, China
| | - Yuemin Pan
- College of Plant Protection, Anhui Agricultural University, 130 West of Changjiang Road, Hefei 230036, Anhui, China
- Anhui Province Key Laboratory of Integrated Pest Management on Crops, Anhui Agricultural University, Hefei 230036, Anhui, China
- Key Laboratory of Biology and Sustainable Management of Plant Diseases and Pests of Anhui Higher Education Institutes, Anhui Agricultural University, Anqing 246003, Anhui, China
| | - Kunyuan Li
- College of Plant Protection, Anhui Agricultural University, 130 West of Changjiang Road, Hefei 230036, Anhui, China
| | - Dandan Li
- College of Plant Protection, Anhui Agricultural University, 130 West of Changjiang Road, Hefei 230036, Anhui, China
| | - Ping Li
- Department of Horticulture and Landscape, Anqing Vocational and Technical College, 99 North of Tianzhushan Road, Anqing 246003, Anhui, China
| | - Zhimou Gao
- College of Plant Protection, Anhui Agricultural University, 130 West of Changjiang Road, Hefei 230036, Anhui, China
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Jay AG, Simard JR, Huang N, Hamilton JA. SSO and other putative inhibitors of FA transport across membranes by CD36 disrupt intracellular metabolism, but do not affect FA translocation. J Lipid Res 2020; 61:790-807. [PMID: 32102800 DOI: 10.1194/jlr.ra120000648] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2020] [Revised: 02/19/2020] [Indexed: 12/19/2022] Open
Abstract
Membrane-bound proteins have been proposed to mediate the transport of long-chain FA (LCFA) transport through the plasma membrane (PM). These proposals are based largely on reports that PM transport of LCFAs can be blocked by a number of enzymes and purported inhibitors of LCFA transport. Here, using the ratiometric pH indicator (2',7'-bis-(2-carboxyethyl)-5-(and-6-)-carboxyfluorescein and acrylodated intestinal FA-binding protein-based dual fluorescence assays, we investigated the effects of nine inhibitors of the putative FA transporter protein CD36 on the binding and transmembrane movement of LCFAs. We particularly focused on sulfosuccinimidyl oleate (SSO), reported to be a competitive inhibitor of CD36-mediated LCFA transport. Using these assays in adipocytes and inhibitor-treated protein-free lipid vesicles, we demonstrate that rapid LCFA transport across model and biological membranes remains unchanged in the presence of these purported inhibitors. We have previously shown in live cells that CD36 does not accelerate the transport of unesterified LCFAs across the PM. Our present experiments indicated disruption of LCFA metabolism inside the cell within minutes upon treatment with many of the "inhibitors" previously assumed to inhibit LCFA transport across the PM. Furthermore, using confocal microscopy and a specific anti-SSO antibody, we found that numerous intracellular and PM-bound proteins are SSO-modified in addition to CD36. Our results support the hypothesis that LCFAs diffuse rapidly across biological membranes and do not require an active protein transporter for their transmembrane movement.
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Affiliation(s)
- Anthony G Jay
- Department of Physiology and Biomedical Engineering,Mayo Clinic, Rochester, MN 55905; Departments of Biochemistry,Boston University School of Medicine, Boston, MA 02118. mailto:
| | - Jeffrey R Simard
- Physiology and Biophysics,Boston University School of Medicine, Boston, MA 02118; Pharmacology and Experimental Therapeutics,Boston University School of Medicine, Boston, MA 02118
| | - Nasi Huang
- Section of Infectious Diseases Department of Medicine,Boston University School of Medicine, Boston, MA 02118
| | - James A Hamilton
- Physiology and Biophysics,Boston University School of Medicine, Boston, MA 02118
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Jeon S, Carr R. Alcohol effects on hepatic lipid metabolism. J Lipid Res 2020; 61:470-479. [PMID: 32029510 DOI: 10.1194/jlr.r119000547] [Citation(s) in RCA: 180] [Impact Index Per Article: 36.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2019] [Revised: 01/28/2020] [Indexed: 12/16/2022] Open
Abstract
Alcoholic liver disease (ALD) is the most prevalent type of chronic liver disease with significant morbidity and mortality worldwide. ALD begins with simple hepatic steatosis and progresses to alcoholic steatohepatitis, fibrosis, and cirrhosis. The severity of hepatic steatosis is highly associated with the development of later stages of ALD. This review explores the disturbances of alcohol-induced hepatic lipid metabolism through altered hepatic lipid uptake, de novo lipid synthesis, fatty acid oxidation, hepatic lipid export, and lipid droplet formation and catabolism. In addition, we review emerging data on the contributions of genetics and bioactive lipid metabolism in alcohol-induced hepatic lipid accumulation.
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Affiliation(s)
- Sookyoung Jeon
- Division of Gastroenterology, University of Pennsylvania, Philadelphia, PA
| | - Rotonya Carr
- Division of Gastroenterology, University of Pennsylvania, Philadelphia, PA
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Hepatic FATP5 expression is associated with histological progression and loss of hepatic fat in NAFLD patients. J Gastroenterol 2020; 55:227-243. [PMID: 31602526 DOI: 10.1007/s00535-019-01633-2] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2019] [Accepted: 09/19/2019] [Indexed: 02/07/2023]
Abstract
BACKGROUND Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) are characterized by the accumulation of excess hepatic fat. However, in the progression from NASH to cirrhosis, hepatic fat is often lost. Our aim was to elucidate the mechanism underlying hepatic fat loss during NASH progression. METHODS Liver biopsies were performed at The University of Tokyo Hospital between November 2011 and March 2016 on 146 patients with NAFLD and 14 patients with cryptogenic cirrhosis who were not being treated with any diabetes or dyslipidemia drugs. Among them, 70 patients underwent liver biopsy after an overnight fast, and 90 patients were biopsied 5 h after an oral glucose tolerance test. Expression differences in genes encoding several fatty acid metabolism-related factors were examined and correlated with hepatic histological changes based on NAFLD activity scores. Prospective patient follow-up continued until June 2018. RESULTS The level of fatty acid transport protein 5 (FATP5), which is associated with free fatty acid intake, was significantly and inversely correlated with features of histological progression, including ballooning and fibrosis. This was confirmed by immunohistochemical analysis. Transcript levels of genes encoding fatty acid metabolism-related proteins were comparable between NASH with severe fibrosis and cryptogenic cirrhosis. Furthermore, a prospective cohort study demonstrated that low FATP5 expression was the most significant risk factor for hepatic fat loss. CONCLUSIONS Decreased hepatic FATP5 expression in NAFLD is linked to histological progression, and may be associated with hepatic fat loss during NASH progression to cirrhosis.
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Kim J, Park J, Kim N, Park HY, Lim K. Inhibition of androgen receptor can decrease fat metabolism by decreasing carnitine palmitoyltransferase I levels in skeletal muscles of trained mice. Nutr Metab (Lond) 2019; 16:82. [PMID: 31788014 PMCID: PMC6880567 DOI: 10.1186/s12986-019-0406-z] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2019] [Accepted: 10/29/2019] [Indexed: 01/10/2023] Open
Abstract
Background Androgen hormone levels are strongly associated with obesity in adult mammals, especially with advanced age. We investigated androgen receptor inhibition on fat metabolism and long-chain fatty acid (LCFA) transport proteins in skeletal muscle during exercise. Methods Male ICR mice were randomly divided into three groups: CON (control), EX (exercise), and EXIN (exercise + androgen receptor inhibition). EX and EXIN groups were trained on a treadmill five times a week. After 4 weeks, the fat metabolism of each group was measured using open-circuit calorimetry during 1 hour of exercise. After the metabolism measurement, the expression levels of LCFA transport proteins (FAT/CD36, CPTI) were analyzed in skeletal muscle. Results Weight gain and final body weight were significantly lower in the EX group than in either the CON or EXIN groups. Conversely, food intake was significantly higher in the EX group than it was in the CON and EXIN groups. The total weight (CON; 2.07 ± 0.6, EX; 1.64 ± 0.2, EXIN; 1.95 ± 0.2) of the abdominal adipose tissue were significantly lower in the EX group than in the CON and EXIN groups (P < 0.05). However, there was no different between the CON and EXIN group. Oxygen uptake and fat oxidation during exercise tended to be lower (12%) in the EXIN group than in the EX group. Total fat oxidation in the EXIN group was significantly lower during the initial 20-min (P < 0.003) and 40-min (P < 0.041) phases compared to that in the EX group. In addition, the level of FAT/CD36 protein in the EX and EXIN groups was approximately double that in the CON group (P < 0.001, P < 0.001). CPTI expression in the EX group was higher than that in the EX group (P < 0.0069) as well as in the CON group. Conclusion Exercise training increases the expression of LCFA transport proteins (FAT/CD36, CPTI). Blocking androgen receptors can decreases the expression of CPTI in the skeletal muscle, which reduces fat metabolism. Thus, reducing sex hormones or suppressing the sensitivity of AR receptors can inhibit energy efficiency and fat metabolism by suppressing CPTI.
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Affiliation(s)
- Jisu Kim
- 1Department of Sports Medicine and Science, Konkuk University, Gwangjin-gu, Seoul Korea.,2Physical Activity and Performance Institute (PAPI), Konkuk University, Gwangjin-gu, Seoul Korea
| | - Jonghoon Park
- 3Department of Physical Education, Korea University, Seoul, Korea
| | - Nahyun Kim
- 3Department of Physical Education, Korea University, Seoul, Korea
| | - Hun-Young Park
- 1Department of Sports Medicine and Science, Konkuk University, Gwangjin-gu, Seoul Korea.,2Physical Activity and Performance Institute (PAPI), Konkuk University, Gwangjin-gu, Seoul Korea
| | - Kiwon Lim
- 1Department of Sports Medicine and Science, Konkuk University, Gwangjin-gu, Seoul Korea.,2Physical Activity and Performance Institute (PAPI), Konkuk University, Gwangjin-gu, Seoul Korea.,4Department of Physical Education, Konkuk University, Gwangjin-gu, Seoul Korea
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Masarwi M, DeSchiffart A, Ham J, Reagan MR. Multiple Myeloma and Fatty Acid Metabolism. JBMR Plus 2019; 3:e10173. [PMID: 30918920 PMCID: PMC6419611 DOI: 10.1002/jbm4.10173] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2018] [Revised: 01/03/2019] [Accepted: 01/13/2019] [Indexed: 12/12/2022] Open
Abstract
Multiple myeloma (MM) accounts for 13% to 15% of all blood cancers1 and is characterized by the proliferation of malignant cells within the bone marrow (BM). Despite important advances in treatment, most patients become refractory and relapse with the disease. As MM tumors grow in the BM, they disrupt hematopoiesis, create monoclonal protein spikes in the blood, initiate systemic organ and immune system shutdown,2 and induce painful osteolytic lesions caused by overactive osteoclasts and inhibited osteoblasts.3, 4 MM cells are also extremely dependent on the BM niche, and targeting the BM niche has been clinically transformative for inhibiting the positive-feedback "vicious cycle" between MM cells and osteoclasts that leads to bone resorption and tumor proliferation.5, 6, 7, 8 Bone marrow adipocytes (BMAs) are dynamic, secretory cells that have complex effects on osteoblasts and tumor cells, but their role in modifying the MM cell phenotype is relatively unexplored.9, 10, 11, 12, 13 Given their active endocrine function, capacity for direct cell-cell communication, correlation with aging and obesity (both MM risk factors), potential roles in bone disease, and physical proximity to MM cells, it appears that BMAs support MM cells.14, 15, 16, 17 This supposition is based on research from many laboratories, including our own. Therapeutically targeting the BMA may prove to be equally transformative in the clinic if the pathways through which BMAs affect MM cells can be determined. In this review, we discuss the potential for BMAs to provide free fatty acids to myeloma cells to support their growth and evolution. We highlight certain proteins in MM cells responsible for fatty acid uptake and oxidation and discuss the potential for therapeutically targeting fatty acid metabolism or BMAs from where they may be derived. © 2019 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.
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Affiliation(s)
- Majdi Masarwi
- Center for Molecular MedicineMaine Medical Center Research InstituteScarboroughMEUSA
| | - Abigail DeSchiffart
- Center for Molecular MedicineMaine Medical Center Research InstituteScarboroughMEUSA
| | - Justin Ham
- Center for Molecular MedicineMaine Medical Center Research InstituteScarboroughMEUSA
| | - Michaela R. Reagan
- Center for Molecular MedicineMaine Medical Center Research InstituteScarboroughMEUSA
- University of Maine Graduate School of Biomedical Science and EngineeringOronoMEUSA
- Sackler School of Graduate Biomedical SciencesTufts UniversityBostonMAUSA
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Grattagliano I, Montezinho LP, Oliveira PJ, Frühbeck G, Gómez-Ambrosi J, Montecucco F, Carbone F, Wieckowski MR, Wang DQH, Portincasa P. Targeting mitochondria to oppose the progression of nonalcoholic fatty liver disease. Biochem Pharmacol 2019; 160:34-45. [PMID: 30508523 DOI: 10.1016/j.bcp.2018.11.020] [Citation(s) in RCA: 46] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2018] [Accepted: 11/28/2018] [Indexed: 02/08/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a condition characterized by the excessive accumulation of triglycerides in hepatocytes. NAFLD is the most frequent chronic liver disease in developed countries, and is often associated with metabolic disorders such as obesity and type 2 diabetes. NAFLD definition encompasses a spectrum of chronic liver abnormalities, ranging from simple steatosis (NAFL), to steatohepatitis (NASH), significant liver fibrosis, cirrhosis, and hepatocellular carcinoma. NAFLD, therefore, represents a global public health issue. Mitochondrial dysfunction occurs in NAFLD, and contributes to the progression to the necro-inflammatory and fibrotic form (NASH). Disrupted mitochondrial function is associated with a decrease in the energy levels and impaired redox balance, and negatively affects cell survival by altering overall metabolism and subcellular trafficking. Such events reduce the tolerance of hepatocytes towards damaging hits, and favour the injurious effects of extra-cellular factors. Here, we discuss the role of mitochondria in NAFLD and focus on potential therapeutic approaches aimed at preserving mitochondrial function.
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Affiliation(s)
- Ignazio Grattagliano
- Clinica Medica "A. Murri", Department of Biomedical Sciences and Human Oncology, University of Bari Medical School, Bari, Italy; Italian College of General Practitioners and Primary Care, Bari, Italy
| | - Liliana P Montezinho
- CNC Center for Neuroscience and Cell Biology, University of Coimbra, UC-Biotech Building, Biocant Park, Cantanhede, Portugal; Center for Investigation Vasco da Gama (CIVG), Department of Veterinary Medicine, Escola Universitária Vasco da Gama, Coimbra, Portugal
| | - Paulo J Oliveira
- CNC Center for Neuroscience and Cell Biology, University of Coimbra, UC-Biotech Building, Biocant Park, Cantanhede, Portugal
| | - Gema Frühbeck
- Metabolic Research Laboratory, Clínica Universidad de Navarra, Pamplona, Spain; CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Pamplona, Spain; Obesity and Adipobiology Group, Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain; Department of Endocrinology & Nutrition, Clínica Universidad de Navarra, Pamplona, Spain
| | - Javier Gómez-Ambrosi
- Metabolic Research Laboratory, Clínica Universidad de Navarra, Pamplona, Spain; CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Pamplona, Spain; Obesity and Adipobiology Group, Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain
| | - Fabrizio Montecucco
- First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa, 6 viale Benedetto XV, 16132 Genoa, Italy; Ospedale Policlinico San Martino, 10 Largo Benzi, 16132 Genoa, Italy; Centre of Excellence for Biomedical Research (CEBR), University of Genoa, 9 Viale Benedetto XV, 16132 Genoa, Italy
| | - Federico Carbone
- First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa, 6 viale Benedetto XV, 16132 Genoa, Italy
| | | | - David Q-H Wang
- Department of Medicine, Division of Gastroenterology and Liver Diseases, Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA
| | - Piero Portincasa
- Clinica Medica "A. Murri", Department of Biomedical Sciences and Human Oncology, University of Bari Medical School, Bari, Italy.
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Duan Y, Zhang L, Li F, Guo Q, Long C, Yin Y, Kong X, Peng M, Wang W. β-Hydroxy-β-methylbutyrate modulates lipid metabolism in adipose tissues of growing pigs. Food Funct 2019; 9:4836-4846. [PMID: 30137075 DOI: 10.1039/c8fo00898a] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
BACKGROUND The effects and roles of the leucine (Leu) metabolite β-hydroxy-β-methylbutyrate (HMB) in lipid metabolism in adipose tissues of pigs are still unknown. OBJECTIVES This study was conducted to investigate the effects of excess Leu versus HMB on growth, carcass traits, and lipid metabolism in adipose tissues of growing pigs. METHODS AND RESULTS Compared to control, the Leu/HMB group significantly increased/reduced weight of total fat mass, respectively, with a concurrent increase of serum adiponectin concentration (P < 0.05). Moreover, dietary HMB supplementation regulated the expression of genes involved in adipose tissue function, accompanied by increases/decreases in the phosphorylation of AMPKα/mTOR in perirenal adipose tissue, respectively (P < 0.05). Serum IL-15 concentration and the mRNA abundance of IL-15, PGC-1α, and NRF-1 were also increased in the HMB group (P < 0.05). CONCLUSIONS HMB supplementation can regulate adipose tissue function including fatty acid oxidation, lipolysis, and adipokine secretion. These effects may be partly mediated by AMPKα-mTOR pathway and associated with mitochondrial biogenesis, the AMPK-PGC-1α axis, and myokines secreted by muscle tissues.
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Affiliation(s)
- Yehui Duan
- Hunan Provincial Key Laboratory of Animal Nutritional Physiology and Metabolic Process; Key Laboratory of Agro-ecological Processes in Subtropical Region, Institute of Subtropical Agriculture, Chinese Academy of Sciences; Hunan Provincial Engineering Research Center for Healthy Livestock and Poultry Production; Scientific Observing and Experimental Station of Animal Nutrition and Feed Science in South-Central, Ministry of Agriculture, Changsha 410125, China.
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Breher-Esch S, Sahini N, Trincone A, Wallstab C, Borlak J. Genomics of lipid-laden human hepatocyte cultures enables drug target screening for the treatment of non-alcoholic fatty liver disease. BMC Med Genomics 2018; 11:111. [PMID: 30547786 PMCID: PMC6295111 DOI: 10.1186/s12920-018-0438-7] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2018] [Accepted: 11/23/2018] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Non-alcoholic fatty liver disease (NAFLD) is a major health burden in need for new medication. To identify potential drug targets a genomic study was performed in lipid-laden primary human hepatocyte (PHH) and human hepatoma cell cultures. METHODS PHH, HuH7 and HepG2 hepatoma cell cultures were treated with lipids and/or TNFα. Intracellular lipid load was quantified with the ORO assay. The Affymetrix HG-U133+ array system was employed to perform transcriptome analysis. The lipid droplet (LD) growth and fusion was determined by fluorescence microscopy. LD associated proteins were imaged by confocal immunofluorescence microscopy and confirmed by Western immunoblotting. Bioinformatics defined perturbed metabolic pathways. RESULTS Whole genome expression profiling identified 227, 1031 and 571 significant regulated genes. Likewise, the combined lipid and TNFα treatment of PHH, HuH7 and HepG2 cell cultures revealed 154, 1238 and 278 differentially expressed genes. Although genomic responses differed among in-vitro systems, commonalities were ascertained by filtering the data for LD associated gene regulations. Among others the LD-growth and fusion associated cell death inducing DFFA like effector C (CIDEC), perilipins (PLIN2, PLIN3), the synaptosome-associated-protein 23 and the vesicle associated membrane protein 3 were strongly up-regulated. Likewise, the PPAR targets pyruvate-dehydrogenase-kinase-4 and angiopoietin-like-4 were up-regulated as was hypoxia-inducible lipid droplet-associated (HILPDA), flotilin and FGF21. Their inhibition ameliorates triglyceride and cholesterol accumulation. TNFα treatment elicited strong induction of the chemokine CXCL8, the kinases MAP3K8, MAP4K4 and negative regulators of cytokine signaling, i.e. SOCS2&SOCS3. Live cell imaging of DsRED calreticulin plasmid transfected HuH7 cells permitted an assessment of LD growth and fusion and confocal immunofluorescence microscopy evidenced induced LD-associated PLIN2, CIDEC, HIF1α, HILPDA, JAK1, PDK4 and ROCK2 expression. Notwithstanding, CPT1A protein was repressed to protect mitochondria from lipid overload. Pharmacological inhibition of the GTPase-dynamin and the fatty acid transporter-2 reduced lipid uptake by 28.5 and 35%, respectively. Finally, a comparisons of in-vitro/NAFLD patient biopsy findings confirmed common gene regulations thus demonstrating clinical relevance. CONCLUSION The genomics of fat-laden hepatocytes revealed LD-associated gene regulations and perturbed metabolic pathways. Immunofluorescence microscopy confirmed expression of coded proteins to provide a rationale for therapeutic intervention strategies. Collectively, the in-vitro system permits testing of drug candidates.
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Affiliation(s)
- Stephanie Breher-Esch
- Centre for Pharmacology and Toxicology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625, Hannover, Germany
| | - Nishika Sahini
- Centre for Pharmacology and Toxicology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625, Hannover, Germany
| | - Anna Trincone
- Centre for Pharmacology and Toxicology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625, Hannover, Germany
| | - Christin Wallstab
- Institute of Biochemistry, Charité - University Medicine Berlin, Charitéplatz 1, 10117, Berlin, Germany
| | - Jürgen Borlak
- Centre for Pharmacology and Toxicology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625, Hannover, Germany.
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Cerf ME. Cardiac Glucolipotoxicity and Cardiovascular Outcomes. ACTA ACUST UNITED AC 2018; 54:medicina54050070. [PMID: 30344301 PMCID: PMC6262512 DOI: 10.3390/medicina54050070] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2018] [Revised: 10/04/2018] [Accepted: 10/05/2018] [Indexed: 01/12/2023]
Abstract
Cardiac insulin signaling can be impaired due to the altered fatty acid metabolism to induce insulin resistance. In diabetes and insulin resistance, the metabolic, structural and ultimately functional alterations in the heart and vasculature culminate in diabetic cardiomyopathy, coronary artery disease, ischemia and eventually heart failure. Glucolipotoxicity describes the combined, often synergistic, adverse effects of elevated glucose and free fatty acid concentrations on heart structure, function, and survival. The quality of fatty acid shapes the cardiac structure and function, often influencing survival. A healthy fatty acid balance is therefore critical for maintaining cardiac integrity and function.
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Affiliation(s)
- Marlon E Cerf
- Biomedical Research and Innovation Platform, South African Medical Research Council, Tygerberg 7505, South Africa.
- Division of Medical Physiology, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, University of Stellenbosch, Tygerberg 7505, South Africa.
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Intestinal Saturated Long-Chain Fatty Acid, Glucose and Fructose Transporters and Their Inhibition by Natural Plant Extracts in Caco-2 Cells. Molecules 2018; 23:molecules23102544. [PMID: 30301205 PMCID: PMC6222386 DOI: 10.3390/molecules23102544] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2018] [Revised: 09/29/2018] [Accepted: 10/04/2018] [Indexed: 02/07/2023] Open
Abstract
The intestinal absorption of fatty acids, glucose and fructose is part of the basic requirements for the provision of energy in the body. High access of saturated long-chain fatty acids (LCFA), glucose and fructose can facilitate the development of metabolic diseases, particularly the metabolic syndrome and type-2 diabetes mellitus (T2DM). Research has been done to find substances which decelerate or inhibit intestinal resorption of these specific food components. Promising targets are the inhibition of intestinal long-chain fatty acid (FATP2, FATP4), glucose (SGLT1, GLUT2) and fructose (GLUT2, GLUT5) transporters by plant extracts and by pure substances. The largest part of active components in plant extracts belongs to the group of polyphenols. This review summarizes the knowledge about binding sites of named transporters and lists the plant extracts which were tested in Caco-2 cells regarding uptake inhibition.
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Wadhwani N, Patil V, Joshi S. Maternal long chain polyunsaturated fatty acid status and pregnancy complications. Prostaglandins Leukot Essent Fatty Acids 2018; 136:143-152. [PMID: 28888333 DOI: 10.1016/j.plefa.2017.08.002] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2016] [Revised: 07/06/2017] [Accepted: 08/09/2017] [Indexed: 12/18/2022]
Abstract
Maternal nutrition plays a crucial role in influencing fetal growth and birth outcome. Any nutritional insult starting several weeks before pregnancy and during critical periods of gestation is known to influence fetal development and increase the risk for diseases during later life. Literature suggests that chronic adult diseases may have their origin during early life - a concept referred to as Developmental Origins of Health and Disease (DOHaD) which states that adverse exposures early in life "program" risks for later chronic disorders. Long chain polyunsaturated fatty acids (LCPUFA), mainly omega-6 and omega-3 fatty acids are known to have an effect on fetal programming. The placental supply of optimal levels of LCPUFA to the fetus during early life is extremely important for the normal growth and development of both placenta and fetus. Any alteration in placental development will result in adverse pregnancy outcome such as gestational diabetes mellitus (GDM), preeclampsia, and intrauterine growth restriction (IUGR). A disturbed materno-fetal LCPUFA supply is known to be linked with each of these pathologies. Further, a disturbed LCPUFA metabolism is reported to be associated with a number of metabolic disorders. It is likely that LCPUFA supplementation during early pregnancy may be beneficial in improving the health of the mother, improving birth outcome and thereby reducing the risk of diseases in later life.
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Affiliation(s)
- Nisha Wadhwani
- Department of Nutritional Medicine, Interactive Research School for Health Affairs, Bharati Vidyapeeth University, Pune Satara Road, Pune 411043, India
| | - Vidya Patil
- Department of Nutritional Medicine, Interactive Research School for Health Affairs, Bharati Vidyapeeth University, Pune Satara Road, Pune 411043, India
| | - Sadhana Joshi
- Department of Nutritional Medicine, Interactive Research School for Health Affairs, Bharati Vidyapeeth University, Pune Satara Road, Pune 411043, India.
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Coverdale JPC, Katundu KGH, Sobczak AIS, Arya S, Blindauer CA, Stewart AJ. Ischemia-modified albumin: Crosstalk between fatty acid and cobalt binding. Prostaglandins Leukot Essent Fatty Acids 2018; 135:147-157. [PMID: 30103926 PMCID: PMC6109191 DOI: 10.1016/j.plefa.2018.07.014] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2018] [Revised: 07/17/2018] [Accepted: 07/17/2018] [Indexed: 02/06/2023]
Abstract
Myocardial ischemia is difficult to diagnose effectively with still few well-defined biochemical markers for identification in advance, or in the absence of myocardial necrosis. "Ischemia-modified albumin" (IMA), a form of albumin displaying reduced cobalt-binding affinity, is significantly elevated in ischemic patients, and the albumin cobalt-binding (ACB) assay can measure its level indirectly. Elucidating the molecular mechanism underlying the identity of IMA and the ACB assay hinges on understanding metal-binding properties of albumin. Albumin binds most metal ions and harbours four primary metal binding sites: site A, site B, the N-terminal site (NTS), and the free thiol at Cys34. Previous efforts to clarify the identity of IMA and the causes for its reduced cobalt-binding capacity were focused on the NTS site, but the degree of N-terminal modification could not be correlated to the presence of ischemia. More recent work suggested that Co2+ ions as used in the ACB assay bind preferentially to site B, then to site A, and finally to the NTS. This insight paved the way for a new consistent molecular basis of the ACB assay: albumin is also the main plasma carrier for free fatty acids (FFAs), and binding of a fatty acid to the high-affinity site FA2 results in conformational changes in albumin which prevent metal binding at site A and partially at site B. Thus, this review advances the hypothesis that high IMA levels in myocardial ischemia and many other conditions originate from high plasma FFA levels hampering the binding of Co2+ to sites A and/or B. This is supported by biophysical studies and the co-association of a range of pathological conditions with positive ACB assays and high plasma FFA levels.
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Affiliation(s)
| | - Kondwani G H Katundu
- School of Medicine, University of St Andrews, St Andrews, United Kingdom; College of Medicine, University of Malawi, Blantyre, Malawi
| | - Amélie I S Sobczak
- School of Medicine, University of St Andrews, St Andrews, United Kingdom
| | - Swati Arya
- School of Medicine, University of St Andrews, St Andrews, United Kingdom
| | | | - Alan J Stewart
- School of Medicine, University of St Andrews, St Andrews, United Kingdom.
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Chen XL, Lui EY, Ip YK, Lam SH. RNA sequencing, de novo assembly and differential analysis of the gill transcriptome of freshwater climbing perch Anabas testudineus after 6 days of seawater exposure. JOURNAL OF FISH BIOLOGY 2018; 93:215-228. [PMID: 29931780 DOI: 10.1111/jfb.13653] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/31/2017] [Accepted: 05/13/2018] [Indexed: 06/08/2023]
Abstract
To obtain transcriptomic insights into branchial responses to salinity challenge in Anabas testudineus, this study employed RNA sequencing (RNA-Seq) to analyse the gill transcriptome of A. testudineus exposed to seawater (SW) for 6 days compared with the freshwater (FW) control group. A combined FW and SW gill transcriptome was de novo assembled from 169.9 million 101 bp paired-end reads. In silico validation employing 17 A. testudineus Sanger full-length coding sequences showed that 15/17 of them had greater than 80% of their sequences aligned to the de novo assembled contigs where 5/17 had their full-length (100%) aligned and 9/17 had greater than 90% of their sequences aligned. The combined FW and SW gill transcriptome was mapped to 13,780 unique human identifiers at E-value ≤1.0E-20 while 952 and 886 identifiers were determined as up and down-regulated by 1.5 fold, respectively, in the gills of A. testudineus in SW when compared with FW. These genes were found to be associated with at least 23 biological processes. A larger proportion of genes encoding enzymes and transporters associated with molecular transport, energy production, metabolisms were up-regulated, while a larger proportion of genes encoding transmembrane receptors, G-protein coupled receptors, kinases and transcription regulators associated with cell cycle, growth, development, signalling, morphology and gene expression were relatively lower in the gills of A. testudineus in SW when compared with FW. High correlation (R = 0.99) was observed between RNA-Seq data and real-time quantitative PCR validation for 13 selected genes. The transcriptomic sequence information will facilitate development of molecular resources and tools while the findings will provide insights for future studies into branchial iono-osmoregulation and related cellular processes in A. testudineus.
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Affiliation(s)
- Xiu L Chen
- Department of Biological Sciences, National University of Singapore, Singapore
| | - Eei Y Lui
- NUS Environmental Research Institute, National University of Singapore, Singapore
| | - Yuen K Ip
- Department of Biological Sciences, National University of Singapore, Singapore
| | - Siew H Lam
- Department of Biological Sciences, National University of Singapore, Singapore
- NUS Environmental Research Institute, National University of Singapore, Singapore
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Kolahi KS, Valent AM, Thornburg KL. Real-time microscopic assessment of fatty acid uptake kinetics in the human term placenta. Placenta 2018; 72-73:1-9. [PMID: 30501875 DOI: 10.1016/j.placenta.2018.07.014] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2018] [Revised: 07/13/2018] [Accepted: 07/25/2018] [Indexed: 12/14/2022]
Abstract
INTRODUCTION The placenta employs an efficient and selective fatty acid transport system to supply lipids for fetal development. Disruptions in placental fatty acid transport lead to restricted fetal growth along with cardiovascular and neurologic deficits. Nevertheless, little is known about the molecular mechanisms involved in human placental fatty acid trafficking during the initial steps of uptake, or the importance of fatty acid chain length in determining uptake rates. METHODS We employed BODIPY fluorophore conjugated fatty acid analogues of three chain lengths, medium (BODIPY-C5), long (BODIPY-C12), and very-long (BODIPY-C16), to study fatty acid uptake in isolated human trophoblast and explants using confocal microscopy. The three BODIPY-labeled fatty acids were added to freshly isolated explants and tracked for up to 30 min. Fatty acid uptake kinetics were quantified in trophoblast (cytotrophoblast and syncytiotrophoblast together) and the fetal capillary lumen. RESULTS Long- (BODIPY-C12) and Very long-chain (BODIPY-C16) fatty acids accumulated more rapidly in the trophoblast layer than did medium-chain (BODIPY-C5) whereas BODIPY-C5 accumulated more rapidly in the fetal capillary than did the longer chain length fatty acids. The long-chain fatty acids, BODIPY-C12 and BODIPY-C16, are esterified and stored in lipid droplets in the cytotrophoblast layer, but medium-chain fatty acid, BODIPY-C5, is not. DISCUSSION Fatty acids accumulate in trophoblast and fetal capillaries inversely according to their chain length. BODIPY-C5 accumulates in the fetal capillary in concentrations far greater than in the trophoblast, suggesting that medium-chain length BODIPY-labeled fatty acids are capable of being transported against a concentration gradient.
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Affiliation(s)
- Kevin S Kolahi
- School of Medicine, Oregon Health and Science University, Portland, OR, 97239, USA; Center for Developmental Health, Knight Cardiovascular Institute Oregon Health and Science University, Portland, OR, 97239, USA; Department of Medicine, Oregon Health and Science University, Portland, OR, 97239, USA
| | - Amy M Valent
- School of Medicine, Oregon Health and Science University, Portland, OR, 97239, USA; Center for Developmental Health, Knight Cardiovascular Institute Oregon Health and Science University, Portland, OR, 97239, USA; Department of Obstetrics and Gynecology, Oregon Health and Science University, Portland, OR, 97239, USA; Department of Medicine, Oregon Health and Science University, Portland, OR, 97239, USA
| | - Kent L Thornburg
- School of Medicine, Oregon Health and Science University, Portland, OR, 97239, USA; Center for Developmental Health, Knight Cardiovascular Institute Oregon Health and Science University, Portland, OR, 97239, USA; Department of Obstetrics and Gynecology, Oregon Health and Science University, Portland, OR, 97239, USA; Department of Medicine, Oregon Health and Science University, Portland, OR, 97239, USA.
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