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Thimme Gowda C, Siraganahalli Eshwaraiah M, Wang J, Lim Y, Tomasi ML, Mavila N, Ramani K. The AKAP12-PKA axis regulates lipid homeostasis during alcohol-associated liver disease. Signal Transduct Target Ther 2025; 10:109. [PMID: 40199859 PMCID: PMC11979000 DOI: 10.1038/s41392-025-02202-1] [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: 08/24/2024] [Revised: 03/02/2025] [Accepted: 03/05/2025] [Indexed: 04/10/2025] Open
Abstract
Disrupted lipogenic signaling and steatosis are key features of alcohol-associated liver disease (ALD). A-kinase anchoring protein 12 (AKAP12) is a scaffolding partner of the cAMP-dependent protein kinase, PKA that controls its spatiotemporal localization. Activation of PKA by cAMP inhibits lipogenesis and facilitates fatty acid oxidation (FAO). The goal of this work is to examine how AKAP12's PKA-anchoring ability regulates outcomes of alcohol-associated steatosis. Crosslinking proteomics identified PKA and its lipogenic substrates as interacting partners of AKAP12. Alcohol exposure diminished AKAP12's interaction with PKA regulatory subunits and PKA substrates, acetyl CoA carboxylase (ACC1), pyruvate dehydrogenase (PDHA) and adipose triglyceride lipase (ATGL). Alcohol inhibited PKA activity and increased triglyceride content in human hepatocytes. Forced expression of AKAP12 restored alcohol suppressed PKA activation and inhibited lipid accumulation, whereas silencing had the reverse effect. Since AKAP12 sustained PKA activity, we evaluated whether the AKAP12-PKA scaffold was important in lipid homeostasis. Inhibition of AKAP12-PKA interaction by CRISPR deletion of AKAP12's PKA binding domain in cultured hepatocytes or in mouse models of ALD dramatically suppressed PKA activity, enhanced ACC1 activity demonstrated by reduced inhibitory phosphorylation, increased lipid accumulation and reduced FAO in hepatocytes. Overexpression of AKAP12 in mouse livers sustained PKA activation, diminished basal and alcohol potentiated triglyceride content, and regulated inflammatory signaling altered by alcohol. Mechanistically, we discovered that alcohol enhanced the inhibitory activity of a kinase, serine/threonine-protein kinase 25 (STK25) on PKA that regulated its interaction with AKAP12. In conclusion, the AKAP12-PKA scaffold controls lipogenic signaling, disruption of which favors steatosis during ALD.
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Affiliation(s)
- Chandana Thimme Gowda
- Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | | | - Jiaohong Wang
- Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Youngyi Lim
- Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Maria Lauda Tomasi
- Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
- Applied Cell Biology Division, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
| | - Nirmala Mavila
- Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
- Applied Cell Biology Division, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
| | - Komal Ramani
- Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
- Applied Cell Biology Division, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
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Ma X, Huang T, Chen X, Li Q, Liao M, Fu L, Huang J, Yuan K, Wang Z, Zeng Y. Molecular mechanisms in liver repair and regeneration: from physiology to therapeutics. Signal Transduct Target Ther 2025; 10:63. [PMID: 39920130 PMCID: PMC11806117 DOI: 10.1038/s41392-024-02104-8] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2023] [Revised: 09/02/2024] [Accepted: 12/12/2024] [Indexed: 02/09/2025] Open
Abstract
Liver repair and regeneration are crucial physiological responses to hepatic injury and are orchestrated through intricate cellular and molecular networks. This review systematically delineates advancements in the field, emphasizing the essential roles played by diverse liver cell types. Their coordinated actions, supported by complex crosstalk within the liver microenvironment, are pivotal to enhancing regenerative outcomes. Recent molecular investigations have elucidated key signaling pathways involved in liver injury and regeneration. Viewed through the lens of metabolic reprogramming, these pathways highlight how shifts in glucose, lipid, and amino acid metabolism support the cellular functions essential for liver repair and regeneration. An analysis of regenerative variability across pathological states reveals how disease conditions influence these dynamics, guiding the development of novel therapeutic strategies and advanced techniques to enhance liver repair and regeneration. Bridging laboratory findings with practical applications, recent clinical trials highlight the potential of optimizing liver regeneration strategies. These trials offer valuable insights into the effectiveness of novel therapies and underscore significant progress in translational research. In conclusion, this review intricately links molecular insights to therapeutic frontiers, systematically charting the trajectory from fundamental physiological mechanisms to innovative clinical applications in liver repair and regeneration.
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Affiliation(s)
- Xiao Ma
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Tengda Huang
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Xiangzheng Chen
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Qian Li
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Mingheng Liao
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Li Fu
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Jiwei Huang
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Kefei Yuan
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Zhen Wang
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China.
| | - Yong Zeng
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China.
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3
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Salas SAS, Damba T, Buist‐Homan M, Moshage H. Protective Effect of Carvedilol Against Oxidative Stress Induced by Palmitic Acid in Primary Rat Hepatocytes. Cell Biochem Funct 2025; 43:e70057. [PMID: 39924769 PMCID: PMC11808198 DOI: 10.1002/cbf.70057] [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: 07/22/2024] [Revised: 01/23/2025] [Accepted: 01/27/2025] [Indexed: 02/11/2025]
Abstract
Hepatocyte lipotoxicity (HL) is an important factor in the pathogenesis of Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD). It is defined as the detrimental effects of exposure to (excessive) amounts of toxic lipid species, leading to increased mitochondrial β-oxidation, oxidative stress (OxS), and organellar dysfunction. Carvedilol (CV) is a β-adrenergic blocker with antioxidant properties. To elucidate whether CV protects hepatocytes against lipotoxicity induced by palmitic acid (PA) by reducing OxS and endoplasmic reticulum (ER) stress. Primary rat hepatocytes (rHep) were used. Lipotoxicity was induced by PA (1 mmol/L). Cell damage was evaluated by Sytox Green staining. Mitochondrial generation of reactive oxygen species (mROS) was assessed by MitoSox. mRNA and protein expression were measured by qPCR and Western blot, respectively. Lipid accumulation was measured by Oil Red O staining and triglyceride (TG) content. PA induced cell death in > 80% of cells and increased mROS generation. PA increased mRNA expression of ER stress markers CHOP and sXBP1 and slightly increased lipid accumulation. Expression of the β-oxidation-related gene Cpt1a was increased. CV (10 µmol/L) significantly reduced PA-induced cell death to control levels (< 8% of total cells), and mROS generation and expression of the mitochondrial antioxidant enzymes Sod2 and Cat were increased by 40% by CV in the presence of PA. CV did not change the expression of ER stress markers. CV, added before PA, protects rHep against PA-induced cytotoxicity by reducing OxS and increasing the expression of antioxidant enzymes without any additional protective effect on ER stress or lipid accumulation.
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Affiliation(s)
- Sandra A. Serna Salas
- Department of Gastroenterology and Hepatology, University Medical Center GroningenUniversity of GroningenGroningenthe Netherlands
| | - Turtushikh Damba
- Department of Gastroenterology and Hepatology, University Medical Center GroningenUniversity of GroningenGroningenthe Netherlands
- School of PharmacyMongolian National University of Medical SciencesUlaanbaatarMongolia
| | - Manon Buist‐Homan
- Department of Gastroenterology and Hepatology, University Medical Center GroningenUniversity of GroningenGroningenthe Netherlands
- Department of Laboratory Medicine, University Medical Center GroningenUniversity of GroningenGroningenthe Netherlands
| | - Han Moshage
- Department of Gastroenterology and Hepatology, University Medical Center GroningenUniversity of GroningenGroningenthe Netherlands
- Department of Laboratory Medicine, University Medical Center GroningenUniversity of GroningenGroningenthe Netherlands
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4
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Ismail VA, Schuetz M, Baker ZN, Castillo-Badillo JA, Naismith TV, Pagliarini DJ, Kast DJ. DFCP1 is a regulator of starvation-driven ATGL-mediated lipid droplet lipolysis. J Lipid Res 2025; 66:100700. [PMID: 39566849 PMCID: PMC11721518 DOI: 10.1016/j.jlr.2024.100700] [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: 10/11/2023] [Revised: 10/31/2024] [Accepted: 11/06/2024] [Indexed: 11/22/2024] Open
Abstract
Lipid droplets (LDs) are transient lipid storage organelles that can be readily tapped to resupply cells with energy or lipid building blocks, and therefore play a central role in cellular metabolism. Double FYVE Domain Containing Protein 1 (DFCP1/ZFYVE1) has emerged as a key regulator of LD metabolism, where the nucleotide-dependent accumulation of DFCP1 on LDs influences their size, number, and dynamics. Here we show that DFCP1 regulates lipid metabolism by directly modulating the activity of Adipose Triglyceride Lipase (ATGL/PNPLA2), the rate-limiting lipase driving the catabolism of LDs. We show through pharmacological inhibition of key enzymes associated with LD metabolism that DFCP1 specifically regulates lipolysis and, to a lesser extent, lipophagy. Consistent with this observation, DFCP1 interacts with and recruits ATGL to LDs in starved cells, irrespective of other known regulatory factors of ATGL. We further establish that this interaction prevents dynamic disassociation of ATGL from LDs and thereby impedes the rate of LD lipolysis. Collectively, our findings indicate that DFCP1 is a nutrient-sensitive regulator of LD catabolism.
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Affiliation(s)
- Victoria A Ismail
- Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri, USA
| | - Meg Schuetz
- Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri, USA
| | - Zak N Baker
- Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri, USA
| | - Jean A Castillo-Badillo
- Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri, USA
| | - Teri V Naismith
- Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri, USA
| | - David J Pagliarini
- Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri, USA; Howard Hughes Medical Institute, Chevy Chase, Maryland, USA; Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, Missouri, USA; Department of Genetics, Washington University School of Medicine, St. Louis, Missouri, USA
| | - David J Kast
- Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri, USA.
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Zheng Y, Chen J, Macwan V, Dixon CL, Li X, Liu S, Yu Y, Xu P, Sun Q, Hu Q, Liu W, Raught B, Fairn GD, Neculai D. S-acylation of ATGL is required for lipid droplet homoeostasis in hepatocytes. Nat Metab 2024; 6:1549-1565. [PMID: 39143266 DOI: 10.1038/s42255-024-01085-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Accepted: 06/21/2024] [Indexed: 08/16/2024]
Abstract
Lipid droplets (LDs) are organelles specialized in the storage of neutral lipids, cholesterol esters and triglycerides, thereby protecting cells from the toxicity of excess lipids while allowing for the mobilization of lipids in times of nutrient deprivation. Defects in LD function are associated with many diseases. S-acylation mediated by zDHHC acyltransferases modifies thousands of proteins, yet the physiological impact of this post-translational modification on individual proteins is poorly understood. Here, we show that zDHHC11 regulates LD catabolism by modifying adipose triacylglyceride lipase (ATGL), the rate-limiting enzyme of lipolysis, both in hepatocyte cultures and in mice. zDHHC11 S-acylates ATGL at cysteine 15. Preventing the S-acylation of ATGL renders it catalytically inactive despite proper localization. Overexpression of zDHHC11 reduces LD size, whereas its elimination enlarges LDs. Mutating ATGL cysteine 15 phenocopies zDHHC11 loss, causing LD accumulation, defective lipolysis and lipophagy. Our results reveal S-acylation as a mode of regulation of ATGL function and LD homoeostasis. Modulating this pathway may offer therapeutic potential for treating diseases linked to defective lipolysis, such as fatty liver disease.
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Affiliation(s)
- Yuping Zheng
- Center for Metabolism Research, The Fourth Affiliated Hospital of School of Medicine and International School of Medicine, International Institutes of Medicine, Zhejiang University, Yiwu, China
| | - Jishun Chen
- Department of Cell Biology, Zhejiang University School of Medicine, Hangzhou, China
| | - Vinitha Macwan
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
| | - Charneal L Dixon
- Keenan Research Centre for Biomedical Science, St. Michael's Hospital, University Health Network, Toronto, Ontario, Canada
- Department of Pathology, Dalhousie University, Halifax, Nova Scotia, Canada
| | - Xinran Li
- ZJU-Hangzhou Global Scientific and Technological Innovation Center, Hangzhou, China
| | - Shengjie Liu
- Westlake AI Therapeutics Lab, Westlake Laboratory of Life Sciences and Biomedicine, School of Life Sciences, Westlake University, Hangzhou, China
| | - Yuyun Yu
- Center for Metabolism Research, The Fourth Affiliated Hospital of School of Medicine and International School of Medicine, International Institutes of Medicine, Zhejiang University, Yiwu, China
| | - Pinglong Xu
- Life Science Institute, Zhejiang University, Hangzhou, China
| | - Qiming Sun
- Center for Metabolism Research, The Fourth Affiliated Hospital of School of Medicine and International School of Medicine, International Institutes of Medicine, Zhejiang University, Yiwu, China
| | - Qi Hu
- Westlake AI Therapeutics Lab, Westlake Laboratory of Life Sciences and Biomedicine, School of Life Sciences, Westlake University, Hangzhou, China
| | - Wei Liu
- Center for Metabolism Research, The Fourth Affiliated Hospital of School of Medicine and International School of Medicine, International Institutes of Medicine, Zhejiang University, Yiwu, China.
| | - Brian Raught
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
| | - Gregory D Fairn
- Keenan Research Centre for Biomedical Science, St. Michael's Hospital, University Health Network, Toronto, Ontario, Canada.
- Department of Pathology, Dalhousie University, Halifax, Nova Scotia, Canada.
| | - Dante Neculai
- Center for Metabolism Research, The Fourth Affiliated Hospital of School of Medicine and International School of Medicine, International Institutes of Medicine, Zhejiang University, Yiwu, China.
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6
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Inderhees J, Schwaninger M. Liver Metabolism in Ischemic Stroke. Neuroscience 2024; 550:62-68. [PMID: 38176607 DOI: 10.1016/j.neuroscience.2023.12.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2023] [Revised: 12/19/2023] [Accepted: 12/26/2023] [Indexed: 01/06/2024]
Abstract
Focal brain damage and neurological deficits are the direct consequences of acute ischemic stroke (AIS). In addition, cerebral ischemia causes systemic alterations across peripheral organs. Dysregulation of the autonomic and endocrine systems as well as the release of brain-derived pro-inflammatory mediators trigger a peripheral immune response and systemic inflammation. As a key metabolic organ, the liver contributes not only to post-stroke immunosuppression but also to stress-induced hyperglycemia. At the same time, increased ketogenesis and glutathione production in the liver are likely to combat inflammation and oxidative stress after AIS. The closely linked lipid metabolism could regulate both glucose and glutathione homeostasis. In addition, increased hepatic very low-density lipoprotein (VLDL) secretion may improve the availability of phospholipids, polyunsaturated fatty acids (PUFAs) and glutathione after AIS. This review provides an overview of recent findings concerning ischemic stroke and the liver and discusses the therapeutic potential of targeting the hepatic metabolism to improve patient outcome after stroke.
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Affiliation(s)
- Julica Inderhees
- Institute of Experimental and Clinical Pharmacology and Toxicology, Center of Brain, Behavior and Metabolism, University of Lübeck, Lübeck, Germany; German Research Centre for Cardiovascular Research (DZHK), Partner Site Hamburg/Lübeck/Kiel, Germany; Bioanalytic Core Facility, Center of Brain, Behavior and Metabolism, University of Lübeck, Lübeck, Germany
| | - Markus Schwaninger
- Institute of Experimental and Clinical Pharmacology and Toxicology, Center of Brain, Behavior and Metabolism, University of Lübeck, Lübeck, Germany; German Research Centre for Cardiovascular Research (DZHK), Partner Site Hamburg/Lübeck/Kiel, Germany.
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7
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Allard J, Bucher S, Ferron PJ, Launay Y, Fromenty B. Busulfan induces steatosis in HepaRG cells but not in primary human hepatocytes: Possible explanations and implication for the prediction of drug-induced liver injury. Fundam Clin Pharmacol 2024; 38:152-167. [PMID: 37665028 DOI: 10.1111/fcp.12951] [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: 01/23/2023] [Revised: 07/27/2023] [Accepted: 08/10/2023] [Indexed: 09/05/2023]
Abstract
BACKGROUND The antineoplastic drug busulfan can induce different hepatic lesions including cholestasis and sinusoidal obstruction syndrome. However, hepatic steatosis has never been reported in patients. OBJECTIVES This study aimed to determine whether busulfan could induce steatosis in primary human hepatocytes (PHH) and differentiated HepaRG cells. METHODS Neutral lipids were determined in PHH and HepaRG cells. Mechanistic investigations were performed in HepaRG cells by measuring metabolic fluxes linked to lipid homeostasis, reduced glutathione (GSH) levels, and expression of genes involved in lipid metabolism and endoplasmic reticulum (ER) stress. Analysis of two previous transcriptomic datasets was carried out. RESULTS Busulfan induced lipid accumulation in HepaRG cells but not in six different batches of PHH. In HepaRG cells, busulfan impaired VLDL secretion, increased fatty acid uptake, and induced ER stress. Transcriptomic data analysis and decreased GSH levels suggested that busulfan-induced steatosis might be linked to the high expression of glutathione S-transferase (GST) isoenzyme A1, which is responsible for the formation of the hepatotoxic sulfonium cation conjugate. In keeping with this, the GST inhibitor ethacrynic acid and the chemical chaperone tauroursodeoxycholic acid alleviated busulfan-induced lipid accumulation in HepaRG cells supporting the role of the sulfonium cation conjugate and ER stress in steatosis. CONCLUSION While the HepaRG cell line is an invaluable tool for pharmacotoxicological studies, it might not be always an appropriate model to predict and mechanistically investigate drug-induced liver injury. Hence, we recommend carrying out toxicological investigations in both HepaRG cells and PHH to avoid drawing wrong conclusions on the potential hepatotoxicity of drugs and other xenobiotics.
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Affiliation(s)
- Julien Allard
- Division of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences, University of Basel, Basel, Switzerland
| | | | - Pierre-Jean Ferron
- INSERM, Univ Rennes, INRAE, Institut NUMECAN (Nutrition Metabolisms and Cancer) UMR_A 1341, UMR_S 1317, Rennes, France
| | - Youenn Launay
- INSERM, Univ Rennes, INRAE, Institut NUMECAN (Nutrition Metabolisms and Cancer) UMR_A 1341, UMR_S 1317, Rennes, France
| | - Bernard Fromenty
- INSERM, Univ Rennes, INRAE, Institut NUMECAN (Nutrition Metabolisms and Cancer) UMR_A 1341, UMR_S 1317, Rennes, France
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8
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Maestri A, Garagnani P, Pedrelli M, Hagberg CE, Parini P, Ehrenborg E. Lipid droplets, autophagy, and ageing: A cell-specific tale. Ageing Res Rev 2024; 94:102194. [PMID: 38218464 DOI: 10.1016/j.arr.2024.102194] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2023] [Revised: 12/22/2023] [Accepted: 01/08/2024] [Indexed: 01/15/2024]
Abstract
Lipid droplets are the essential organelle for storing lipids in a cell. Within the variety of the human body, different cells store, utilize and release lipids in different ways, depending on their intrinsic function. However, these differences are not well characterized and, especially in the context of ageing, represent a key factor for cardiometabolic diseases. Whole body lipid homeostasis is a central interest in the field of cardiometabolic diseases. In this review we characterize lipid droplets and their utilization via autophagy and describe their diverse fate in three cells types central in cardiometabolic dysfunctions: adipocytes, hepatocytes, and macrophages.
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Affiliation(s)
- Alice Maestri
- Division of Cardiovascular Medicine, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden; Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Paolo Garagnani
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Bologna, Italy; IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Matteo Pedrelli
- Cardio Metabolic Unit, Department of Laboratory Medicine, and Department of Medicine (Huddinge), Karolinska Institutet, Stockholm, Sweden; Medicine Unit of Endocrinology, Theme Inflammation and Ageing, Karolinska University Hospital, Stockholm, Sweden
| | - Carolina E Hagberg
- Division of Cardiovascular Medicine, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden; Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Paolo Parini
- Cardio Metabolic Unit, Department of Laboratory Medicine, and Department of Medicine (Huddinge), Karolinska Institutet, Stockholm, Sweden; Medicine Unit of Endocrinology, Theme Inflammation and Ageing, Karolinska University Hospital, Stockholm, Sweden
| | - Ewa Ehrenborg
- Division of Cardiovascular Medicine, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden; Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
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9
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Zelows MM, Cady C, Dharanipragada N, Mead AE, Kipp ZA, Bates EA, Varadharajan V, Banerjee R, Park SH, Shelman NR, Clarke HA, Hawkinson TR, Medina T, Sun RC, Lydic TA, Hinds TD, Brown JM, Softic S, Graf GA, Helsley RN. Loss of carnitine palmitoyltransferase 1a reduces docosahexaenoic acid-containing phospholipids and drives sexually dimorphic liver disease in mice. Mol Metab 2023; 78:101815. [PMID: 37797918 PMCID: PMC10568566 DOI: 10.1016/j.molmet.2023.101815] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2023] [Revised: 09/22/2023] [Accepted: 09/28/2023] [Indexed: 10/07/2023] Open
Abstract
BACKGROUND AND AIMS Genome and epigenome wide association studies identified variants in carnitine palmitoyltransferase 1a (CPT1a) that associate with lipid traits. The goal of this study was to determine the role of liver-specific CPT1a on hepatic lipid metabolism. APPROACH AND RESULTS Male and female liver-specific knockout (LKO) and littermate controls were placed on a low-fat or high-fat diet (60% kcal fat) for 15 weeks. Mice were necropsied after a 16 h fast, and tissues were collected for lipidomics, matrix-assisted laser desorption ionization mass spectrometry imaging, kinome analysis, RNA-sequencing, and protein expression by immunoblotting. Female LKO mice had increased serum alanine aminotransferase levels which were associated with greater deposition of hepatic lipids, while male mice were not affected by CPT1a deletion relative to male control mice. Mice with CPT1a deletion had reductions in DHA-containing phospholipids at the expense of monounsaturated fatty acids (MUFA)-containing phospholipids in whole liver and at the level of the lipid droplet (LD). Male and female LKO mice increased RNA levels of genes involved in LD lipolysis (Plin2, Cidec, G0S2) and in polyunsaturated fatty acid metabolism (Elovl5, Fads1, Elovl2), while only female LKO mice increased genes involved in inflammation (Ly6d, Mmp12, Cxcl2). Kinase profiling showed decreased protein kinase A activity, which coincided with increased PLIN2, PLIN5, and G0S2 protein levels and decreased triglyceride hydrolysis in LKO mice. CONCLUSIONS Liver-specific deletion of CPT1a promotes sexually dimorphic steatotic liver disease (SLD) in mice, and here we have identified new mechanisms by which females are protected from HFD-induced liver injury.
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Affiliation(s)
- Mikala M Zelows
- Department of Pharmaceutical Sciences, University of Kentucky College of Pharmacy, Lexington, KY, USA
| | - Corissa Cady
- Department of Physiology, University of Kentucky College of Medicine, Lexington, KY, USA
| | - Nikitha Dharanipragada
- Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, KY, USA
| | - Anna E Mead
- Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, KY, USA
| | - Zachary A Kipp
- Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, KY, USA
| | - Evelyn A Bates
- Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, KY, USA
| | | | - Rakhee Banerjee
- Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Se-Hyung Park
- Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, KY, USA; Department of Pediatrics and Gastroenterology, University of Kentucky College of Medicine, Lexington, KY, USA
| | - Nathan R Shelman
- Department of Pathology and Laboratory Medicine, University of Kentucky College of Medicine, Lexington, KY, USA
| | - Harrison A Clarke
- Department of Biochemistry & Molecular Biology, University of Florida College of Medicine, Gainesville, FL, USA; Center for Advanced Spatial Biomolecule Research, University of Florida College of Medicine, Gainesville, FL, USA
| | - Tara R Hawkinson
- Department of Biochemistry & Molecular Biology, University of Florida College of Medicine, Gainesville, FL, USA; Center for Advanced Spatial Biomolecule Research, University of Florida College of Medicine, Gainesville, FL, USA
| | - Terrymar Medina
- Department of Biochemistry & Molecular Biology, University of Florida College of Medicine, Gainesville, FL, USA; Center for Advanced Spatial Biomolecule Research, University of Florida College of Medicine, Gainesville, FL, USA
| | - Ramon C Sun
- Department of Biochemistry & Molecular Biology, University of Florida College of Medicine, Gainesville, FL, USA; Center for Advanced Spatial Biomolecule Research, University of Florida College of Medicine, Gainesville, FL, USA
| | - Todd A Lydic
- Department of Physiology, Michigan State University, East Lansing, MI, USA
| | - Terry D Hinds
- Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, KY, USA; Barnstable Brown Diabetes Center, University of Kentucky College of Medicine, Lexington, KY, USA; Markey Cancer Center, University of Kentucky College of Medicine, Lexington, KY, USA
| | - J Mark Brown
- Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Samir Softic
- Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, KY, USA; Department of Pediatrics and Gastroenterology, University of Kentucky College of Medicine, Lexington, KY, USA
| | - Gregory A Graf
- Department of Physiology, University of Kentucky College of Medicine, Lexington, KY, USA; Saha Cardiovascular Research Center, University of Kentucky, Lexington, KY, USA
| | - Robert N Helsley
- Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, KY, USA; Barnstable Brown Diabetes Center, University of Kentucky College of Medicine, Lexington, KY, USA; Markey Cancer Center, University of Kentucky College of Medicine, Lexington, KY, USA; Saha Cardiovascular Research Center, University of Kentucky, Lexington, KY, USA; Department of Internal Medicine, Division of Endocrinology, Diabetes, and Metabolism, University of Kentucky College of Medicine, Lexington, KY, USA.
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10
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Zelows MM, Cady C, Dharanipragada N, Mead AE, Kipp ZA, Bates EA, Varadharajan V, Banerjee R, Park SH, Shelman NR, Clarke HA, Hawkinson TR, Medina T, Sun RC, Lydic TA, Hinds TD, Brown JM, Softic S, Graf GA, Helsley RN. Loss of Carnitine Palmitoyltransferase 1a Reduces Docosahexaenoic Acid-Containing Phospholipids and Drives Sexually Dimorphic Liver Disease in Mice. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.08.17.553705. [PMID: 37645721 PMCID: PMC10462091 DOI: 10.1101/2023.08.17.553705] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/31/2023]
Abstract
Background and Aims Genome and epigenome wide association studies identified variants in carnitine palmitoyltransferase 1a (CPT1a) that associate with lipid traits. The goal of this study was to determine the impact by which liver-specific CPT1a deletion impacts hepatic lipid metabolism. Approach and Results Six-to-eight-week old male and female liver-specific knockout (LKO) and littermate controls were placed on a low-fat or high-fat diet (HFD; 60% kcal fat) for 15 weeks. Mice were necropsied after a 16 hour fast, and tissues were collected for lipidomics, matrix-assisted laser desorption ionization mass spectrometry imaging (MALDI-MSI), kinome analysis, RNA-sequencing, and protein expression by immunoblotting. Female LKO mice had increased serum alanine aminotransferase (ALT) levels which were associated with greater deposition of hepatic lipids, while male mice were not affected by CPT1a deletion relative to male control mice. Mice with CPT1a deletion had reductions in DHA-containing phospholipids at the expense of monounsaturated fatty acids (MUFA)-containing phospholipids in both whole liver and at the level of the lipid droplet (LD). Male and female LKO mice increased RNA levels of genes involved in LD lipolysis ( Plin2 , Cidec , G0S2 ) and in polyunsaturated fatty acid (PUFA) metabolism ( Elovl5, Fads1, Elovl2 ), while only female LKO mice increased genes involved in inflammation ( Ly6d, Mmp12, Cxcl2 ). Kinase profiling showed decreased protein kinase A (PKA) activity, which coincided with increased PLIN2, PLIN5, and G0S2 protein levels and decreased triglyceride hydrolysis in LKO mice. Conclusions Liver-specific deletion of CPT1a promotes sexually dimorphic steatotic liver disease (SLD) in mice, and here we have identified new mechanisms by which females are protected from HFD-induced liver injury. Graphical Summary
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Adori M, Bhat S, Gramignoli R, Valladolid-Acebes I, Bengtsson T, Uhlèn M, Adori C. Hepatic Innervations and Nonalcoholic Fatty Liver Disease. Semin Liver Dis 2023; 43:149-162. [PMID: 37156523 PMCID: PMC10348844 DOI: 10.1055/s-0043-57237] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 05/10/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disorder. Increased sympathetic (noradrenergic) nerve tone has a complex role in the etiopathomechanism of NAFLD, affecting the development/progression of steatosis, inflammation, fibrosis, and liver hemodynamical alterations. Also, lipid sensing by vagal afferent fibers is an important player in the development of hepatic steatosis. Moreover, disorganization and progressive degeneration of liver sympathetic nerves were recently described in human and experimental NAFLD. These structural alterations likely come along with impaired liver sympathetic nerve functionality and lack of adequate hepatic noradrenergic signaling. Here, we first overview the anatomy and physiology of liver nerves. Then, we discuss the nerve impairments in NAFLD and their pathophysiological consequences in hepatic metabolism, inflammation, fibrosis, and hemodynamics. We conclude that further studies considering the spatial-temporal dynamics of structural and functional changes in the hepatic nervous system may lead to more targeted pharmacotherapeutic advances in NAFLD.
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Affiliation(s)
- Monika Adori
- Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden
| | - Sadam Bhat
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Roberto Gramignoli
- Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Ismael Valladolid-Acebes
- Department of Molecular Medicine and Surgery, The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, Stockholm, Sweden
| | - Tore Bengtsson
- Department of Molecular Biosciences, The Wenner-Gren Institute (MBW), Stockholm University, Stockholm, Sweden
| | - Mathias Uhlèn
- Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden
- Science for Life Laboratory, Royal Institute of Technology, Stockholm, Sweden
| | - Csaba Adori
- Department of Molecular Biosciences, The Wenner-Gren Institute (MBW), Stockholm University, Stockholm, Sweden
- Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden
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12
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Zorec R, Vardjan N. Adrenergic regulation of astroglial aerobic glycolysis and lipid metabolism: Towards a noradrenergic hypothesis of neurodegeneration. Neurobiol Dis 2023; 182:106132. [PMID: 37094775 DOI: 10.1016/j.nbd.2023.106132] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2023] [Revised: 04/18/2023] [Accepted: 04/19/2023] [Indexed: 04/26/2023] Open
Abstract
Ageing is a key factor in the development of cognitive decline and dementia, an increasing and challenging problem of the modern world. The most commonly diagnosed cognitive decline is related to Alzheimer's disease (AD), the pathophysiology of which is poorly understood. Several hypotheses have been proposed. The cholinergic hypothesis is the oldest, however, recently the noradrenergic system has been considered to have a role as well. The aim of this review is to provide evidence that supports the view that an impaired noradrenergic system is causally linked to AD. Although dementia is associated with neurodegeneration and loss of neurons, this likely develops due to a primary failure of homeostatic cells, astrocytes, abundant and heterogeneous neuroglial cells in the central nervous system (CNS). The many functions that astrocytes provide to maintain the viability of neural networks include the control of ionic balance, neurotransmitter turnover, synaptic connectivity and energy balance. This latter function is regulated by noradrenaline, released from the axon varicosities of neurons arising from the locus coeruleus (LC), the primary site of noradrenaline release in the CNS. The demise of the LC is linked to AD, whereby a hypometabolic CNS state is observed clinically. This is likely due to impaired release of noradrenaline in the AD brain during states of arousal, attention and awareness. These functions controlled by the LC are needed for learning and memory formation and require activation of the energy metabolism. In this review, we address first the process of neurodegeneration and cognitive decline, highlighting the function of astrocytes. Cholinergic and/or noradrenergic deficits lead to impaired astroglial function. Then, we focus on adrenergic control of astroglial aerobic glycolysis and lipid droplet metabolism, which play a protective role but also promote neurodegeneration under some circumstances, supporting the noradrenergic hypothesis of cognitive decline. We conclude that targeting astroglial metabolism, glycolysis and/or mitochondrial processes may lead to important new developments in the future when searching for medicines to prevent or even halt cognitive decline.
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Affiliation(s)
- Robert Zorec
- Laboratory of Neuroendocrinology - Molecular Cell Physiology, Institute of Pathophysiology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia; Laboratory of Cell Engineering, Celica Biomedical, Ljubljana, Slovenia.
| | - Nina Vardjan
- Laboratory of Neuroendocrinology - Molecular Cell Physiology, Institute of Pathophysiology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia; Laboratory of Cell Engineering, Celica Biomedical, Ljubljana, Slovenia.
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Wang D, Ji DC, Yu CY, Wu DN, Qi L. Research progress on the mitochondrial mechanism of age-related non-alcoholic fatty liver. World J Gastroenterol 2023; 29:1982-1993. [PMID: 37155524 PMCID: PMC10122792 DOI: 10.3748/wjg.v29.i13.1982] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Revised: 02/20/2023] [Accepted: 03/13/2023] [Indexed: 04/06/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease worldwide. Reduced activity and slower metabolism in the elderly affect the balance of lipid metabolism in the liver leading to the accumulation of lipids. This affects the mitochondrial respiratory chain and the efficiency of β-oxidation and induces the overproduction of reactive oxygen species. In addition, the dynamic balance of the mitochondria is disrupted during the ageing process, which inhibits its phagocytic function and further aggravates liver injury, leading to a higher incidence of NAFLD in the elderly population. The present study reviewed the manifestations, role and mechanism of mitochondrial dysfunction in the progression of NAFLD in the elderly. Based on the understanding of mitochondrial dysfunction and abnormal lipid metabolism, this study discusses the treatment strategies and the potential therapeutic targets for NAFLD, including lipid accumulation, antioxidation, mitophagy and liver-protecting drugs. The purpose is to provide new ideas for the development of innovative drugs for the prevention and treatment of NAFLD.
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Affiliation(s)
- Dan Wang
- College of Basic Medicine, Beihua University, Jilin 132013, Jilin Province, China
| | - Duo-Chun Ji
- College of Basic Medicine, Beihua University, Jilin 132013, Jilin Province, China
| | - Chun-Yan Yu
- College of Basic Medicine, Beihua University, Jilin 132013, Jilin Province, China
| | - Dan-Ni Wu
- College of Basic Medicine, Beihua University, Jilin 132013, Jilin Province, China
| | - Ling Qi
- Central Laboratory, Qingyuan People's Hospital, Qingyuan 511518, Guangdong Province, China
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14
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Fan Y, Lu J, Fan J, Guan S. 1,3-dichloro-2-propanol caused lipid droplets accumulation by suppressing neutral lipases via BMAL1 in hepatocytes. Food Chem Toxicol 2023; 174:113670. [PMID: 36805544 DOI: 10.1016/j.fct.2023.113670] [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: 12/14/2022] [Revised: 02/03/2023] [Accepted: 02/13/2023] [Indexed: 02/19/2023]
Abstract
Circadian rhythm regulates body physiology and metabolism to adapt to the external environment. 1,3-dichloro-2-propanol (1,3-DCP) is a food pollutant formed during food processing. Our study explored whether toxicity of 1,3-DCP was related to circadian rhythm. We discovered that 1,3-DCP caused lipid droplets (LDs) accumulation via suppression of neutral lipases ATGL and HSL in mice liver and HepG2 cells. Meanwhile, 1,3-DCP caused rhythmic disruption of key circadian rhythm molecules BMAL1/CLOCK at protein and mRNA levels in HepG2 cells. Studies have shown that BMAL1 regulates PPARα by binding to the promoter E-box. 1,3-DCP inhibited PPARα expression. A PPARα activator WY-14643 up-regulated ATGL and HSL expression. BMAL1 overexpression up-regulated PPARα, ATGL and HSL expression. WY-14643 or BMAL1 overexpression attenuated 1,3-DCP-caused LDs accumulation in HepG2 cells. The results revealed that 1,3-DCP caused LDs accumulation by neutral lipases suppression via inhibiting key circadian rhythm protein BMAL1, indicating that circadian rhythm can be related to the regulation of LDs accumulation caused by 1,3-DCP.
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Affiliation(s)
- Yong Fan
- College of Food Science and Engineering, Jilin University, Changchun, Jilin, 130062, People's Republic of China
| | - Jing Lu
- College of Food Science and Engineering, Jilin University, Changchun, Jilin, 130062, People's Republic of China; Key Laboratory of Zoonosis, Ministry of Education College of Veterinary Medicine, Jilin University, Changchun, Jilin, 130062, People's Republic of China
| | - Jinghui Fan
- Department of Pharmacy, Hongqi Hospital Affiliated to Mudanjiang Medical University, Mudanjiang, 157011, People's Republic of China
| | - Shuang Guan
- College of Food Science and Engineering, Jilin University, Changchun, Jilin, 130062, People's Republic of China; Key Laboratory of Zoonosis, Ministry of Education College of Veterinary Medicine, Jilin University, Changchun, Jilin, 130062, People's Republic of China.
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15
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Kim HH, Shim YR, Choi SE, Kim MH, Lee G, You HJ, Choi WM, Yang K, Ryu T, Kim K, Kim MJ, Woo C, Chung KPS, Hong SH, Eun HS, Kim SH, Ko G, Park JE, Gao B, Kim W, Jeong WI. Catecholamine induces Kupffer cell apoptosis via growth differentiation factor 15 in alcohol-associated liver disease. Exp Mol Med 2023; 55:158-170. [PMID: 36631664 PMCID: PMC9898237 DOI: 10.1038/s12276-022-00921-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2022] [Revised: 10/26/2022] [Accepted: 11/18/2022] [Indexed: 01/13/2023] Open
Abstract
Chronic alcohol consumption often induces hepatic steatosis but rarely causes severe inflammation in Kupffer cells (KCs) despite the increased hepatic influx of lipopolysaccharide (LPS), suggesting the presence of a veiled tolerance mechanism. In addition to LPS, the liver is affected by several gut-derived neurotransmitters through the portal blood, but the effects of catecholamines on KCs have not been clearly explored in alcohol-associated liver disease (ALD). Hence, we investigated the regulatory roles of catecholamine on inflammatory KCs under chronic alcohol exposure. We discovered that catecholamine levels were significantly elevated in the cecum, portal blood, and liver tissues of chronic ethanol-fed mice. Increased catecholamines induced mitochondrial translocation of cytochrome P450 2E1 in perivenous hepatocytes expressing the β2-adrenergic receptor (ADRB2), leading to the enhanced production of growth differentiation factor 15 (GDF15). Subsequently, GDF15 profoundly increased ADRB2 expression in adjacent inflammatory KCs to facilitate catecholamine/ADRB2-mediated apoptosis. Single-cell RNA sequencing of KCs confirmed the elevated expression of Adrb2 and apoptotic genes after chronic ethanol intake. Genetic ablation of Adrb2 or hepatic Gdf15 robustly decreased the number of apoptotic KCs near perivenous areas, exacerbating alcohol-associated inflammation. Consistently, we found that blood and stool catecholamine levels and perivenous GDF15 expression were increased in patients with early-stage ALD along with an increase in apoptotic KCs. Our findings reveal a novel protective mechanism against ALD, in which the catecholamine/GDF15 axis plays a critical role in KC apoptosis, and identify a unique neuro-metabo-immune axis between the gut and liver that elicits hepatoprotection against alcohol-mediated pathogenic challenges.
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Affiliation(s)
- Hee-Hoon Kim
- grid.37172.300000 0001 2292 0500Laboratory of Liver Research, Graduate School of Medical Science and Engineering, KAIST, Daejeon, 34141 Republic of Korea
| | - Young-Ri Shim
- grid.37172.300000 0001 2292 0500Laboratory of Liver Research, Graduate School of Medical Science and Engineering, KAIST, Daejeon, 34141 Republic of Korea
| | - Sung Eun Choi
- grid.37172.300000 0001 2292 0500Laboratory of Liver Research, Graduate School of Medical Science and Engineering, KAIST, Daejeon, 34141 Republic of Korea
| | - Myung-Ho Kim
- grid.37172.300000 0001 2292 0500Laboratory of Liver Research, Graduate School of Medical Science and Engineering, KAIST, Daejeon, 34141 Republic of Korea ,grid.32224.350000 0004 0386 9924Liver Center, Gastrointestinal Division, Massachusetts General Hospital, Boston, MA USA
| | - Giljae Lee
- grid.31501.360000 0004 0470 5905Department of Environmental Health Sciences, Graduate School of Public Health, Seoul National University, Seoul, 08826 Republic of Korea
| | - Hyun Ju You
- grid.31501.360000 0004 0470 5905Department of Environmental Health Sciences, Graduate School of Public Health, Seoul National University, Seoul, 08826 Republic of Korea
| | - Won-Mook Choi
- grid.37172.300000 0001 2292 0500Laboratory of Liver Research, Graduate School of Medical Science and Engineering, KAIST, Daejeon, 34141 Republic of Korea ,grid.413967.e0000 0001 0842 2126Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505 Republic of Korea
| | - Keungmo Yang
- grid.37172.300000 0001 2292 0500Laboratory of Liver Research, Graduate School of Medical Science and Engineering, KAIST, Daejeon, 34141 Republic of Korea
| | - Tom Ryu
- grid.37172.300000 0001 2292 0500Laboratory of Liver Research, Graduate School of Medical Science and Engineering, KAIST, Daejeon, 34141 Republic of Korea
| | - Kyurae Kim
- grid.37172.300000 0001 2292 0500Laboratory of Liver Research, Graduate School of Medical Science and Engineering, KAIST, Daejeon, 34141 Republic of Korea
| | - Min Jeong Kim
- grid.37172.300000 0001 2292 0500Laboratory of Liver Research, Graduate School of Medical Science and Engineering, KAIST, Daejeon, 34141 Republic of Korea
| | - Chaerin Woo
- grid.37172.300000 0001 2292 0500Laboratory of Liver Research, Graduate School of Medical Science and Engineering, KAIST, Daejeon, 34141 Republic of Korea
| | - Katherine Po Sin Chung
- grid.37172.300000 0001 2292 0500Laboratory of Liver Research, Graduate School of Medical Science and Engineering, KAIST, Daejeon, 34141 Republic of Korea
| | - Song Hwa Hong
- grid.37172.300000 0001 2292 0500Laboratory of Liver Research, Graduate School of Medical Science and Engineering, KAIST, Daejeon, 34141 Republic of Korea
| | - Hyuk Soo Eun
- grid.37172.300000 0001 2292 0500Laboratory of Liver Research, Graduate School of Medical Science and Engineering, KAIST, Daejeon, 34141 Republic of Korea ,grid.254230.20000 0001 0722 6377Department of Internal Medicine, Chungnam National University, College of Medicine, Daejeon, 35015 Republic of Korea
| | - Seok-Hwan Kim
- grid.254230.20000 0001 0722 6377Department of Surgery, Chungnam National University, College of Medicine, Daejeon, 35015 Republic of Korea
| | - GwangPyo Ko
- grid.31501.360000 0004 0470 5905Department of Environmental Health Sciences, Graduate School of Public Health, Seoul National University, Seoul, 08826 Republic of Korea
| | - Jong-Eun Park
- grid.37172.300000 0001 2292 0500Single-Cell Medical Genomics Laboratory, Graduate School of Medical Science and Engineering, KAIST, Daejeon, 34141 Republic of Korea
| | - Bin Gao
- grid.420085.b0000 0004 0481 4802Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institute of Health, Bethesda, MD 20892 USA
| | - Won Kim
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul Metropolitan Government Boramae Medical Center, Seoul, 07061, Republic of Korea.
| | - Won-Il Jeong
- Laboratory of Liver Research, Graduate School of Medical Science and Engineering, KAIST, Daejeon, 34141, Republic of Korea.
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Li SX, Chen L, Li MQ, Lv GY. Pharmacological agents for defatting livers by normothermic machine perfusion. Artif Organs 2022. [PMID: 36514256 DOI: 10.1111/aor.14478] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Revised: 11/28/2022] [Accepted: 12/04/2022] [Indexed: 12/15/2022]
Abstract
BACKGROUND Ex-vivo normothermic machine perfusion (NMP) preserves the liver metabolism at 37°C and has rapidly developed as a promising approach for assessing the viability and improving the performance of organs from expanded criteria donors, including fatty liver grafts. NMP is an effective method for defatting fatty livers when combined with pharmaceutical therapies. Pharmacological agents have been shown to facilitate liver defatting by NMP. OBSERVATIONS This systematic review summarizes available pharmacological therapies for liver defatting, with a particular emphasis on defatting agents that can be employed clinically as defatting components during liver NMP as an ex vivo translational paradigm. CONCLUSION NMP provides an opportunity for organ treatment and can be used as a defatting platform in the future with defatting agents. Nagrath's cocktail is the most commonly used defatting cocktail in NMP; however, its carcinogenic components may limit its clinical application. Thus, the combination of a defatting cocktail with a new clinically applicable component, for example, a polyphenolic natural compound, may be a novel pharmacological option.
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Affiliation(s)
- Shu-Xuan Li
- Department of Hepatobiliary and Pancreatic Surgery, First Hospital of Jilin University, Jilin, China
| | - Lanlan Chen
- Department of Hepatobiliary and Pancreatic Surgery, First Hospital of Jilin University, Jilin, China
| | - Ming-Qian Li
- Department of Hepatobiliary and Pancreatic Surgery, First Hospital of Jilin University, Jilin, China
| | - Guo-Yue Lv
- Department of Hepatobiliary and Pancreatic Surgery, First Hospital of Jilin University, Jilin, China
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Morphofunctional State and Circadian Rhythms of the Liver of Female Rats under the Influence of Chronic Alcohol Intoxication and Constant Lighting. Int J Mol Sci 2022; 23:ijms231810744. [PMID: 36142658 PMCID: PMC9502101 DOI: 10.3390/ijms231810744] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2022] [Revised: 09/12/2022] [Accepted: 09/13/2022] [Indexed: 11/17/2022] Open
Abstract
A separate and combined effect of constant illumination and chronic alcohol intoxication (CAI) on diurnal dynamics of micromorphometric parameters of hepatocytes in female Wistar rats and p53, Ki-67, PER2, BMAL1, and ADH5 expression in these cells were studied. The increase in apoptotic activity and proliferation in all animals under the action of chronodestructors is shown. All experimental animals showed a decrease in BMAL1 expression and increase in PER2 expression; ADH5 is overexpressed under the influence of ethanol. Circadian rhythms (CRs) of BMAL1, PER2, p53, and Ki-67 expression persist in all groups, except combined action of chronodestructors, and ADH5 CRs persist in all groups—thus, these rhythms in females are quite stable. CRs of the hepatocyte nuclei area are preserved in all the studied groups, although they undergo a significant shift. At the same time, the CRs of the hepatocyte area are destroyed under the action of light, both independently and in combination with CAI, and the CR of the nuclear-cytoplasmic ratio (NCR) is destroyed by exposure to CAI. It can be assumed that CRs of the hepatocyte area are significantly affected by dark deprivation and NCR rhythm is sensitive to ethanol consumption, while the stability of studied genes’ expression rhythms at separate influences of studied chronodestructors is maintained by yet unknown adaptation mechanisms. It is necessary to note that, according to our previous studies of male rats, rat females show significantly greater stability of the studied CRs.
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Yang S, Liu T, Hu C, Li W, Meng Y, Li H, Song C, He C, Zhou Y, Fan Y. Ginsenoside Compound K Protects against Obesity through Pharmacological Targeting of Glucocorticoid Receptor to Activate Lipophagy and Lipid Metabolism. Pharmaceutics 2022; 14:pharmaceutics14061192. [PMID: 35745765 PMCID: PMC9231161 DOI: 10.3390/pharmaceutics14061192] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2022] [Revised: 05/19/2022] [Accepted: 05/23/2022] [Indexed: 12/10/2022] Open
Abstract
(1) Background: The glucocorticoid receptor (GR) plays a key role in lipid metabolism, but investigations of GR activation as a potential therapeutic approach have been hampered by a lack of selective agonists. Ginsenoside compound K (CK) is natural small molecule with a steroid-like structure that offers a variety of therapeutic benefits. Our study validates CK as a novel GR agonist for the treatment of obesity. (2) Methods: By using pulldown and RNA interference, we determined that CK binds to GR. The anti-obesity potential effects of CK were investigated in obese mice, including through whole-body energy homeostasis, glucose and insulin tolerance, and biochemical and proteomic analysis. Using chromatin immunoprecipitation, we identified GR binding sites upstream of lipase ATGL. (3) Results: We demonstrated that CK reduced the weight and blood lipids of mice more significantly than the drug Orlistat. Proteomics data showed that CK up-regulated autophagy regulatory proteins, enhanced fatty acid oxidation proteins, and decreased fatty acid synthesis proteins. CK induced lipophagy with the initial formation of the phagophore via AMPK/ULK1 activation. However, a blockade of autophagy did not disturb the increase in CK on lipase expression, suggesting that autophagy and lipase are independent pathways in the function of CK. The pulldown and siRNA experiments showed that GR is the critical target. After binding to GR, CK not only activated lipophagy, but also promoted the binding of GR to the ATGL promoter. (4) Conclusions: Our findings indicate that CK is a natural food candidate for reducing fat content and weight.
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Affiliation(s)
- Siwen Yang
- Engineering Research Center of Glycoconjugates of Ministry of Education, Jilin Provincial Key Laboratory of Chemistry and Biology of Changbai Mountain Natural Drugs, School of Life Sciences, Northeast Normal University, Changchun 130024, China; (S.Y.); (T.L.); (C.H.); (W.L.); (Y.M.); (H.L.); (C.S.)
| | - Ting Liu
- Engineering Research Center of Glycoconjugates of Ministry of Education, Jilin Provincial Key Laboratory of Chemistry and Biology of Changbai Mountain Natural Drugs, School of Life Sciences, Northeast Normal University, Changchun 130024, China; (S.Y.); (T.L.); (C.H.); (W.L.); (Y.M.); (H.L.); (C.S.)
| | - Chenxing Hu
- Engineering Research Center of Glycoconjugates of Ministry of Education, Jilin Provincial Key Laboratory of Chemistry and Biology of Changbai Mountain Natural Drugs, School of Life Sciences, Northeast Normal University, Changchun 130024, China; (S.Y.); (T.L.); (C.H.); (W.L.); (Y.M.); (H.L.); (C.S.)
| | - Weili Li
- Engineering Research Center of Glycoconjugates of Ministry of Education, Jilin Provincial Key Laboratory of Chemistry and Biology of Changbai Mountain Natural Drugs, School of Life Sciences, Northeast Normal University, Changchun 130024, China; (S.Y.); (T.L.); (C.H.); (W.L.); (Y.M.); (H.L.); (C.S.)
| | - Yuhan Meng
- Engineering Research Center of Glycoconjugates of Ministry of Education, Jilin Provincial Key Laboratory of Chemistry and Biology of Changbai Mountain Natural Drugs, School of Life Sciences, Northeast Normal University, Changchun 130024, China; (S.Y.); (T.L.); (C.H.); (W.L.); (Y.M.); (H.L.); (C.S.)
| | - Haiyang Li
- Engineering Research Center of Glycoconjugates of Ministry of Education, Jilin Provincial Key Laboratory of Chemistry and Biology of Changbai Mountain Natural Drugs, School of Life Sciences, Northeast Normal University, Changchun 130024, China; (S.Y.); (T.L.); (C.H.); (W.L.); (Y.M.); (H.L.); (C.S.)
| | - Chengcheng Song
- Engineering Research Center of Glycoconjugates of Ministry of Education, Jilin Provincial Key Laboratory of Chemistry and Biology of Changbai Mountain Natural Drugs, School of Life Sciences, Northeast Normal University, Changchun 130024, China; (S.Y.); (T.L.); (C.H.); (W.L.); (Y.M.); (H.L.); (C.S.)
| | - Congcong He
- Department of Cell and Molecular Biology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA;
| | - Yifa Zhou
- Engineering Research Center of Glycoconjugates of Ministry of Education, Jilin Provincial Key Laboratory of Chemistry and Biology of Changbai Mountain Natural Drugs, School of Life Sciences, Northeast Normal University, Changchun 130024, China; (S.Y.); (T.L.); (C.H.); (W.L.); (Y.M.); (H.L.); (C.S.)
- Correspondence: (Y.Z.); (Y.F.)
| | - Yuying Fan
- Engineering Research Center of Glycoconjugates of Ministry of Education, Jilin Provincial Key Laboratory of Chemistry and Biology of Changbai Mountain Natural Drugs, School of Life Sciences, Northeast Normal University, Changchun 130024, China; (S.Y.); (T.L.); (C.H.); (W.L.); (Y.M.); (H.L.); (C.S.)
- Correspondence: (Y.Z.); (Y.F.)
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Neuman MG, Seitz HK, Tuma PL, Osna NA, Casey CA, Kharbanda KK, Cohen LB, Malnick SDH, Adhikari R, Mitra R, Dagur RS, Ganesan M, Srinivas C, Madan Kumar A, New-Aaron M, Poluektova L, Thomes PG, Rasineni K, Opris M, Teschke R. Alcohol: basic and translational research; 15th annual Charles Lieber &1st Samuel French satellite symposium. Exp Mol Pathol 2022; 126:104750. [PMID: 35192844 PMCID: PMC9167794 DOI: 10.1016/j.yexmp.2022.104750] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Revised: 12/28/2021] [Accepted: 01/24/2022] [Indexed: 02/05/2023]
Abstract
The present review is based on the research presented at the symposium dedicated to the legacy of the two scientists that made important discoveries in the field of alcohol-induced liver damage: Professors C.S. Lieber and S.W. French. The invited speakers described pharmacological, toxicological and patho-physiological effects of alcohol misuse. Moreover, genetic biomarkers determining adverse drug reactions due to interactions between therapeutics used for chronic or infectious diseases and alcohol exposure were discussed. The researchers presented their work in areas of alcohol-induced impairment in lipid protein trafficking and endocytosis, as well as the role of lipids in the development of fatty liver. The researchers showed that alcohol leads to covalent modifications that promote hepatic dysfunction and injury. We concluded that using new advanced techniques and research ideas leads to important discoveries in science.
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Affiliation(s)
- Manuela G Neuman
- In Vitro Drug Safety and Biotechnology, Department of Pharmacology and Toxicology, University of Toronto, Toronto, Canada.
| | - Helmut K Seitz
- Centre of Liver and Alcohol Diseases, Ethianum Clinic, University of Heidelberg, Germany
| | - Pamela L Tuma
- The Catholic University of America, Department of Biology, Washington, DC 20064, USA
| | - Natalia A Osna
- VA-Nebraska-Western Iowa Health Care System, Department of Veterans' Affairs, Omaha, NE, and Department of Internal Medicine, Section of Gastroenterology-Hepatology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Carol A Casey
- VA-Nebraska-Western Iowa Health Care System, Department of Veterans' Affairs, Omaha, NE, and Department of Internal Medicine, Section of Gastroenterology-Hepatology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Kusum K Kharbanda
- VA-Nebraska-Western Iowa Health Care System, Department of Veterans' Affairs, Omaha, NE, and Department of Internal Medicine, Section of Gastroenterology-Hepatology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Lawrence B Cohen
- Division of Gastroenterology, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Canada
| | - Steve D H Malnick
- Department of Internal Medicine C, Kaplan Medical Center, Affiliated Hebrew University, Jerusalem, Israel
| | - Raghabendra Adhikari
- The Catholic University of America, Department of Biology, Washington, DC 20064, USA
| | - Ramyajit Mitra
- The Catholic University of America, Department of Biology, Washington, DC 20064, USA
| | - Raghubendra Singh Dagur
- VA-Nebraska-Western Iowa Health Care System, Department of Veterans' Affairs, Omaha, NE, and Department of Internal Medicine, Section of Gastroenterology-Hepatology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Murali Ganesan
- VA-Nebraska-Western Iowa Health Care System, Department of Veterans' Affairs, Omaha, NE, and Department of Internal Medicine, Section of Gastroenterology-Hepatology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Chava Srinivas
- VA-Nebraska-Western Iowa Health Care System, Department of Veterans' Affairs, Omaha, NE, and Department of Internal Medicine, Section of Gastroenterology-Hepatology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Arumugam Madan Kumar
- VA-Nebraska-Western Iowa Health Care System, Department of Veterans' Affairs, Omaha, NE, and Department of Internal Medicine, Section of Gastroenterology-Hepatology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Moses New-Aaron
- VA-Nebraska-Western Iowa Health Care System, Department of Veterans' Affairs, Omaha, NE, and Department of Internal Medicine, Section of Gastroenterology-Hepatology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Larisa Poluektova
- VA-Nebraska-Western Iowa Health Care System, Department of Veterans' Affairs, Omaha, NE, and Department of Internal Medicine, Section of Gastroenterology-Hepatology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Paul G Thomes
- VA-Nebraska-Western Iowa Health Care System, Department of Veterans' Affairs, Omaha, NE, and Department of Internal Medicine, Section of Gastroenterology-Hepatology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Karuna Rasineni
- VA-Nebraska-Western Iowa Health Care System, Department of Veterans' Affairs, Omaha, NE, and Department of Internal Medicine, Section of Gastroenterology-Hepatology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Mihai Opris
- In Vitro Drug Safety and Biotechnology, Department of Pharmacology and Toxicology, University of Toronto, Toronto, Canada; Family Medicine Clinic CAR, Bucharest, Romania
| | - Rolf Teschke
- Department of Internal Medicine II, Division of Gastroenterology and Hepatology, Klinikum Hanau, Hanau, Academic Teaching Hospital of the Medical Faculty, Goethe University Frankfurt/ Main, Frankfurt/Main, Germany
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20
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Sandoval C, Mella L, Godoy K, Adeli K, Farías J. β-Carotene Increases Activity of Cytochrome P450 2E1 during Ethanol Consumption. Antioxidants (Basel) 2022; 11:1033. [PMID: 35624897 PMCID: PMC9137679 DOI: 10.3390/antiox11051033] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2022] [Revised: 04/27/2022] [Accepted: 05/13/2022] [Indexed: 02/01/2023] Open
Abstract
One of the key routes through which ethanol induces oxidative stress appears to be the activation of cytochrome P450 2E1 at different levels of ethanol intake. Our aim was to determine if oral β-carotene intake had an antioxidant effect on CYP2E1 gene expression in mice that had previously consumed ethanol. C57BL/6 mice were used and distributed into: control (C), low-dose alcohol (LA), moderate-dose alcohol (MA), β-carotene (B), low-dose alcohol+β-carotene (LA + B), and moderate-dose alcohol+β-carotene (MA + B). Animals were euthanized at the end of the experiment, and liver tissue was taken from each one. CYP2E1 was measured using qPCR to detect liver damage. The relative expression level of each RNA was estimated using the comparative threshold cycle (Ct) technique (2-ΔΔCT method) by averaging the Ct values from three replicates. The LA+B (2267 ± 0.707) and MA+B (2.307 ± 0.384) groups had the highest CYP2E1 fold change values. On the other hand, the C (1.053 ± 0.292) and LA (1.240 ± 0.163) groups had the lowest levels. These results suggest that ethanol feeding produced a fold increase in CYP2E1 protein in mice as compared to the control group. Increased CYP2E1 activity was found to support the hypothesis that β-carotene might be dangerous during ethanol exposure in animal models. Our findings imply that β-carotene can increase the hepatic damage caused by low and high doses of alcohol. Therefore, the quantity of alcohol ingested, the exposure period, the regulatory mechanisms of alcoholic liver damage, and the signaling pathways involved in the consumption of both alcohol and antioxidant must all be considered.
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Affiliation(s)
- Cristian Sandoval
- Escuela de Tecnología Médica, Facultad de Salud, Universidad Santo Tomás, Los Carreras 753, Osorno 5310431, Chile
- Departamento de Ingeniería Química, Facultad de Ingeniería y Ciencias, Universidad de La Frontera, Temuco 4811230, Chile
- Departamento de Ciencias Preclínicas, Facultad de Medicina, Universidad de La Frontera, Temuco 4811230, Chile
| | - Luciana Mella
- Carrera de Tecnología Médica, Facultad de Medicina, Universidad de La Frontera, Temuco 4811230, Chile;
| | - Karina Godoy
- Núcleo Científico y Tecnológico en Biorecursos (BIOREN), Universidad de La Frontera, Temuco 4811230, Chile;
| | - Khosrow Adeli
- Molecular Medicine, Research Institute The Hospital for Sick Children University of Toronto, Toronto, ON M5G 1X8, Canada;
| | - Jorge Farías
- Departamento de Ingeniería Química, Facultad de Ingeniería y Ciencias, Universidad de La Frontera, Temuco 4811230, Chile
- Núcleo Científico y Tecnológico en Biorecursos (BIOREN), Universidad de La Frontera, Temuco 4811230, Chile;
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21
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Lelou E, Corlu A, Nesseler N, Rauch C, Mallédant Y, Seguin P, Aninat C. The Role of Catecholamines in Pathophysiological Liver Processes. Cells 2022; 11:cells11061021. [PMID: 35326472 PMCID: PMC8947265 DOI: 10.3390/cells11061021] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2022] [Revised: 03/10/2022] [Accepted: 03/15/2022] [Indexed: 02/06/2023] Open
Abstract
Over the last few years, the number of research publications about the role of catecholamines (epinephrine, norepinephrine, and dopamine) in the development of liver diseases such as liver fibrosis, fatty liver diseases, or liver cancers is constantly increasing. However, the mechanisms involved in these effects are not well understood. In this review, we first recapitulate the way the liver is in contact with catecholamines and consider liver implications in their metabolism. A focus on the expression of the adrenergic and dopaminergic receptors by the liver cells is also discussed. Involvement of catecholamines in physiological (glucose metabolism, lipids metabolism, and liver regeneration) and pathophysiological (impact on drug-metabolizing enzymes expression, liver dysfunction during sepsis, fibrosis development, or liver fatty diseases and liver cancers) processes are then discussed. This review highlights the importance of understanding the mechanisms through which catecholamines influence liver functions in order to draw benefit from the adrenergic and dopaminergic antagonists currently marketed. Indeed, as these molecules are well-known drugs, their use as therapies or adjuvant treatments in several liver diseases could be facilitated.
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Affiliation(s)
- Elise Lelou
- INSERM, Université Rennes, INRAE, Institut NuMeCan, Nutrition, Metabolisms and Cancer, F-35000 Rennes, France; (E.L.); (A.C.); (N.N.); (C.R.); (Y.M.); (P.S.)
| | - Anne Corlu
- INSERM, Université Rennes, INRAE, Institut NuMeCan, Nutrition, Metabolisms and Cancer, F-35000 Rennes, France; (E.L.); (A.C.); (N.N.); (C.R.); (Y.M.); (P.S.)
| | - Nicolas Nesseler
- INSERM, Université Rennes, INRAE, Institut NuMeCan, Nutrition, Metabolisms and Cancer, F-35000 Rennes, France; (E.L.); (A.C.); (N.N.); (C.R.); (Y.M.); (P.S.)
- CHU Rennes, Department of Anesthesia and Critical Care, F-35000 Rennes, France
| | - Claudine Rauch
- INSERM, Université Rennes, INRAE, Institut NuMeCan, Nutrition, Metabolisms and Cancer, F-35000 Rennes, France; (E.L.); (A.C.); (N.N.); (C.R.); (Y.M.); (P.S.)
| | - Yannick Mallédant
- INSERM, Université Rennes, INRAE, Institut NuMeCan, Nutrition, Metabolisms and Cancer, F-35000 Rennes, France; (E.L.); (A.C.); (N.N.); (C.R.); (Y.M.); (P.S.)
- CHU Rennes, Department of Anesthesia and Critical Care, F-35000 Rennes, France
| | - Philippe Seguin
- INSERM, Université Rennes, INRAE, Institut NuMeCan, Nutrition, Metabolisms and Cancer, F-35000 Rennes, France; (E.L.); (A.C.); (N.N.); (C.R.); (Y.M.); (P.S.)
- CHU Rennes, Department of Anesthesia and Critical Care, F-35000 Rennes, France
| | - Caroline Aninat
- INSERM, Université Rennes, INRAE, Institut NuMeCan, Nutrition, Metabolisms and Cancer, F-35000 Rennes, France; (E.L.); (A.C.); (N.N.); (C.R.); (Y.M.); (P.S.)
- Correspondence: ; Tel.: +33-2-23-23-48-68
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22
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Sandoval C, Farías J, Zamorano M, Herrera C. Vitamin Supplements as a Nutritional Strategy against Chronic Alcohol Consumption? An Updated Review. Antioxidants (Basel) 2022; 11:564. [PMID: 35326214 PMCID: PMC8945215 DOI: 10.3390/antiox11030564] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2022] [Revised: 03/12/2022] [Accepted: 03/12/2022] [Indexed: 02/07/2023] Open
Abstract
Several studies have shown that blood vitamin levels are low in alcoholic patients. In effect, alcohol use abuse is considered a chronic disease that promotes the pathogenesis of many fatal diseases, such as cancer and liver cirrhosis. The alcohol effects in the liver can be prevented by antioxidant mechanisms, which induces enzymatic as well as other nonenzymatic pathways. The effectiveness of several antioxidants has been evaluated. However, these studies have been accompanied by uncertainty as mixed results were reported. Thus, the aim of the present review article was to examine the current knowledge on vitamin deficiency and its role in chronic liver disease. Our review found that deficiencies in nutritional vitamins could develop rapidly during chronic liver disease due to diminished hepatic storage and that inadequate vitamins intake and alcohol consumption may interact to deplete vitamin levels. Numerous studies have described that vitamin supplementation could reduce hepatotoxicity. However, further studies with reference to the changes in vitamin status and the nutritional management of chronic liver disease are in demand.
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Affiliation(s)
- Cristian Sandoval
- Escuela de Tecnología Médica, Facultad de Salud, Universidad Santo Tomás, Los Carreras 753, Osorno 5310431, Chile
- Departamento de Ingeniería Química, Facultad de Ingeniería y Ciencias, Universidad de La Frontera, Temuco 4811230, Chile; (J.F.); (M.Z.)
- Departamento de Ciencias Preclínicas, Facultad de Medicina, Universidad de La Frontera, Temuco 4811230, Chile;
| | - Jorge Farías
- Departamento de Ingeniería Química, Facultad de Ingeniería y Ciencias, Universidad de La Frontera, Temuco 4811230, Chile; (J.F.); (M.Z.)
- Núcleo Científico y Tecnológico en Biorecursos (BIOREN), Universidad de La Frontera, Temuco 4811230, Chile
| | - Mauricio Zamorano
- Departamento de Ingeniería Química, Facultad de Ingeniería y Ciencias, Universidad de La Frontera, Temuco 4811230, Chile; (J.F.); (M.Z.)
- Núcleo Científico y Tecnológico en Biorecursos (BIOREN), Universidad de La Frontera, Temuco 4811230, Chile
| | - Christian Herrera
- Departamento de Ciencias Preclínicas, Facultad de Medicina, Universidad de La Frontera, Temuco 4811230, Chile;
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23
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Abstract
Lipophagy is a central cellular process for providing the cell with a readily utilized, high energy source of neutral lipids. Since its discovery over a decade ago, we are just starting to understand the molecular components that drive lipophagy, how it is activated in response to nutrient availability, and its potential as a therapeutic target in disease. In this Cell Science at a Glance article and the accompanying poster, we first provide a brief overview of the different structural and enzymatic proteins that comprise the lipid droplet (LD) proteome and reside within the limiting phospholipid monolayer of this complex organelle. We then highlight key players in the catabolic breakdown of LDs during the functionally linked lipolysis and lipophagy processes. Finally, we discuss what is currently known about macro- and micro-lipophagy based on findings in yeast, mammalian and other model systems, and how impairment of these important functions can lead to disease states.
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Affiliation(s)
- Micah B. Schott
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, 985870 Nebraska Medical Center, Omaha, NE 68198, USA
| | - Cody N. Rozeveld
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, 985870 Nebraska Medical Center, Omaha, NE 68198, USA
| | - Shaun G. Weller
- Department of Biochemistry and Molecular Biology and the Center for Digestive Diseases, Mayo Clinic, 200 1st St SW, Rochester, MN 55905, USA
| | - Mark A. McNiven
- Department of Biochemistry and Molecular Biology and the Center for Digestive Diseases, Mayo Clinic, 200 1st St SW, Rochester, MN 55905, USA
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24
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Adipose Triglyceride Lipase in Hepatic Physiology and Pathophysiology. Biomolecules 2021; 12:biom12010057. [PMID: 35053204 PMCID: PMC8773762 DOI: 10.3390/biom12010057] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Revised: 12/28/2021] [Accepted: 12/28/2021] [Indexed: 12/25/2022] Open
Abstract
The liver is extremely active in oxidizing triglycerides (TG) for energy production. An imbalance between TG synthesis and hydrolysis leads to metabolic disorders in the liver, including excessive lipid accumulation, oxidative stress, and ultimately liver damage. Adipose triglyceride lipase (ATGL) is the rate-limiting enzyme that catalyzes the first step of TG breakdown to glycerol and fatty acids. Although its role in controlling lipid homeostasis has been relatively well-studied in the adipose tissue, heart, and skeletal muscle, it remains largely unknown how and to what extent ATGL is regulated in the liver, responds to stimuli and regulators, and mediates disease progression. Therefore, in this review, we describe the current understanding of the structure–function relationship of ATGL, the molecular mechanisms of ATGL regulation at translational and post-translational levels, and—most importantly—its role in lipid and glucose homeostasis in health and disease with a focus on the liver. Advances in understanding the molecular mechanisms underlying hepatic lipid accumulation are crucial to the development of targeted therapies for treating hepatic metabolic disorders.
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25
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Smolič T, Zorec R, Vardjan N. Pathophysiology of Lipid Droplets in Neuroglia. Antioxidants (Basel) 2021; 11:22. [PMID: 35052526 PMCID: PMC8773017 DOI: 10.3390/antiox11010022] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Revised: 12/16/2021] [Accepted: 12/17/2021] [Indexed: 12/12/2022] Open
Abstract
In recent years, increasing evidence regarding the functional importance of lipid droplets (LDs), cytoplasmic storage organelles in the central nervous system (CNS), has emerged. Although not abundantly present in the CNS under normal conditions in adulthood, LDs accumulate in the CNS during development and aging, as well as in some neurologic disorders. LDs are actively involved in cellular lipid turnover and stress response. By regulating the storage of excess fatty acids, cholesterol, and ceramides in addition to their subsequent release in response to cell needs and/or environmental stressors, LDs are involved in energy production, in the synthesis of membranes and signaling molecules, and in the protection of cells against lipotoxicity and free radicals. Accumulation of LDs in the CNS appears predominantly in neuroglia (astrocytes, microglia, oligodendrocytes, ependymal cells), which provide trophic, metabolic, and immune support to neuronal networks. Here we review the most recent findings on the characteristics and functions of LDs in neuroglia, focusing on astrocytes, the key homeostasis-providing cells in the CNS. We discuss the molecular mechanisms affecting LD turnover in neuroglia under stress and how this may protect neural cell function. We also highlight the role (and potential contribution) of neuroglial LDs in aging and in neurologic disorders.
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Affiliation(s)
- Tina Smolič
- Laboratory of Neuroendocrinology-Molecular Cell Physiology, Institute of Pathophysiology, Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia; (T.S.); (R.Z.)
- Laboratory of Cell Engineering, Celica Biomedical, 1000 Ljubljana, Slovenia
| | - Robert Zorec
- Laboratory of Neuroendocrinology-Molecular Cell Physiology, Institute of Pathophysiology, Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia; (T.S.); (R.Z.)
- Laboratory of Cell Engineering, Celica Biomedical, 1000 Ljubljana, Slovenia
| | - Nina Vardjan
- Laboratory of Neuroendocrinology-Molecular Cell Physiology, Institute of Pathophysiology, Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia; (T.S.); (R.Z.)
- Laboratory of Cell Engineering, Celica Biomedical, 1000 Ljubljana, Slovenia
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26
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Kozlova MA, Kirillov YA, Makartseva LA, Chernov I, Areshidze DA. Morphofunctional State and Circadian Rhythms of the Liver under the Influence of Chronic Alcohol Intoxication and Constant Lighting. Int J Mol Sci 2021; 22:ijms222313007. [PMID: 34884810 PMCID: PMC8657715 DOI: 10.3390/ijms222313007] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Revised: 11/25/2021] [Accepted: 11/29/2021] [Indexed: 01/10/2023] Open
Abstract
A study of the influence of chronic alcohol intoxication, constant illumination and their combined effects on the morphofunctional state of the rat liver and the circadian rhythms (CR) of the studied parameters of the organism was carried out. It was found that both alcohol and constant illumination caused significant changes in the structure of the liver, as well as in the circadian rhythmicity of micromorphometric parameters of hepatocytes, ALT, and total and direct bilirubin rhythms; however, the combined effects of ethanol and constant illumination had the most significant effect on the studied parameters of the organism. These two factors caused disturbances in the circadian rhythms of the micromorphometric parameters of hepatocytes, disruption of the circadian rhythms of total protein, albumin, AST, ALT, and direct and total bilirubin, as well as disturbances in the expression and rhythmicity of the studied clock genes against a background of the development of an inflammatory process in the liver.
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Affiliation(s)
- Maria A. Kozlova
- Laboratory of Cell Pathology, A.P. Avtsyn Research Institute of Human Morphology, 117218 Moscow, Russia; (M.A.K.); (Y.A.K.); (L.A.M.)
| | - Yuri A. Kirillov
- Laboratory of Cell Pathology, A.P. Avtsyn Research Institute of Human Morphology, 117218 Moscow, Russia; (M.A.K.); (Y.A.K.); (L.A.M.)
| | - Lyudmila A. Makartseva
- Laboratory of Cell Pathology, A.P. Avtsyn Research Institute of Human Morphology, 117218 Moscow, Russia; (M.A.K.); (Y.A.K.); (L.A.M.)
| | - Igor Chernov
- Department of Pathological Anatomy, Tyumen State Medical University, 625023 Tyumen, Russia;
| | - David A. Areshidze
- Laboratory of Cell Pathology, A.P. Avtsyn Research Institute of Human Morphology, 117218 Moscow, Russia; (M.A.K.); (Y.A.K.); (L.A.M.)
- Experimental Tumor Chemotherapy Group, Center for Screening and Preclinical Testing, Institute of Problems of Chemical Physics of the Russian Academy of Science, 142432 Chernogolovka, Russia
- Correspondence: ; Tel.: +7-909-643-37-56
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27
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Ashraf S, Ashraf N, Yilmaz G, Harmancey R. Crosstalk between beta-adrenergic and insulin signaling mediates mechanistic target of rapamycin hyperactivation in liver of high-fat diet-fed male mice. Physiol Rep 2021; 9:e14958. [PMID: 34231324 PMCID: PMC8261682 DOI: 10.14814/phy2.14958] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2021] [Revised: 06/17/2021] [Accepted: 06/17/2021] [Indexed: 11/24/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease. While increased nutrient intake and sympathetic activity have been associated with the disease, the pathogenesis of NAFLD remains incompletely understood. We investigated the impact of the interaction of high dietary fat and sugar intake with increased beta-adrenergic receptor (β-AR) signaling on the activity of nutrient-sensing pathways and fuel storage in the liver. C57BL/6J mice were fed a standard rodent diet (STD), a high-fat diet (HFD), a high-fat/high-sugar Western diet (WD), a high-sugar diet with mixed carbohydrates (HCD), or a high-sucrose diet (HSD). After 6 week on diets, mice were treated with isoproterenol (ISO) and the activity of liver mTOR complex 1 (mTORC1)-related signaling analyzed by immunoblotting and correlated with tissue triglyceride and glycogen contents. ISO-stimulated AKT- and ERK-mediated activation of mTORC1 in STD-fed mice. Consumption of all four high-calorie diets exacerbated downstream activation of ribosomal protein S6 kinase beta-1 (S6K1) in response to ISO. S6K1 activity was greater with the fat-enriched HFD and WD and correlated with the presence of metabolic syndrome and a stronger activation of AKT and ERK1/2 pathways. Fat-enriched diets also increased triglyceride accumulation and inhibited glycogen mobilization under β-AR stimulation. In conclusion, crosstalk between β-AR and insulin signaling may contribute to HFD-induced hepatic steatosis through ERK1/2- and AKT-mediated hyperactivation of the mTORC1/S6K1 axis. The findings provide further rationale for the development of therapies aimed at targeting augmented β-AR signaling in the pathogenesis of NAFLD.
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Affiliation(s)
- Sadia Ashraf
- Department of Physiology and BiophysicsUniversity of Mississippi Medical CenterJacksonMSUSA
- Mississippi Center for Obesity ResearchUniversity of Mississippi Medical CenterJacksonMSUSA
| | | | - Gizem Yilmaz
- Department of Physiology and BiophysicsUniversity of Mississippi Medical CenterJacksonMSUSA
- Mississippi Center for Obesity ResearchUniversity of Mississippi Medical CenterJacksonMSUSA
| | - Romain Harmancey
- Department of Physiology and BiophysicsUniversity of Mississippi Medical CenterJacksonMSUSA
- Mississippi Center for Obesity ResearchUniversity of Mississippi Medical CenterJacksonMSUSA
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28
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Smolič T, Tavčar P, Horvat A, Černe U, Halužan Vasle A, Tratnjek L, Kreft ME, Scholz N, Matis M, Petan T, Zorec R, Vardjan N. Astrocytes in stress accumulate lipid droplets. Glia 2021; 69:1540-1562. [PMID: 33609060 PMCID: PMC8248329 DOI: 10.1002/glia.23978] [Citation(s) in RCA: 68] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2020] [Revised: 01/14/2021] [Accepted: 02/01/2021] [Indexed: 02/06/2023]
Abstract
When the brain is in a pathological state, the content of lipid droplets (LDs), the lipid storage organelles, is increased, particularly in glial cells, but rarely in neurons. The biology and mechanisms leading to LD accumulation in astrocytes, glial cells with key homeostatic functions, are poorly understood. We imaged fluorescently labeled LDs by microscopy in isolated and brain tissue rat astrocytes and in glia-like cells in Drosophila brain to determine the (sub)cellular localization, mobility, and content of LDs under various stress conditions characteristic for brain pathologies. LDs exhibited confined mobility proximal to mitochondria and endoplasmic reticulum that was attenuated by metabolic stress and by increased intracellular Ca2+ , likely to enhance the LD-organelle interaction imaged by electron microscopy. When de novo biogenesis of LDs was attenuated by inhibition of DGAT1 and DGAT2 enzymes, the astrocyte cell number was reduced by ~40%, suggesting that in astrocytes LD turnover is important for cell survival and/or proliferative cycle. Exposure to noradrenaline, a brain stress response system neuromodulator, and metabolic and hypoxic stress strongly facilitated LD accumulation in astrocytes. The observed response of stressed astrocytes may be viewed as a support for energy provision, but also to be neuroprotective against the stress-induced lipotoxicity.
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Affiliation(s)
- Tina Smolič
- Laboratory of Neuroendocrinology-Molecular Cell Physiology, Faculty of Medicine, Institute of Pathophysiology, University of Ljubljana, Ljubljana, Slovenia
| | - Petra Tavčar
- Laboratory of Neuroendocrinology-Molecular Cell Physiology, Faculty of Medicine, Institute of Pathophysiology, University of Ljubljana, Ljubljana, Slovenia
| | - Anemari Horvat
- Laboratory of Neuroendocrinology-Molecular Cell Physiology, Faculty of Medicine, Institute of Pathophysiology, University of Ljubljana, Ljubljana, Slovenia.,Laboratory of Cell Engineering, Celica Biomedical, Ljubljana, Slovenia
| | - Urška Černe
- Laboratory of Neuroendocrinology-Molecular Cell Physiology, Faculty of Medicine, Institute of Pathophysiology, University of Ljubljana, Ljubljana, Slovenia
| | - Ana Halužan Vasle
- Laboratory of Neuroendocrinology-Molecular Cell Physiology, Faculty of Medicine, Institute of Pathophysiology, University of Ljubljana, Ljubljana, Slovenia
| | - Larisa Tratnjek
- Faculty of Medicine, Institute of Cell Biology, University of Ljubljana, Ljubljana, Slovenia
| | - Mateja Erdani Kreft
- Faculty of Medicine, Institute of Cell Biology, University of Ljubljana, Ljubljana, Slovenia
| | - Nicole Scholz
- Division of General Biochemistry, Medical Faculty, Rudolf Schönheimer Institute of Biochemistry, Leipzig University, Leipzig, Germany
| | - Maja Matis
- Medical Faculty, Institute of Cell Biology, University of Münster, Münster, Germany.,Cells in Motion Interfaculty Centre, University of Münster, Münster, Germany
| | - Toni Petan
- Department of Molecular and Biomedical Sciences, Jožef Stefan Institute, Ljubljana, Slovenia
| | - Robert Zorec
- Laboratory of Neuroendocrinology-Molecular Cell Physiology, Faculty of Medicine, Institute of Pathophysiology, University of Ljubljana, Ljubljana, Slovenia.,Laboratory of Cell Engineering, Celica Biomedical, Ljubljana, Slovenia
| | - Nina Vardjan
- Laboratory of Neuroendocrinology-Molecular Cell Physiology, Faculty of Medicine, Institute of Pathophysiology, University of Ljubljana, Ljubljana, Slovenia.,Laboratory of Cell Engineering, Celica Biomedical, Ljubljana, Slovenia
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Carrasco D, Carrasco C, Souza-Mello V, Sandoval C. Effectiveness of antioxidant treatments on cytochrome P450 2E1 (CYP2E1) activity after alcohol exposure in humans and in vitro models: A systematic review. INTERNATIONAL JOURNAL OF FOOD PROPERTIES 2021; 24:1300-1317. [DOI: 10.1080/10942912.2021.1961801] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/12/2021] [Revised: 07/21/2021] [Accepted: 07/23/2021] [Indexed: 01/09/2023]
Affiliation(s)
- Danitza Carrasco
- Carrera De Tecnología Médica, Facultad De Medicina, Universidad De La Frontera, Temuco, Chile
| | - Camila Carrasco
- Carrera De Tecnología Médica, Facultad De Medicina, Universidad De La Frontera, Temuco, Chile
| | - Vanessa Souza-Mello
- Laboratorio De Morfometría, Metabolismo Y Enfermedades Cardiovasculares, Centro Biomédico, Instituto De Biología, Universidade Do Estado Do Rio De Janeiro, Rio De Janeiro, Brazil
| | - Cristian Sandoval
- Escuela de Tecnología Médica, Facultad de Salud, Universidad Santo Tomás, Los Carreras, Osorno, Chile
- Departamento De Ciencias Preclínicas, Facultad De Medicina, Universidad De La Frontera, Temuco, Chile
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Schulze RJ, Krueger EW, Weller SG, Johnson KM, Casey CA, Schott MB, McNiven MA. Direct lysosome-based autophagy of lipid droplets in hepatocytes. Proc Natl Acad Sci U S A 2020; 117:32443-32452. [PMID: 33288726 PMCID: PMC7768785 DOI: 10.1073/pnas.2011442117] [Citation(s) in RCA: 151] [Impact Index Per Article: 30.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Hepatocytes metabolize energy-rich cytoplasmic lipid droplets (LDs) in the lysosome-directed process of autophagy. An organelle-selective form of this process (macrolipophagy) results in the engulfment of LDs within double-membrane delimited structures (autophagosomes) before lysosomal fusion. Whether this is an exclusive autophagic mechanism used by hepatocytes to catabolize LDs is unclear. It is also unknown whether lysosomes alone might be sufficient to mediate LD turnover in the absence of an autophagosomal intermediate. We performed live-cell microscopy of hepatocytes to monitor the dynamic interactions between lysosomes and LDs in real-time. We additionally used a fluorescent variant of the LD-specific protein (PLIN2) that exhibits altered fluorescence in response to LD interactions with the lysosome. We find that mammalian lysosomes and LDs undergo interactions during which proteins and lipids can be transferred from LDs directly into lysosomes. Electron microscopy (EM) of primary hepatocytes or hepatocyte-derived cell lines supports the existence of these interactions. It reveals a dramatic process whereby the lipid contents of the LD can be "extruded" directly into the lysosomal lumen under nutrient-limited conditions. Significantly, these interactions are not affected by perturbations to crucial components of the canonical macroautophagy machinery and can occur in the absence of double-membrane lipoautophagosomes. These findings implicate the existence of an autophagic mechanism used by mammalian cells for the direct transfer of LD components into the lysosome for breakdown. This process further emphasizes the critical role of lysosomes in hepatic LD catabolism and provides insights into the mechanisms underlying lipid homeostasis in the liver.
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Affiliation(s)
- Ryan J Schulze
- Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN 55905
| | - Eugene W Krueger
- Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN 55905
| | - Shaun G Weller
- Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN 55905
| | - Katherine M Johnson
- Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN 55905
| | - Carol A Casey
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198
| | - Micah B Schott
- Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN 55905
| | - Mark A McNiven
- Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905;
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN 55905
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31
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cAMP Signaling in Pathobiology of Alcohol Associated Liver Disease. Biomolecules 2020; 10:biom10101433. [PMID: 33050657 PMCID: PMC7600246 DOI: 10.3390/biom10101433] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2020] [Revised: 10/07/2020] [Accepted: 10/08/2020] [Indexed: 02/07/2023] Open
Abstract
The importance of cyclic adenosine monophosphate (cAMP) in cellular responses to extracellular signals is well established. Many years after discovery, our understanding of the intricacy of cAMP signaling has improved dramatically. Multiple layers of regulation exist to ensure the specificity of cellular cAMP signaling. Hence, disturbances in cAMP homeostasis could arise at multiple levels, from changes in G protein coupled receptors and production of cAMP to the rate of degradation by phosphodiesterases. cAMP signaling plays critical roles in metabolism, inflammation and development of fibrosis in several tissues. Alcohol-associated liver disease (ALD) is a multifactorial condition ranging from a simple steatosis to steatohepatitis and fibrosis and ultimately cirrhosis, which might lead to hepatocellular cancer. To date, there is no FDA-approved therapy for ALD. Hence, identifying the targets for the treatment of ALD is an important undertaking. Several human studies have reported the changes in cAMP homeostasis in relation to alcohol use disorders. cAMP signaling has also been extensively studied in in vitro and in vivo models of ALD. This review focuses on the role of cAMP in the pathobiology of ALD with emphasis on the therapeutic potential of targeting cAMP signaling for the treatment of various stages of ALD.
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Rozeveld CN, Johnson KM, Zhang L, Razidlo GL. KRAS Controls Pancreatic Cancer Cell Lipid Metabolism and Invasive Potential through the Lipase HSL. Cancer Res 2020; 80:4932-4945. [PMID: 32816911 DOI: 10.1158/0008-5472.can-20-1255] [Citation(s) in RCA: 97] [Impact Index Per Article: 19.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2020] [Revised: 07/16/2020] [Accepted: 08/14/2020] [Indexed: 12/28/2022]
Abstract
Oncogene-induced metabolic reprogramming is a hallmark of pancreatic cancer (PDAC), yet the metabolic drivers of metastasis are unclear. In PDAC, obesity and excess fatty acids accelerate tumor growth and increase metastasis. Here, we report that excess lipids, stored in organelles called lipid droplets (LD), are a key resource to fuel the energy-intensive process of metastasis. The oncogene KRAS controlled the storage and utilization of LD through regulation of hormone-sensitive lipase (HSL), which was downregulated in human PDAC. Disruption of the KRAS-HSL axis reduced lipid storage, reprogrammed tumor cell metabolism, and inhibited invasive migration in vitro and metastasis in vivo. Finally, microscopy-based metabolic analysis revealed that migratory cells selectively utilize oxidative metabolism during the process of migration to metabolize stored lipids and fuel invasive migration. Taken together, these results reveal a mechanism that can be targeted to attenuate PDAC metastasis. SIGNIFICANCE: KRAS-dependent regulation of HSL biases cells towards lipid storage for subsequent utilization during invasion of pancreatic cancer cells, representing a potential target for therapeutic intervention.See related commentary by Man et al., p. 4886.
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Affiliation(s)
- Cody N Rozeveld
- Mayo Graduate School of Biomedical Sciences, Mayo Clinic, Rochester, Minnesota
| | - Katherine M Johnson
- Division of Gastroenterology & Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Lizhi Zhang
- Department of Anatomic Pathology, Mayo Clinic, Rochester, Minnesota
| | - Gina L Razidlo
- Division of Gastroenterology & Hepatology, Mayo Clinic, Rochester, Minnesota. .,Department of Biochemistry & Molecular Biology, Mayo Clinic, Rochester, Minnesota
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Li Z, Weller SG, Drizyte-Miller K, Chen J, Krueger EW, Mehall B, Stöckli J, Casey CA, Cao H, McNiven MA. Maturation of Lipophagic Organelles in Hepatocytes Is Dependent Upon a Rab10/Dynamin-2 Complex. Hepatology 2020; 72:486-502. [PMID: 31808574 PMCID: PMC8919976 DOI: 10.1002/hep.31059] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2019] [Accepted: 11/14/2019] [Indexed: 12/29/2022]
Abstract
BACKGROUND AND AIMS Hepatocytes play a central role in storage and utilization of fat by the liver. Selective breakdown of lipid droplets (LDs) by autophagy (also called lipophagy) is a key process utilized to catabolize these lipids as an energy source. How the autophagic machinery is selectively targeted to LDs, where it mediates membrane engulfment and subsequent degradation, is unclear. Recently, we have reported that two distinct GTPases, the mechanoenzyme, dynamin2 (Dyn2), and the small regulatory Rab GTPase, Rab10, work independently at distinct steps of lipophagy in hepatocytes. APPROACH AND RESULTS In an attempt to understand how these proteins are regulated and recruited to autophagic organelles, we performed a nonbiased biochemical screen for Dyn2-binding partners and found that Dyn2 actually binds Rab10 directly through a defined effector domain of Rab10 and the middle domain of Dyn2. These two GTPases can be observed to interact transiently on membrane tubules in hepatoma cells and along LD-centric autophagic membranes. Most important, we found that a targeted disruption of this interaction leads to an inability of cells to trim tubulated cytoplasmic membranes, some of which extend from lipophagic organelles, resulting in LD accumulation. CONCLUSIONS This study identifies a functional, and direct, interaction between Dyn2 and a regulatory Rab GTPase that may play an important role in hepatocellular metabolism.
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Affiliation(s)
- Zhipeng Li
- Biochemistry and Molecular Biology Program, Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic, Rochester, MN
| | - Shaun G. Weller
- Center for Basic Research in Digestive Diseases, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN
| | - Kristina Drizyte-Miller
- Biochemistry and Molecular Biology Program, Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic, Rochester, MN
| | - Jing Chen
- Center for Basic Research in Digestive Diseases, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN
| | - Eugene W. Krueger
- Center for Basic Research in Digestive Diseases, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN
| | - Bridget Mehall
- Center for Basic Research in Digestive Diseases, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN
| | - Jacqueline Stöckli
- Charles Perkins Centre, School of Life and Environmental Sciences, University of Sydney, Sydney, Australia
| | - Carol A. Casey
- Department of Internal Medicine, University of Nebraska Medical Center, 988090 Nebraska Medical Center, Omaha, NE
| | - Hong Cao
- Center for Basic Research in Digestive Diseases, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN
| | - Mark A. McNiven
- Biochemistry and Molecular Biology Program, Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic, Rochester, MN,Center for Basic Research in Digestive Diseases, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN,Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN
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Shan B, Ai Z, Zeng S, Song Y, Song J, Zeng Q, Liao Z, Wang T, Huang C, Su D. Gut microbiome-derived lactate promotes to anxiety-like behaviors through GPR81 receptor-mediated lipid metabolism pathway. Psychoneuroendocrinology 2020; 117:104699. [PMID: 32402927 DOI: 10.1016/j.psyneuen.2020.104699] [Citation(s) in RCA: 53] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/26/2019] [Revised: 04/18/2020] [Accepted: 04/20/2020] [Indexed: 01/06/2023]
Abstract
Accumulating evidence suggests that chronic stress could perturb the composition of the gut microbiota and induce host anxiety- and depression-like behaviors. In particular, microorganism-derived products that can directly or indirectly signal to the nervous system. This study sought to investigate whether high levels of Lactobacillus and lactate in the gut of rats under chronic unpredictable stress (CUS) were the factors leading to anxiety behavior. We collected faeces and blood samples in a sterile laboratory bench to study the microbiome and plasma metabolome from adult male rats age and environment matched healthy individuals. We sequenced the V3 and V4 regions of the 16S rRNA gene from faeces samples. UPLC-MS metabolomics were used to examine plasma samples. Search for potential biomarkers by combining the different data types. Finally, we found a regulated signaling pathway through the relative expression of protein and mRNA. Both lactate feeding and fecal microbiota transplantation caused behavioral abnormalities such as psychomotor malaise, impaired learning and memory in the recipient animals. These rats also showed inhibition of the adenylate cyclase (AC)-protein kinase A (PKA) pathway of lipolysis after activation of G protein-coupled receptor 81 (GPR81) by lactate in the liver, as well as increased tumor necrosis factor α (TNF-α), compared with healthy controls. Furthermore, we showed that sphingosine-1-phosphate receptor 2 (S1PR2) protein expression in hippocampus was reduced in chronic unpredictable stress compared to control group and its expression negatively correlates with symptom severity. Our study suggest that the gut microbiome-derived lactate promotes to anxiety-like behaviors through GPR81 receptor-mediated lipid metabolism pathway.
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Affiliation(s)
- Baixi Shan
- Laboratory Animal Science and Technology Center, College of Pharmacy, College of Science and Technology, Jiangxi University of Traditional Chinese Medicine, 1688 Meiling Road, Nanchang, 330004, China
| | - Zhifu Ai
- Laboratory Animal Science and Technology Center, College of Pharmacy, College of Science and Technology, Jiangxi University of Traditional Chinese Medicine, 1688 Meiling Road, Nanchang, 330004, China
| | - Sufen Zeng
- Laboratory Animal Science and Technology Center, College of Pharmacy, College of Science and Technology, Jiangxi University of Traditional Chinese Medicine, 1688 Meiling Road, Nanchang, 330004, China
| | - Yonggui Song
- Laboratory Animal Science and Technology Center, College of Pharmacy, College of Science and Technology, Jiangxi University of Traditional Chinese Medicine, 1688 Meiling Road, Nanchang, 330004, China.
| | - Jiagui Song
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), and State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing, 100191, China
| | - Qiang Zeng
- Laboratory Animal Science and Technology Center, College of Pharmacy, College of Science and Technology, Jiangxi University of Traditional Chinese Medicine, 1688 Meiling Road, Nanchang, 330004, China
| | - Zhou Liao
- Laboratory Animal Science and Technology Center, College of Pharmacy, College of Science and Technology, Jiangxi University of Traditional Chinese Medicine, 1688 Meiling Road, Nanchang, 330004, China
| | - Tingting Wang
- Laboratory Animal Science and Technology Center, College of Pharmacy, College of Science and Technology, Jiangxi University of Traditional Chinese Medicine, 1688 Meiling Road, Nanchang, 330004, China
| | - Chao Huang
- Laboratory Animal Science and Technology Center, College of Pharmacy, College of Science and Technology, Jiangxi University of Traditional Chinese Medicine, 1688 Meiling Road, Nanchang, 330004, China
| | - Dan Su
- Laboratory Animal Science and Technology Center, College of Pharmacy, College of Science and Technology, Jiangxi University of Traditional Chinese Medicine, 1688 Meiling Road, Nanchang, 330004, China.
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Arumugam MK, Talawar S, Listenberger L, Donohue TM, Osna NA, Kharbanda KK. Role of Elevated Intracellular S-Adenosylhomocysteine in the Pathogenesis of Alcohol-Related Liver Disease. Cells 2020; 9:1526. [PMID: 32585865 PMCID: PMC7349643 DOI: 10.3390/cells9061526] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2020] [Revised: 06/19/2020] [Accepted: 06/21/2020] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND The earliest manifestation of alcohol-related liver disease (ALD) is steatosis, characterized by the accumulation of lipid droplets (LDs) in hepatocytes. Findings from our laboratory have indicated that many pathological changes, including steatosis, correlate with the alcohol-induced hepatocellular increases in S-adenosylhomocysteine (SAH). Based on these considerations, we hypothesized that an experimental increase in intracellular SAH alone will result in similar steatotic changes to those seen after alcohol exposure. METHODS Freshly isolated rat hepatocytes grown on collagen-coated plates were exposed to serum-free medium containing 50 µmol/L oleic acid and varying concentrations of 3-deazaadenosine (DZA) to experimentally elevate intracellular SAH levels. RESULTS Overnight exposure to DZA treatment dose-dependently increased hepatocellular triglyceride accumulation, which was also evident by morphological visualization of larger-sized LDs. The rise in triglycerides and LDs accompanied increases in mRNA and protein levels of several LD-associated proteins known to regulate LD number and size. Furthermore, DZA treatment caused a decline in the levels of lipases that prevent fat accumulation as well as increased the expression of factors involved in lipogenesis and fatty acid mobilization. Collectively, our results indicate that the elevation of intracellular SAH is sufficient to promote fat accumulation in hepatocytes, which is similar to that seen after alcohol exposure.
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Affiliation(s)
- Madan Kumar Arumugam
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USA; (M.K.A.); (S.T.); (T.M.D.J.); (N.A.O.)
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Sharanappa Talawar
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USA; (M.K.A.); (S.T.); (T.M.D.J.); (N.A.O.)
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Laura Listenberger
- Departments of Biology and Chemistry, St. Olaf College, Northfield, MN 55057, USA;
| | - Terrence M. Donohue
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USA; (M.K.A.); (S.T.); (T.M.D.J.); (N.A.O.)
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA
- Department of Biochemistry & Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Natalia A. Osna
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USA; (M.K.A.); (S.T.); (T.M.D.J.); (N.A.O.)
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Kusum K. Kharbanda
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USA; (M.K.A.); (S.T.); (T.M.D.J.); (N.A.O.)
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA
- Department of Biochemistry & Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA
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Drizyte-Miller K, Chen J, Cao H, Schott MB, McNiven MA. The small GTPase Rab32 resides on lysosomes to regulate mTORC1 signaling. J Cell Sci 2020; 133:jcs236661. [PMID: 32295849 PMCID: PMC7295596 DOI: 10.1242/jcs.236661] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2019] [Accepted: 04/01/2020] [Indexed: 12/24/2022] Open
Abstract
Epithelial cells, such as liver-resident hepatocytes, rely heavily on the Rab family of small GTPases to perform membrane trafficking events that dictate cell physiology and metabolism. Not surprisingly, disruption of several Rab proteins can manifest in metabolic diseases or cancer. Rab32 is expressed in many secretory epithelial cells but its role in cellular metabolism is virtually unknown. In this study, we find that Rab32 associates with lysosomes and regulates proliferation and cell size of Hep3B hepatoma and HeLa cells. Specifically, we identify that Rab32 supports the mechanistic target of rapamycin complex 1 (mTORC1) signaling under basal and amino acid-stimulated conditions. Consistent with inhibited mTORC1, an increase in nuclear TFEB localization and lysosome biogenesis is also observed in Rab32-depleted cells. Finally, we find that Rab32 interacts with mTOR kinase, and that loss of Rab32 reduces the association of mTOR and mTORC1 pathway proteins with lysosomes, suggesting that Rab32 regulates lysosomal mTOR trafficking. In summary, these findings suggest that Rab32 functions as a novel regulator of cellular metabolism through supporting mTORC1 signaling.This article has an associated First Person interview with the first author of the paper.
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Affiliation(s)
- Kristina Drizyte-Miller
- Biochemistry and Molecular Biology Program, Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic, 200 1st Street SW, Rochester, MN 55905, USA
| | - Jing Chen
- Center for Basic Research in Digestive Diseases, Division of Gastroenterology and Hepatology, Mayo Clinic, 200 1st Street SW, Rochester, MN 55905, USA
| | - Hong Cao
- Center for Basic Research in Digestive Diseases, Division of Gastroenterology and Hepatology, Mayo Clinic, 200 1st Street SW, Rochester, MN 55905, USA
| | - Micah B Schott
- Center for Basic Research in Digestive Diseases, Division of Gastroenterology and Hepatology, Mayo Clinic, 200 1st Street SW, Rochester, MN 55905, USA
| | - Mark A McNiven
- Biochemistry and Molecular Biology Program, Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic, 200 1st Street SW, Rochester, MN 55905, USA
- Center for Basic Research in Digestive Diseases, Division of Gastroenterology and Hepatology, Mayo Clinic, 200 1st Street SW, Rochester, MN 55905, USA
- Department of Biochemistry and Molecular Biology, Mayo Clinic, 200 1st Street SW, Rochester, MN 55905, USA
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Abstract
The rising incidence of alcohol-related liver disease (ALD) demands making urgent progress in understanding the fundamental molecular basis of alcohol-related hepatocellular damage. One of the key early events accompanying chronic alcohol usage is the accumulation of lipid droplets (LDs) in the hepatocellular cytoplasm. LDs are far from inert sites of neutral lipid storage; rather, they represent key organelles that play vital roles in the metabolic state of the cell. In this review, we will examine the biology of these structures and outline recent efforts being made to understand the effects of alcohol exposure on the biogenesis, catabolism, and motility of LDs and how their dynamic nature is perturbed in the context of ALD.
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Affiliation(s)
- Ryan J. Schulze
- Department of Biochemistry and Molecular Biology and the Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA,Corresponding author. Department of Biochemistry and Molecular Biology and the Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA. (R.J. Schulze)
| | - Wen-Xing Ding
- Department of Pharmacology, Toxicology, and Therapeutics, The University of Kansas Medical Center, Kansas City, KS, USA
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Donohue TM, Osna NA, Kharbanda KK, Thomes PG. Lysosome and proteasome dysfunction in alcohol-induced liver injury. LIVER RESEARCH 2019; 3:191-205. [DOI: 10.1016/j.livres.2019.11.001] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
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Yang J, Zhang X, Yi L, Yang L, Wang WE, Zeng C, Mi M, Chen X. Hepatic PKA inhibition accelerates the lipid accumulation in liver. Nutr Metab (Lond) 2019; 16:69. [PMID: 31632452 PMCID: PMC6788098 DOI: 10.1186/s12986-019-0400-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2019] [Accepted: 09/26/2019] [Indexed: 02/06/2023] Open
Abstract
Background/aims Liver lipid accumulation induced by high-fat diet (HFD) is an early onset process of non-alcoholic fatty liver diseases (NAFLD). Protein kinase A (PKA) is known to be involved in hepatic lipid metabolism. However, the role of PKA in NAFLD has not been well tested in vivo due to the lack of optimal PKA deficient mouse model. Methods A novel PKA-specific inhibitor gene was conditionally overexpressed in mouse (PKAi mouse) liver using LoxP/Cre system. PKA activity in the liver extract was measured with a commercial assay kit. The PKAi and control mice of 8-week age, were subjected to HFD or chow diet (CD) for 2 months. Body weight, liver index, and triglyceride in the liver were measured. RNA sequencing was performed for the liver tissues and analyzed with Gene Ontology (GO) and pathway enrichment. Results PKAi-GFP protein was overexpressed in the liver and the PKA activation was significantly inhibited in the liver of PKAi mouse. When fed with CD, RNA sequencing revealed 56 up-regulated and 51 down-regulated genes in PKAi mice compared with control mice, which were mainly involved in lipid metabolism though no significant differences in the body weight, liver index, triglyceride accumulation were observed between PKAi and control mice. However, when fed with HFD for 2 months, the liver was enlarged more, and the accumulation of triglyceride in the liver was more severe in PKAi mice. When comparing the transcriptomes of CD-fed and HFD-fed control mice, GO enrichment showed that the genes down-regulated by HFD were mainly enriched in immune-related GO terms, and up-regulated genes were enriched in metabolism. When comparing the transcriptomes of CD-fed and HFD-fed PKAi mice, GO analysis showed that the down-regulated genes were enriched in metabolism, while the up-regulated genes were clustered in ER stress-related pathways. When comparing HFD-fed PKAi and HFD-fed control mice, the genes with lower expression level in PKAi mice were enriched in the lipoprotein synthesis, which might explain that more TG is accumulated in PKAi liver after HFD feeding. Conclusions Reduced PKA activity could be a factor promoting the TG accumulation in the liver and the development of NAFLD.
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Affiliation(s)
- Jining Yang
- 1Research Center for Nutrition and Food Safety, Chongqing Key Laboratory of Nutrition and Food Safety, Institute of Military Preventive Medicine, Third Military Medical University, Chongqing, People's Republic of China
| | - Xiaoying Zhang
- 2Department of Physiology & Cardiovascular Research Center, Temple University Lewis Katz School of Medicine, Philadelphia, PA USA
| | - Long Yi
- 1Research Center for Nutrition and Food Safety, Chongqing Key Laboratory of Nutrition and Food Safety, Institute of Military Preventive Medicine, Third Military Medical University, Chongqing, People's Republic of China
| | - Ling Yang
- 3Department of Medical Genetics & Molecular Biochemistry, Temple University Lewis Katz School of Medicine, Room 624 Kresge Hall, Philadelphia, PA USA
| | - Wei Eric Wang
- 4Daping Hospital, The Third Military Medical University, Chongqing, People's Republic of China
| | - Chunyu Zeng
- 4Daping Hospital, The Third Military Medical University, Chongqing, People's Republic of China
| | - Mantian Mi
- 1Research Center for Nutrition and Food Safety, Chongqing Key Laboratory of Nutrition and Food Safety, Institute of Military Preventive Medicine, Third Military Medical University, Chongqing, People's Republic of China
| | - Xiongwen Chen
- 2Department of Physiology & Cardiovascular Research Center, Temple University Lewis Katz School of Medicine, Philadelphia, PA USA
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Yan S, Khambu B, Hong H, Liu G, Huda N, Yin XM. Autophagy, Metabolism, and Alcohol-Related Liver Disease: Novel Modulators and Functions. Int J Mol Sci 2019; 20:ijms20205029. [PMID: 31614437 PMCID: PMC6834312 DOI: 10.3390/ijms20205029] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2019] [Revised: 10/02/2019] [Accepted: 10/09/2019] [Indexed: 02/06/2023] Open
Abstract
Alcohol-related liver disease (ALD) is caused by over-consumption of alcohol. ALD can develop a spectrum of pathological changes in the liver, including steatosis, inflammation, cirrhosis, and complications. Autophagy is critical to maintain liver homeostasis, but dysfunction of autophagy has been observed in ALD. Generally, autophagy is considered to protect the liver from alcohol-induced injury and steatosis. In this review, we will summarize novel modulators of autophagy in hepatic metabolism and ALD, including autophagy-mediating non-coding RNAs (ncRNAs), and crosstalk of autophagy machinery and nuclear factors. We will also discuss novel functions of autophagy in hepatocytes and non-parenchymal hepatic cells during the pathogenesis of ALD and other liver diseases.
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Affiliation(s)
- Shengmin Yan
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
| | - Bilon Khambu
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
| | - Honghai Hong
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
| | - Gang Liu
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
| | - Nazmul Huda
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
| | - Xiao-Ming Yin
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
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Groebner JL, Girón-Bravo MT, Rothberg ML, Adhikari R, Tuma DJ, Tuma PL. Alcohol-induced microtubule acetylation leads to the accumulation of large, immobile lipid droplets. Am J Physiol Gastrointest Liver Physiol 2019; 317:G373-G386. [PMID: 31373507 PMCID: PMC6842993 DOI: 10.1152/ajpgi.00026.2019] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Although steatosis (fatty liver) is a clinically well-described early stage of alcoholic liver disease, surprisingly little is known about how it promotes hepatotoxicity. We have shown that ethanol consumption leads to microtubule hyperacetylation that can explain ethanol-induced defects in protein trafficking. Because almost all steps of the lipid droplet life cycle are microtubule dependent and because microtubule acetylation promotes adipogenesis, we examined droplet dynamics in ethanol-treated cells. In WIF-B cells treated with ethanol and/or oleic acid (a fatty acid associated with the "Western" diet), we found that ethanol dramatically increased lipid droplet numbers and led to the formation of large, peripherally located droplets. Enhanced droplet formation required alcohol dehydrogenase-mediated ethanol metabolism, and peripheral droplet distributions required intact microtubules. We also determined that ethanol-induced microtubule acetylation led to impaired droplet degradation. Live-cell imaging revealed that droplet motility was microtubule dependent and that droplets were virtually stationary in ethanol-treated cells. To determine more directly whether microtubule hyperacetylation could explain impaired droplet motility, we overexpressed the tubulin-specific acetyltransferase αTAT1 to promote microtubule acetylation in the absence of alcohol. Droplet motility was impaired in αTAT1-expressing cells but to a lesser extent than in ethanol-treated cells. However, in both cases, the large immotile droplets (but not small motile ones) colocalized with dynein and dynactin (but not kinesin), implying that altered droplet-motor microtubule interactions may explain altered dynamics. These studies further suggest that modulating cellular acetylation is a potential strategy for treating alcoholic liver disease.NEW & NOTEWORTHY Chronic alcohol consumption with the "Western diet" enhances the development of fatty liver and leads to impaired droplet motility, which may have serious deletrious effects on hepatocyte function.
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Affiliation(s)
| | | | - Mia L. Rothberg
- 1Department of Biology, The Catholic University of America, Washington D. C.
| | | | - Dean J. Tuma
- 2Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska
| | - Pamela L. Tuma
- 1Department of Biology, The Catholic University of America, Washington D. C.
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Schott MB, Weller SG, Schulze RJ, Krueger EW, Drizyte-Miller K, Casey CA, McNiven MA. Lipid droplet size directs lipolysis and lipophagy catabolism in hepatocytes. J Cell Biol 2019; 218:3320-3335. [PMID: 31391210 PMCID: PMC6781454 DOI: 10.1083/jcb.201803153] [Citation(s) in RCA: 229] [Impact Index Per Article: 38.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2018] [Revised: 09/18/2018] [Accepted: 07/17/2019] [Indexed: 12/20/2022] Open
Abstract
Lipid droplet (LD) catabolism in hepatocytes is mediated by a combination of lipolysis and a selective autophagic mechanism called lipophagy, but the relative contributions of these seemingly distinct pathways remain unclear. We find that inhibition of lipolysis, lipophagy, or both resulted in similar overall LD content but dramatic differences in LD morphology. Inhibition of the lipolysis enzyme adipose triglyceride lipase (ATGL) resulted in large cytoplasmic LDs, whereas lysosomal inhibition caused the accumulation of numerous small LDs within the cytoplasm and degradative acidic vesicles. Combined inhibition of ATGL and LAL resulted in large LDs, suggesting that lipolysis targets these LDs upstream of lipophagy. Consistent with this, ATGL was enriched in larger-sized LDs, whereas lipophagic vesicles were restricted to small LDs as revealed by immunofluorescence, electron microscopy, and Western blot of size-separated LDs. These findings provide new evidence indicating a synergistic relationship whereby lipolysis targets larger-sized LDs to produce both size-reduced and nascently synthesized small LDs that are amenable for lipophagic internalization.
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Affiliation(s)
- Micah B Schott
- Department of Biochemistry and Molecular Biology, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN
| | - Shaun G Weller
- Department of Biochemistry and Molecular Biology, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN
| | - Ryan J Schulze
- Department of Biochemistry and Molecular Biology, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN
| | - Eugene W Krueger
- Department of Biochemistry and Molecular Biology, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN
| | - Kristina Drizyte-Miller
- Department of Biochemistry and Molecular Biology, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN
| | - Carol A Casey
- Department of Internal Medicine and Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE.,Research Service, Department of Veterans Affairs, Nebraska-Western Iowa Health Care System, Omaha, NE
| | - Mark A McNiven
- Department of Biochemistry and Molecular Biology, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN
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43
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Schulze RJ, Schott MB, Casey CA, Tuma PL, McNiven MA. The cell biology of the hepatocyte: A membrane trafficking machine. J Cell Biol 2019; 218:2096-2112. [PMID: 31201265 PMCID: PMC6605791 DOI: 10.1083/jcb.201903090] [Citation(s) in RCA: 124] [Impact Index Per Article: 20.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2019] [Revised: 05/24/2019] [Accepted: 05/28/2019] [Indexed: 12/24/2022] Open
Abstract
The liver performs numerous vital functions, including the detoxification of blood before access to the brain while simultaneously secreting and internalizing scores of proteins and lipids to maintain appropriate blood chemistry. Furthermore, the liver also synthesizes and secretes bile to enable the digestion of food. These diverse attributes are all performed by hepatocytes, the parenchymal cells of the liver. As predicted, these cells possess a remarkably well-developed and complex membrane trafficking machinery that is dedicated to moving specific cargos to their correct cellular locations. Importantly, while most epithelial cells secrete nascent proteins directionally toward a single lumen, the hepatocyte secretes both proteins and bile concomitantly at its basolateral and apical domains, respectively. In this Beyond the Cell review, we will detail these central features of the hepatocyte and highlight how membrane transport processes play a key role in healthy liver function and how they are affected by disease.
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Affiliation(s)
- Ryan J Schulze
- Division of Gastroenterology and Hepatology, Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN
| | - Micah B Schott
- Division of Gastroenterology and Hepatology, Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN
| | - Carol A Casey
- Research Service, Department of Veterans Affairs, Nebraska-Western Iowa Health Care System, Omaha, NE
- Departments of Internal Medicine and Biochemistry & Molecular Biology, University of Nebraska Medical Center, Omaha, NE
| | | | - Mark A McNiven
- Division of Gastroenterology and Hepatology, Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN
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44
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Abstract
Lipid droplets (LDs) are key sites of neutral lipid storage that can be found in all cells. Metabolic imbalances between the synthesis and degradation of LDs can result in the accumulation of significant amounts of lipid deposition, a characteristic feature of hepatocytes in patients with fatty liver disease, a leading indication for liver transplant in the United States. In this review, the authors highlight new literature related to the synthesis and autophagic catabolism of LDs, discussing key proteins and machinery involved in these processes. They also discuss recent findings that have revealed novel genetic risk factors associated with LD biology that contribute to lipid retention in the diseased liver.
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Affiliation(s)
- Ryan J. Schulze
- Department of Biochemistry and Molecular Biology and the Center for Digestive Diseases, Mayo Clinic, Rochester, Minnesota
| | - Mark A. McNiven
- Department of Biochemistry and Molecular Biology and the Center for Digestive Diseases, Mayo Clinic, Rochester, Minnesota
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45
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Yang L, Yang C, Thomes PG, Kharbanda KK, Casey CA, McNiven MA, Donohue TM. Lipophagy and Alcohol-Induced Fatty Liver. Front Pharmacol 2019; 10:495. [PMID: 31143122 PMCID: PMC6521574 DOI: 10.3389/fphar.2019.00495] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2019] [Accepted: 04/18/2019] [Indexed: 12/14/2022] Open
Abstract
This review describes the influence of ethanol consumption on hepatic lipophagy, a selective form of autophagy during which fat-storing organelles known as lipid droplets (LDs) are degraded in lysosomes. During classical autophagy, also known as macroautophagy, all forms of macromolecules and organelles are sequestered in autophagosomes, which, with their cargo, fuse with lysosomes, forming autolysosomes in which the cargo is degraded. It is well established that excessive drinking accelerates intrahepatic lipid biosynthesis, enhances uptake of fatty acids by the liver from the plasma and impairs hepatic secretion of lipoproteins. All the latter contribute to alcohol-induced fatty liver (steatosis). Here, our principal focus is on lipid catabolism, specifically the impact of excessive ethanol consumption on lipophagy, which significantly influences the pathogenesis alcohol-induced steatosis. We review findings, which demonstrate that chronic ethanol consumption retards lipophagy, thereby exacerbating steatosis. This is important for two reasons: (1) Unlike adipose tissue, the liver is considered a fat-burning, not a fat-storing organ. Thus, under normal conditions, lipophagy in hepatocytes actively prevents lipid droplet accumulation, thereby maintaining lipostasis; (2) Chronic alcohol consumption subverts this fat-burning function by slowing lipophagy while accelerating lipogenesis, both contributing to fatty liver. Steatosis was formerly regarded as a benign consequence of heavy drinking. It is now recognized as the "first hit" in the spectrum of alcohol-induced pathologies that, with continued drinking, progresses to more advanced liver disease, liver failure, and/or liver cancer. Complete lipid droplet breakdown requires that LDs be digested to release their high-energy cargo, consisting principally of cholesteryl esters and triacylglycerols (triglycerides). These subsequently undergo lipolysis, yielding free fatty acids that are oxidized in mitochondria to generate energy. Our review will describe recent findings on the role of lipophagy in LD catabolism, how continuous heavy alcohol consumption affects this process, and the putative mechanism(s) by which this occurs.
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Affiliation(s)
- Li Yang
- Division of Gastroenterology and Hepatology, Digestive Disease Institute, Shanghai Tongji Hospital, Tongji University School of Medicine, Shanghai, China
| | - Changqing Yang
- Division of Gastroenterology and Hepatology, Digestive Disease Institute, Shanghai Tongji Hospital, Tongji University School of Medicine, Shanghai, China
| | - Paul G. Thomes
- Research Service, Department of Veterans Affairs, Nebraska-Western Iowa Health Care System, Omaha, NE, United States
- Departments of Internal Medicine and of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, United States
| | - Kusum K. Kharbanda
- Research Service, Department of Veterans Affairs, Nebraska-Western Iowa Health Care System, Omaha, NE, United States
- Departments of Internal Medicine and of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, United States
| | - Carol A. Casey
- Research Service, Department of Veterans Affairs, Nebraska-Western Iowa Health Care System, Omaha, NE, United States
- Departments of Internal Medicine and of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, United States
| | - Mark A. McNiven
- Division of Gastroenterology and Hepatology, Department of Biochemistry and Molecular Biology, Center for Basic Research in Digestive Diseases, Mayo Clinic, Rochester, MN, United States
| | - Terrence M. Donohue
- Research Service, Department of Veterans Affairs, Nebraska-Western Iowa Health Care System, Omaha, NE, United States
- Departments of Internal Medicine and of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, United States
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Thomes PG, Rasineni K, Yang L, Donohue TM, Kubik JL, McNiven MA, Casey CA. Ethanol withdrawal mitigates fatty liver by normalizing lipid catabolism. Am J Physiol Gastrointest Liver Physiol 2019; 316:G509-G518. [PMID: 30714813 PMCID: PMC6957361 DOI: 10.1152/ajpgi.00376.2018] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
We are investigating the changes in hepatic lipid catabolism that contribute to alcohol-induced fatty liver. Following chronic ethanol (EtOH) exposure, abstinence from alcohol resolves steatosis. Here, we investigated the hepatocellular events that lead to this resolution by quantifying specific catabolic parameters that returned to control levels after EtOH was withdrawn. We hypothesized that, after its chronic consumption, EtOH withdrawal reactivates lipid catabolic processes that restore lipostasis. Male Wistar rats were fed control and EtOH liquid diets for 6 wk. Randomly chosen EtOH-fed rats were then fed control diet for 7 days. Liver triglycerides (TG), lipid peroxides, key markers of fatty acid (FA) metabolism, lipophagy, and autophagy were quantified. Compared with controls, EtOH-fed rats had higher hepatic triglycerides, lipid peroxides, and serum free fatty acids (FFA). The latter findings were associated with higher levels of FA transporters (FATP 2, 4, and 5) but lower quantities of peroxisome proliferator-activated receptor-α (PPAR-α), which governs FA oxidation. EtOH-fed animals also had lower nuclear levels of the autophagy-regulating transcription factor EB (TFEB), associated with lower hepatic lipophagy and autophagy. After EtOH-fed rats were refed control diet for 7 days, their serum FFA levels and those of FATPs fell to control (normal) levels, whereas PPAR-α levels rose to normal. Hepatic TG and malondialdehyde levels in EtOH-withdrawn rats declined to near control levels. EtOH withdrawal restored nuclear TFEB content, hepatic lipophagy, and autophagy activity to control levels. EtOH withdrawal reversed aberrant FA metabolism and restored lysosomal function to promote resolution of alcohol-induced fatty liver. NEW & NOTEWORTHY Here, using an animal model, we show mechanisms of reversal of fatty liver and injury following EtOH withdrawal. Our data indicate that reactivation of autophagy and lysosome function through the restoration of transcription factor EB contribute to reversal of fatty liver and injury following EtOH withdrawal.
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Affiliation(s)
- Paul G. Thomes
- 1The Liver Study Unit, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, Nebraska,2Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska
| | - Karuna Rasineni
- 1The Liver Study Unit, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, Nebraska,2Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska
| | - Li Yang
- 7Departmentof Internal Medicine, Tongji Hospital, Tongji University School of Medicine, Shanghai, China
| | - Terrence M. Donohue
- 1The Liver Study Unit, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, Nebraska,2Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska,3Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska,4Pathology and Microbiology; College of Medicine; University of Nebraska Medical Center, Omaha, Nebraska,5The Center for Environmental Toxicology; College of Public Health, University of Nebraska Medical Center, Omaha, Nebraska
| | - Jacy L. Kubik
- 1The Liver Study Unit, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, Nebraska
| | - Mark A. McNiven
- 6Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, Minnesota
| | - Carol A. Casey
- 1The Liver Study Unit, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, Nebraska,2Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska,3Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska
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47
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Chao X, Ding WX. Role and mechanisms of autophagy in alcohol-induced liver injury. ADVANCES IN PHARMACOLOGY (SAN DIEGO, CALIF.) 2019; 85:109-131. [PMID: 31307584 PMCID: PMC7141786 DOI: 10.1016/bs.apha.2019.01.008] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Alcoholic liver disease (ALD) is one of the major causes of chronic liver disease worldwide. Currently, no successful treatments are available for ALD. The pathogenesis of ALD is characterized as simple steatosis, fibrosis, cirrhosis, alcoholic hepatitis (AH), and eventually hepatocellular carcinoma (HCC). Autophagy is a highly conserved intracellular catabolic process, which aims at recycling cellular components and removing damaged organelles in response to starvation and stresses. Therefore, autophagy is considered as an important cellular adaptive and survival mechanism under various pathophysiological conditions. Recent studies from our lab and others suggest that chronic alcohol consumption may impair autophagy and contribute to the pathogenesis of ALD. In this chapter, we summarize recent progress on the role and mechanisms of autophagy in the development of ALD. Understanding the roles of autophagy in ALD may offer novel therapeutic avenues against ALD by targeting these pathways.
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Affiliation(s)
- Xiaojuan Chao
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS, United States
| | - Wen-Xing Ding
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS, United States.
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48
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Ohashi K, Pimienta M, Seki E. Alcoholic liver disease: A current molecular and clinical perspective. LIVER RESEARCH 2018; 2:161-172. [PMID: 31214376 PMCID: PMC6581514 DOI: 10.1016/j.livres.2018.11.002] [Citation(s) in RCA: 84] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Heavy alcohol use is the cause of alcoholic liver disease (ALD). The ALD spectrum ranges from alcoholic steatosis to steatohepatitis, fibrosis, and cirrhosis. In Western countries, approximately 50% of cirrhosis-related deaths are due to alcohol use. While alcoholic cirrhosis is no longer considered a completely irreversible condition, no effective anti-fibrotic therapies are currently available. Another significant clinical aspect of ALD is alcoholic hepatitis (AH). AH is an acute inflammatory condition that is often comorbid with cirrhosis, and severe AH has a high mortality rate. Therapeutic options for ALD are limited. The established treatment for AH is corticosteroids, which improve short-term survival but do not affect long-term survival. Liver transplantation is a curative treatment option for alcoholic cirrhosis and AH, but patients must abstain from alcohol use for 6 months to qualify. Additional effective therapies are needed. The molecular mechanisms underlying ALD are complex and have not been fully elucidated. Various molecules, signaling pathways, and crosstalk between multiple hepatic and extrahepatic cells contribute to ALD progression. This review highlights established and emerging concepts in ALD clinicopathology, their underlying molecular mechanisms, and current and future ALD treatment options.
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Affiliation(s)
- Koichiro Ohashi
- Division of Digestive and Liver Diseases, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Michael Pimienta
- Division of Digestive and Liver Diseases, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA,University of California San Diego, School of Medicine, La Jolla, CA, USA
| | - Ekihiro Seki
- Division of Digestive and Liver Diseases, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA,University of California San Diego, School of Medicine, La Jolla, CA, USA,Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA,Department of Medicine, University of California Los Angeles, David Geffen School of Medicine, Los Angeles, CA, USA,Corresponding author. Division of Digestive and Liver Diseases, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA., (E. Seki)
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49
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Boteon YL, Boteon APCS, Attard J, Mergental H, Mirza DF, Bhogal RH, Afford SC. Ex situ machine perfusion as a tool to recondition steatotic donor livers: Troublesome features of fatty livers and the role of defatting therapies. A systematic review. Am J Transplant 2018; 18:2384-2399. [PMID: 29947472 DOI: 10.1111/ajt.14992] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2018] [Revised: 06/13/2018] [Accepted: 06/18/2018] [Indexed: 02/06/2023]
Abstract
Long-standing research has shown that increased lipid content in donor livers is associated with inferior graft outcomes posttransplant. The global epidemic that is obesity has increased the prevalence of steatosis in organ donors, to the extent that it has become one of the main reasons for declining livers for transplantation. Consequently, it is one of the major culprits behind the discrepancy between the number of donor livers offered for transplantation and those that go on to be transplanted. Steatotic livers are characterized by poor microcirculation, depleted energy stores because of an impaired capacity for mitochondrial recovery, and a propensity for an exaggerated inflammatory response following reperfusion injury culminating in poorer graft function postoperatively. Ex situ machine perfusion, currently a novel method in graft preservation, is showing great promise in providing a tool for the recovery and reconditioning of marginal livers. Hence, reconditioning these steatotic livers using machine perfusion has the potential to increase the number of liver transplants performed. In this review, we consider the problematic issues associated with fatty livers in the realm of transplantation and discuss pharmacological and nonpharmacological options that are being developed to enhance recovery of these organs using machine perfusion and defatting strategies.
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Affiliation(s)
- Yuri L Boteon
- Liver Unit, Queen Elizabeth Hospital, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
- National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre, Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, UK
| | - Amanda P C S Boteon
- Liver Unit, Queen Elizabeth Hospital, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
| | - Joseph Attard
- Liver Unit, Queen Elizabeth Hospital, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
| | - Hynek Mergental
- Liver Unit, Queen Elizabeth Hospital, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
| | - Darius F Mirza
- Liver Unit, Queen Elizabeth Hospital, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
| | - Ricky H Bhogal
- Liver Unit, Queen Elizabeth Hospital, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
| | - Simon C Afford
- National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre, Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, UK
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50
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Wahlang B, McClain C, Barve S, Gobejishvili L. Role of cAMP and phosphodiesterase signaling in liver health and disease. Cell Signal 2018; 49:105-115. [PMID: 29902522 PMCID: PMC6445381 DOI: 10.1016/j.cellsig.2018.06.005] [Citation(s) in RCA: 106] [Impact Index Per Article: 15.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2018] [Revised: 06/08/2018] [Accepted: 06/09/2018] [Indexed: 02/06/2023]
Abstract
Liver disease is a significant health problem worldwide with mortality reaching around 2 million deaths a year. Non-alcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD) are the major causes of chronic liver disease. Pathologically, NAFLD and ALD share similar patterns of hepatic disorders ranging from simple steatosis to steatohepatitis, fibrosis and cirrhosis. It is becoming increasingly important to identify new pharmacological targets, given that there is no FDA-approved therapy yet for either NAFLD or ALD. Since the evolution of liver diseases is a multifactorial process, several mechanisms involving parenchymal and non-parenchymal hepatic cells contribute to the initiation and progression of liver pathologies. Moreover, certain protective molecular pathways become repressed during liver injury including signaling pathways such as the cyclic adenosine monophosphate (cAMP) pathway. cAMP, a key second messenger molecule, regulates various cellular functions including lipid metabolism, inflammation, cell differentiation and injury by affecting gene/protein expression and function. This review addresses the current understanding of the role of cAMP metabolism and consequent cAMP signaling pathway(s) in the context of liver health and disease. The cAMP pathway is extremely sophisticated and complex with specific cellular functions dictated by numerous factors such abundance, localization and degradation by phosphodiesterases (PDEs). Furthermore, because of the distinct yet divergent roles of both of its effector molecules, the cAMP pathway is extensively targeted in liver injury to modify its role from physiological to therapeutic, depending on the hepatic condition. This review also examines the behavior of the cAMP-dependent pathway in NAFLD, ALD and in other liver diseases and focuses on PDE inhibition as an excellent therapeutic target in these conditions.
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Affiliation(s)
- Banrida Wahlang
- University of Louisville Alcohol Research Center, School of Medicine, University of Louisville, KY, USA; Department of Medicine, School of Medicine, University of Louisville, KY, USA
| | - Craig McClain
- University of Louisville Alcohol Research Center, School of Medicine, University of Louisville, KY, USA; Department of Medicine, School of Medicine, University of Louisville, KY, USA; Department of Pharmacology and Toxicology, School of Medicine, University of Louisville, KY, USA; Hepatobiology & Toxicology Center, School of Medicine, University of Louisville, KY, USA; Robley Rex Louisville VAMC, Louisville, KY, USA
| | - Shirish Barve
- University of Louisville Alcohol Research Center, School of Medicine, University of Louisville, KY, USA; Department of Medicine, School of Medicine, University of Louisville, KY, USA; Department of Pharmacology and Toxicology, School of Medicine, University of Louisville, KY, USA; Hepatobiology & Toxicology Center, School of Medicine, University of Louisville, KY, USA
| | - Leila Gobejishvili
- University of Louisville Alcohol Research Center, School of Medicine, University of Louisville, KY, USA; Department of Medicine, School of Medicine, University of Louisville, KY, USA; Department of Pharmacology and Toxicology, School of Medicine, University of Louisville, KY, USA; Hepatobiology & Toxicology Center, School of Medicine, University of Louisville, KY, USA.
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