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Teskey G, Tiwari N, Butcko AJ, Kumar A, Yadav A, Huang YMM, Kelly CV, Granneman JG, Perfield JW, Mottillo EP. Lipid droplet targeting of the lipase coactivator ABHD5 and the fatty liver disease-causing variant PNPLA3 I148M is required to promote liver steatosis. J Biol Chem 2025; 301:108186. [PMID: 39814233 PMCID: PMC11849118 DOI: 10.1016/j.jbc.2025.108186] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2024] [Revised: 01/02/2025] [Accepted: 01/08/2025] [Indexed: 01/18/2025] Open
Abstract
The storage and release of triacylglycerol (TAG) in lipid droplets (LDs) is regulated by dynamic protein interactions. α/β Hydrolase domain-containing protein 5 (ABHD5; also known as CGI-58) is a membrane/LD-bound protein that functions as a co-activator of patatin-like phospholipase domain-containing 2 (PNPLA2; also known as adipose triglyceride lipase) the rate-limiting enzyme for TAG hydrolysis. The dysregulation of TAG hydrolysis is involved in various metabolic diseases such as metabolic dysfunction-associated steatotic liver disease (MASLD). We previously demonstrated that ABHD5 interacted with PNPLA3, a closely related family member to PNPLA2. Importantly, a common missense variant in PNPLA3 (I148M) is the greatest genetic risk factor for MASLD. PNPLA3 148M functions to sequester ABHD5 and prevent coactivation of PNPLA2, which has implications for initiating MASLD; however, the exact mechanisms involved are not understood. Here, we demonstrate that LD targeting of both ABHD5 and PNPLA3 I148M is required for the interaction. Molecular modeling demonstrates important residues in the C terminus of PNPLA3 for LD binding and fluorescence cross-correlation spectroscopy demonstrates that PNPLA3 I148M has greater association with ABHD5 than WT PNPLA3. Moreover, the C terminus of PNPLA3 is sufficient for functional targeting of PNPLAs to LD and the interaction with ABHD5. In addition, ABHD5 is a general binding partner of LD-bound PNPLAs. Finally, PNPLA3 I148M targeting to LD is required to promote steatosis in vitro and in the liver. Overall results suggest that the interaction of PNPLA3 I148M with ABHD5 on LD is required to promote liver steatosis.
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Affiliation(s)
- Grace Teskey
- Hypertension and Vascular Research Division, Department of Internal Medicine, Henry Ford Hospital, Detroit, Michigan, USA
| | - Nivedita Tiwari
- Hypertension and Vascular Research Division, Department of Internal Medicine, Henry Ford Hospital, Detroit, Michigan, USA
| | - Andrew J Butcko
- Hypertension and Vascular Research Division, Department of Internal Medicine, Henry Ford Hospital, Detroit, Michigan, USA; Department of Physiology, Wayne State University School of Medicine, Detroit, Michigan, USA
| | - Amit Kumar
- Department of Physics and Astronomy, Wayne State University, Detroit, Michigan, USA
| | - Anuradha Yadav
- Department of Physics and Astronomy, Wayne State University, Detroit, Michigan, USA
| | - Yu-Ming M Huang
- Department of Physics and Astronomy, Wayne State University, Detroit, Michigan, USA
| | - Christopher V Kelly
- Department of Physics and Astronomy, Wayne State University, Detroit, Michigan, USA
| | - James G Granneman
- Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, Michigan, USA
| | - James W Perfield
- Lilly Research Laboratories, Eli Lilly and Company, Indianapolis Indiana, USA
| | - Emilio P Mottillo
- Hypertension and Vascular Research Division, Department of Internal Medicine, Henry Ford Hospital, Detroit, Michigan, USA; Department of Physiology, Wayne State University School of Medicine, Detroit, Michigan, USA.
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Liermann-Wooldrik KT, Kosmacek EA, Oberley-Deegan RE. Adipose Tissues Have Been Overlooked as Players in Prostate Cancer Progression. Int J Mol Sci 2024; 25:12137. [PMID: 39596205 PMCID: PMC11594286 DOI: 10.3390/ijms252212137] [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: 10/07/2024] [Revised: 11/07/2024] [Accepted: 11/10/2024] [Indexed: 11/28/2024] Open
Abstract
Obesity is a common risk factor in multiple tumor types, including prostate cancer. Obesity has been associated with driving metastasis, therapeutic resistance, and increased mortality. The effect of adipose tissue on the tumor microenvironment is still poorly understood. This review aims to highlight the work conducted in the field of obesity and prostate cancer and bring attention to areas where more research is needed. In this review, we have described key differences between healthy adipose tissues and obese adipose tissues, as they relate to the tumor microenvironment, focusing on mechanisms related to metabolic changes, abnormal adipokine secretion, altered immune cell presence, and heightened oxidative stress as drivers of prostate cancer formation and progression. Interestingly, common treatment options for prostate cancer ignore the adipose tissue located near the site of the tumor. Because of this, we have outlined how excess adipose tissue potentially affects therapeutics' efficacy, such as androgen deprivation, chemotherapy, and radiation treatment, and identified possible drug targets to increase prostate cancer responsiveness to clinical treatments. Understanding how obesity affects the tumor microenvironment will pave the way for understanding why some prostate cancers become metastatic or treatment-resistant, and why patients experience recurrence.
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Affiliation(s)
| | | | - Rebecca E. Oberley-Deegan
- Department of Biochemistry and Molecular Biology, 985870 University of Nebraska Medical Center, Omaha, NE 68198, USA; (K.T.L.-W.)
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Johnson SM, Bao H, McMahon CE, Chen Y, Burr SD, Anderson AM, Madeyski-Bengtson K, Lindén D, Han X, Liu J. PNPLA3 is a triglyceride lipase that mobilizes polyunsaturated fatty acids to facilitate hepatic secretion of large-sized very low-density lipoprotein. Nat Commun 2024; 15:4847. [PMID: 38844467 PMCID: PMC11156938 DOI: 10.1038/s41467-024-49224-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2023] [Accepted: 05/22/2024] [Indexed: 06/09/2024] Open
Abstract
The I148M variant of PNPLA3 is closely associated with hepatic steatosis. Recent evidence indicates that the I148M mutant functions as an inhibitor of PNPLA2/ATGL-mediated lipolysis, leaving the role of wild-type PNPLA3 undefined. Despite showing a triglyceride hydrolase activity in vitro, PNPLA3 has yet to be established as a lipase in vivo. Here, we show that PNPLA3 preferentially hydrolyzes polyunsaturated triglycerides, mobilizing polyunsaturated fatty acids for phospholipid desaturation and enhancing hepatic secretion of triglyceride-rich lipoproteins. Under lipogenic conditions, mice with liver-specific knockout or acute knockdown of PNPLA3 exhibit aggravated liver steatosis and reduced plasma VLDL-triglyceride levels. Similarly, I148M-knockin mice show decreased hepatic triglyceride secretion during lipogenic stimulation. Our results highlight a specific context whereby the wild-type PNPLA3 facilitates the balance between hepatic triglyceride storage and secretion, and suggest the potential contribution of a loss-of-function by the I148M variant to the development of fatty liver disease in humans.
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Affiliation(s)
- Scott M Johnson
- Department of Biochemistry and Molecular Biology; Mayo Clinic College of Medicine & Science, Rochester, MN, 55905, USA
- Mayo Clinic Graduate School of Biomedical Sciences; Mayo Clinic College of Medicine & Science, Rochester, MN, 55905, USA
- Department of Cell Biology; University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA
| | - Hanmei Bao
- Barshop Institute for Longevity and Aging Studies and Department of Medicine, Division of Diabetes; University of Texas Health San Antonio, San Antonio, TX, 78229, USA
| | - Cailin E McMahon
- Molecular Biology and Genetics Department; Cornell College of Agriculture and Life Sciences, Ithaca, NY, 14853, USA
| | - Yongbin Chen
- Department of Biochemistry and Molecular Biology; Mayo Clinic College of Medicine & Science, Rochester, MN, 55905, USA
| | - Stephanie D Burr
- Department of Biochemistry and Molecular Biology; Mayo Clinic College of Medicine & Science, Rochester, MN, 55905, USA
| | - Aaron M Anderson
- Department of Developmental Biology; Washington University School of Medicine in St. Louis, St. Louis, MO, 63110, USA
| | - Katja Madeyski-Bengtson
- Translational Genomics, Discovery Sciences; BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - Daniel Lindén
- Bioscience Metabolism, Research and Early Development Cardiovascular, Renal and Metabolism (CVRM); BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
- Division of Endocrinology, Department of Neuroscience and Physiology; Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Xianlin Han
- Barshop Institute for Longevity and Aging Studies and Department of Medicine, Division of Diabetes; University of Texas Health San Antonio, San Antonio, TX, 78229, USA
| | - Jun Liu
- Department of Biochemistry and Molecular Biology; Mayo Clinic College of Medicine & Science, Rochester, MN, 55905, USA.
- Division of Endocrinology, Diabetes, Metabolism and Nutrition; Mayo Clinic in Rochester, Rochester, MN, 55905, USA.
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Caon E, Martins M, Hodgetts H, Blanken L, Vilia MG, Levi A, Thanapirom K, Al-Akkad W, Abu-Hanna J, Baselli G, Hall AR, Luong TV, Taanman JW, Vacca M, Valenti L, Romeo S, Mazza G, Pinzani M, Rombouts K. Exploring the impact of the PNPLA3 I148M variant on primary human hepatic stellate cells using 3D extracellular matrix models. J Hepatol 2024; 80:941-956. [PMID: 38365182 DOI: 10.1016/j.jhep.2024.01.032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2022] [Revised: 01/24/2024] [Accepted: 01/27/2024] [Indexed: 02/18/2024]
Abstract
BACKGROUND & AIMS The PNPLA3 rs738409 C>G (encoding for I148M) variant is a risk locus for the fibrogenic progression of chronic liver diseases, a process driven by hepatic stellate cells (HSCs). We investigated how the PNPLA3 I148M variant affects HSC biology using transcriptomic data and validated findings in 3D-culture models. METHODS RNA sequencing was performed on 2D-cultured primary human HSCs and liver biopsies of individuals with obesity, genotyped for the PNPLA3 I148M variant. Data were validated in wild-type (WT) or PNPLA3 I148M variant-carrying HSCs cultured on 3D extracellular matrix (ECM) scaffolds from human healthy and cirrhotic livers, with/without TGFB1 or cytosporone B (Csn-B) treatment. RESULTS Transcriptomic analyses of liver biopsies and HSCs highlighted shared PNPLA3 I148M-driven dysregulated pathways related to mitochondrial function, antioxidant response, ECM remodelling and TGFB1 signalling. Analogous pathways were dysregulated in WT/PNPLA3-I148M HSCs cultured in 3D liver scaffolds. Mitochondrial dysfunction in PNPLA3-I148M cells was linked to respiratory chain complex IV insufficiency. Antioxidant capacity was lower in PNPLA3-I148M HSCs, while reactive oxygen species secretion was increased in PNPLA3-I148M HSCs and higher in bioengineered cirrhotic vs. healthy scaffolds. TGFB1 signalling followed the same trend. In PNPLA3-I148M cells, expression and activation of the endogenous TGFB1 inhibitor NR4A1 were decreased: treatment with the Csn-B agonist increased total NR4A1 in HSCs cultured in healthy but not in cirrhotic 3D scaffolds. NR4A1 regulation by TGFB1/Csn-B was linked to Akt signalling in PNPLA3-WT HSCs and to Erk signalling in PNPLA3-I148M HSCs. CONCLUSION HSCs carrying the PNPLA3 I148M variant have impaired mitochondrial function, antioxidant responses, and increased TGFB1 signalling, which dampens antifibrotic NR4A1 activity. These features are exacerbated by cirrhotic ECM, highlighting the dual impact of the PNPLA3 I148M variant and the fibrotic microenvironment in progressive chronic liver diseases. IMPACT AND IMPLICATIONS Hepatic stellate cells (HSCs) play a key role in the fibrogenic process associated with chronic liver disease. The PNPLA3 genetic mutation has been linked with increased risk of fibrogenesis, but its role in HSCs requires further investigation. Here, by using comparative transcriptomics and a novel 3D in vitro model, we demonstrate the impact of the PNPLA3 genetic mutation on primary human HSCs' behaviour, and we show that it affects the cell's mitochondrial function and antioxidant response, as well as the antifibrotic gene NR4A1. Our publicly available transcriptomic data, 3D platform and our findings on NR4A1 could facilitate the discovery of targets to develop more effective treatments for chronic liver diseases.
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Affiliation(s)
- Elisabetta Caon
- Regenerative Medicine and Fibrosis Group, Institute for Liver and Digestive Health, University College London, Royal Free Campus, London, UK
| | - Maria Martins
- Regenerative Medicine and Fibrosis Group, Institute for Liver and Digestive Health, University College London, Royal Free Campus, London, UK
| | - Harry Hodgetts
- Regenerative Medicine and Fibrosis Group, Institute for Liver and Digestive Health, University College London, Royal Free Campus, London, UK
| | - Lieke Blanken
- Regenerative Medicine and Fibrosis Group, Institute for Liver and Digestive Health, University College London, Royal Free Campus, London, UK
| | - Maria Giovanna Vilia
- Regenerative Medicine and Fibrosis Group, Institute for Liver and Digestive Health, University College London, Royal Free Campus, London, UK
| | - Ana Levi
- Regenerative Medicine and Fibrosis Group, Institute for Liver and Digestive Health, University College London, Royal Free Campus, London, UK
| | - Kessarin Thanapirom
- Regenerative Medicine and Fibrosis Group, Institute for Liver and Digestive Health, University College London, Royal Free Campus, London, UK
| | - Walid Al-Akkad
- Regenerative Medicine and Fibrosis Group, Institute for Liver and Digestive Health, University College London, Royal Free Campus, London, UK
| | - Jeries Abu-Hanna
- Research Department of Surgical Biotechnology, Division of Surgery and Interventional Science, University College London, London, UK
| | - Guido Baselli
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy
| | - Andrew R Hall
- Sheila Sherlock Liver Centre, Royal Free London NHS Foundation Trust, London, UK; Department of Cellular Pathology, Royal Free London NHS Foundation Trust, London, UK
| | - Tu Vinh Luong
- Sheila Sherlock Liver Centre, Royal Free London NHS Foundation Trust, London, UK; Department of Cellular Pathology, Royal Free London NHS Foundation Trust, London, UK
| | - Jan-Willem Taanman
- Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, University College London, London UK
| | - Michele Vacca
- Laboratory of Hepatic Metabolism and NAFLD, Roger Williams Institute of Hepatology, London, UK; Clinica Medica "Frugoni", Interdisciplinary Department of Medicine, University of Bari "Aldo Moro", Bari, Italy
| | - Luca Valenti
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy; Precision Medicine, Biological Resource Center, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Stefano Romeo
- Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, Wallenberg Laboratory, University of Gothenburg, Gothenburg, Sweden
| | - Giuseppe Mazza
- Regenerative Medicine and Fibrosis Group, Institute for Liver and Digestive Health, University College London, Royal Free Campus, London, UK
| | - Massimo Pinzani
- Regenerative Medicine and Fibrosis Group, Institute for Liver and Digestive Health, University College London, Royal Free Campus, London, UK
| | - Krista Rombouts
- Regenerative Medicine and Fibrosis Group, Institute for Liver and Digestive Health, University College London, Royal Free Campus, London, UK.
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Lan D, Fu W, Ji W, Mipam TD, Xiong X, Ying S, Xiong Y, Sheng P, Ni J, Bai L, Shan T, Kong X, Li J. Pangenome and multi-tissue gene atlas provide new insights into the domestication and highland adaptation of yaks. J Anim Sci Biotechnol 2024; 15:64. [PMID: 38706000 PMCID: PMC11071219 DOI: 10.1186/s40104-024-01027-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2023] [Accepted: 03/18/2024] [Indexed: 05/07/2024] Open
Abstract
BACKGROUND The genetic diversity of yak, a key domestic animal on the Qinghai-Tibetan Plateau (QTP), is a vital resource for domestication and breeding efforts. This study presents the first yak pangenome obtained through the de novo assembly of 16 yak genomes. RESULTS We discovered 290 Mb of nonreference sequences and 504 new genes. Our pangenome-wide presence and absence variation (PAV) analysis revealed 5,120 PAV-related genes, highlighting a wide range of variety-specific genes and genes with varying frequencies across yak populations. Principal component analysis (PCA) based on binary gene PAV data classified yaks into three new groups: wild, domestic, and Jinchuan. Moreover, we proposed a 'two-haplotype genomic hybridization model' for understanding the hybridization patterns among breeds by integrating gene frequency, heterozygosity, and gene PAV data. A gene PAV-GWAS identified a novel gene (BosGru3G009179) that may be associated with the multirib trait in Jinchuan yaks. Furthermore, an integrated transcriptome and pangenome analysis highlighted the significant differences in the expression of core genes and the mutational burden of differentially expressed genes between yaks from high and low altitudes. Transcriptome analysis across multiple species revealed that yaks have the most unique differentially expressed mRNAs and lncRNAs (between high- and low-altitude regions), especially in the heart and lungs, when comparing high- and low-altitude adaptations. CONCLUSIONS The yak pangenome offers a comprehensive resource and new insights for functional genomic studies, supporting future biological research and breeding strategies.
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Affiliation(s)
- Daoliang Lan
- Ministry of Education of Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource and Utilization, Southwest Minzu University, Chengdu, China.
- College of Animal & Veterinary Sciences, Southwest Minzu University, Chengdu, China.
- Institute of Qinghai-Tibetan Plateau, Southwest Minzu University, Chengdu, China.
| | - Wei Fu
- College of Animal & Veterinary Sciences, Southwest Minzu University, Chengdu, China
- Institute of Qinghai-Tibetan Plateau, Southwest Minzu University, Chengdu, China
| | - Wenhui Ji
- College of Animal & Veterinary Sciences, Southwest Minzu University, Chengdu, China
| | - Tserang-Donko Mipam
- Institute of Qinghai-Tibetan Plateau, Southwest Minzu University, Chengdu, China
| | - Xianrong Xiong
- Ministry of Education of Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource and Utilization, Southwest Minzu University, Chengdu, China
- College of Animal & Veterinary Sciences, Southwest Minzu University, Chengdu, China
| | - Shi Ying
- College of Animal & Veterinary Sciences, Southwest Minzu University, Chengdu, China
| | - Yan Xiong
- Ministry of Education of Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource and Utilization, Southwest Minzu University, Chengdu, China
- College of Animal & Veterinary Sciences, Southwest Minzu University, Chengdu, China
| | - Peng Sheng
- Jiguang Gene Biotechnology Co., Ltd., Nanjing, China
| | - Jiangping Ni
- Jiguang Gene Biotechnology Co., Ltd., Nanjing, China
| | - Lijun Bai
- Chengdu Genepre Technology Co., Ltd., Chengdu, China
| | - Tongling Shan
- Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai, China
| | | | - Jian Li
- Ministry of Education of Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource and Utilization, Southwest Minzu University, Chengdu, China
- College of Animal & Veterinary Sciences, Southwest Minzu University, Chengdu, China
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Sherman DJ, Liu L, Mamrosh JL, Xie J, Ferbas J, Lomenick B, Ladinsky MS, Verma R, Rulifson IC, Deshaies RJ. The fatty liver disease-causing protein PNPLA3-I148M alters lipid droplet-Golgi dynamics. Proc Natl Acad Sci U S A 2024; 121:e2318619121. [PMID: 38657050 PMCID: PMC11067037 DOI: 10.1073/pnas.2318619121] [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: 10/25/2023] [Accepted: 03/16/2024] [Indexed: 04/26/2024] Open
Abstract
Nonalcoholic fatty liver disease, recently renamed metabolic dysfunction-associated steatotic liver disease (MASLD), is a progressive metabolic disorder that begins with aberrant triglyceride accumulation in the liver and can lead to cirrhosis and cancer. A common variant in the gene PNPLA3, encoding the protein PNPLA3-I148M, is the strongest known genetic risk factor for MASLD. Despite its discovery 20 y ago, the function of PNPLA3, and now the role of PNPLA3-I148M, remain unclear. In this study, we sought to dissect the biogenesis of PNPLA3 and PNPLA3-I148M and characterize changes induced by endogenous expression of the disease-causing variant. Contrary to bioinformatic predictions and prior studies with overexpressed proteins, we demonstrate here that PNPLA3 and PNPLA3-I148M are not endoplasmic reticulum-resident transmembrane proteins. To identify their intracellular associations, we generated a paired set of isogenic human hepatoma cells expressing PNPLA3 and PNPLA3-I148M at endogenous levels. Both proteins were enriched in lipid droplet, Golgi, and endosomal fractions. Purified PNPLA3 and PNPLA3-I148M proteins associated with phosphoinositides commonly found in these compartments. Despite a similar fractionation pattern as the wild-type variant, PNPLA3-I148M induced morphological changes in the Golgi apparatus, including increased lipid droplet-Golgi contact sites, which were also observed in I148M-expressing primary human patient hepatocytes. In addition to lipid droplet accumulation, PNPLA3-I148M expression caused significant proteomic and transcriptomic changes that resembled all stages of liver disease. Cumulatively, we validate an endogenous human cellular system for investigating PNPLA3-I148M biology and identify the Golgi apparatus as a central hub of PNPLA3-I148M-driven cellular change.
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Affiliation(s)
| | - Lei Liu
- Amgen Research, South San Francisco, CA94080
| | | | | | | | - Brett Lomenick
- Proteome Exploration Laboratory, Beckman Institute, California Institute of Technology, Pasadena, CA91125
| | - Mark S. Ladinsky
- Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA91125
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Merenda T, Juszczak F, Ferier E, Duez P, Patris S, Declèves AÉ, Nachtergael A. Natural compounds proposed for the management of non-alcoholic fatty liver disease. NATURAL PRODUCTS AND BIOPROSPECTING 2024; 14:24. [PMID: 38556609 PMCID: PMC10982245 DOI: 10.1007/s13659-024-00445-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/16/2024] [Accepted: 03/20/2024] [Indexed: 04/02/2024]
Abstract
Although non-alcoholic fatty liver disease (NAFLD) presents as an intricate condition characterized by a growing prevalence, the often-recommended lifestyle interventions mostly lack high-level evidence of efficacy and there are currently no effective drugs proposed for this indication. The present review delves into NAFLD pathology, its diverse underlying physiopathological mechanisms and the available in vitro, in vivo, and clinical evidence regarding the use of natural compounds for its management, through three pivotal targets (oxidative stress, cellular inflammation, and insulin resistance). The promising perspectives that natural compounds offer for NAFLD management underscore the need for additional clinical and lifestyle intervention trials. Encouraging further research will contribute to establishing more robust evidence and practical recommendations tailored to patients with varying NAFLD grades.
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Affiliation(s)
- Théodora Merenda
- Unit of Clinical Pharmacy, Research Institute for Health Sciences and Technology, University of Mons (UMONS), Mons, Belgium
| | - Florian Juszczak
- Department of Metabolic and Molecular Biochemistry, Research Institute for Health Sciences and Technology, University of Mons (UMONS), Mons, Belgium
| | - Elisabeth Ferier
- Department of Metabolic and Molecular Biochemistry, Research Institute for Health Sciences and Technology, University of Mons (UMONS), Mons, Belgium
- Unit of Therapeutic Chemistry and Pharmacognosy, Research Institute for Health Sciences and Technology, University of Mons (UMONS), Mons, Belgium
| | - Pierre Duez
- Unit of Therapeutic Chemistry and Pharmacognosy, Research Institute for Health Sciences and Technology, University of Mons (UMONS), Mons, Belgium
| | - Stéphanie Patris
- Unit of Clinical Pharmacy, Research Institute for Health Sciences and Technology, University of Mons (UMONS), Mons, Belgium
| | - Anne-Émilie Declèves
- Department of Metabolic and Molecular Biochemistry, Research Institute for Health Sciences and Technology, University of Mons (UMONS), Mons, Belgium
| | - Amandine Nachtergael
- Unit of Therapeutic Chemistry and Pharmacognosy, Research Institute for Health Sciences and Technology, University of Mons (UMONS), Mons, Belgium.
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Colaço-Gaspar M, Hofer P, Oberer M, Zechner R. PNPLA-mediated lipid hydrolysis and transacylation - At the intersection of catabolism and anabolism. Biochim Biophys Acta Mol Cell Biol Lipids 2024; 1869:159410. [PMID: 37951382 DOI: 10.1016/j.bbalip.2023.159410] [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: 07/31/2023] [Revised: 10/24/2023] [Accepted: 10/30/2023] [Indexed: 11/14/2023]
Abstract
Patatin-like phospholipase domain containing proteins (PNPLAs) play diverse roles in lipid metabolism. In this review, we focus on the enzymatic properties and predicted 3D structures of PNPLA1-5. PNPLA2-4 exert both catabolic and anabolic functions. Whereas PNPLA1 is predominantly expressed in the epidermis and involved in sphingolipid biosynthesis, PNPLA2 and 4 are ubiquitously expressed and exhibit several enzymatic activities, including hydrolysis and transacylation of various (glycero-)lipid species. This review summarizes known biological roles for PNPLA-mediated hydrolysis and transacylation reactions and highlights open questions concerning their physiological function.
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Affiliation(s)
| | - Peter Hofer
- Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria
| | - Monika Oberer
- Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria; Field of Excellence BioHealth, University of Graz, 8010 Graz, Austria; BioTechMed-Graz, 8010 Graz, Austria.
| | - Rudolf Zechner
- Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria; Field of Excellence BioHealth, University of Graz, 8010 Graz, Austria; BioTechMed-Graz, 8010 Graz, Austria.
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9
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Butcko AJ, Putman AK, Mottillo EP. The Intersection of Genetic Factors, Aberrant Nutrient Metabolism and Oxidative Stress in the Progression of Cardiometabolic Disease. Antioxidants (Basel) 2024; 13:87. [PMID: 38247511 PMCID: PMC10812494 DOI: 10.3390/antiox13010087] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2023] [Revised: 12/06/2023] [Accepted: 01/07/2024] [Indexed: 01/23/2024] Open
Abstract
Cardiometabolic disease (CMD), which encompasses metabolic-associated fatty liver disease (MAFLD), chronic kidney disease (CKD) and cardiovascular disease (CVD), has been increasing considerably in the past 50 years. CMD is a complex disease that can be influenced by genetics and environmental factors such as diet. With the increased reliance on processed foods containing saturated fats, fructose and cholesterol, a mechanistic understanding of how these molecules cause metabolic disease is required. A major pathway by which excessive nutrients contribute to CMD is through oxidative stress. In this review, we discuss how oxidative stress can drive CMD and the role of aberrant nutrient metabolism and genetic risk factors and how they potentially interact to promote progression of MAFLD, CVD and CKD. This review will focus on genetic mutations that are known to alter nutrient metabolism. We discuss the major genetic risk factors for MAFLD, which include Patatin-like phospholipase domain-containing protein 3 (PNPLA3), Membrane Bound O-Acyltransferase Domain Containing 7 (MBOAT7) and Transmembrane 6 Superfamily Member 2 (TM6SF2). In addition, mutations that prevent nutrient uptake cause hypercholesterolemia that contributes to CVD. We also discuss the mechanisms by which MAFLD, CKD and CVD are mutually associated with one another. In addition, some of the genetic risk factors which are associated with MAFLD and CVD are also associated with CKD, while some genetic risk factors seem to dissociate one disease from the other. Through a better understanding of the causative effect of genetic mutations in CMD and how aberrant nutrient metabolism intersects with our genetics, novel therapies and precision approaches can be developed for treating CMD.
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Affiliation(s)
- Andrew J. Butcko
- Hypertension and Vascular Research Division, Henry Ford Hospital, 6135 Woodward Avenue, Detroit, MI 48202, USA; (A.J.B.); (A.K.P.)
- Department of Physiology, Wayne State University, 540 E. Canfield Street, Detroit, MI 48202, USA
| | - Ashley K. Putman
- Hypertension and Vascular Research Division, Henry Ford Hospital, 6135 Woodward Avenue, Detroit, MI 48202, USA; (A.J.B.); (A.K.P.)
- Department of Large Animal Clinical Sciences, College of Veterinary Medicine, Michigan State University, 784 Wilson Road, East Lansing, MI 48823, USA
| | - Emilio P. Mottillo
- Hypertension and Vascular Research Division, Henry Ford Hospital, 6135 Woodward Avenue, Detroit, MI 48202, USA; (A.J.B.); (A.K.P.)
- Department of Physiology, Wayne State University, 540 E. Canfield Street, Detroit, MI 48202, USA
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10
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Kulminskaya N, Rodriguez Gamez CF, Hofer P, Cerk IK, Dubey N, Viertlmayr R, Sagmeister T, Pavkov-Keller T, Zechner R, Oberer M. Unmasking crucial residues in adipose triglyceride lipase for coactivation with comparative gene identification-58. J Lipid Res 2024; 65:100491. [PMID: 38135254 PMCID: PMC10828586 DOI: 10.1016/j.jlr.2023.100491] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2023] [Revised: 12/04/2023] [Accepted: 12/08/2023] [Indexed: 12/24/2023] Open
Abstract
Lipolysis is an essential metabolic process that releases unesterified fatty acids from neutral lipid stores to maintain energy homeostasis in living organisms. Adipose triglyceride lipase (ATGL) plays a key role in intracellular lipolysis and can be coactivated upon interaction with the protein comparative gene identification-58 (CGI-58). The underlying molecular mechanism of ATGL stimulation by CGI-58 is incompletely understood. Based on analysis of evolutionary conservation, we used site directed mutagenesis to study a C-terminally truncated variant and full-length mouse ATGL providing insights in the protein coactivation on a per-residue level. We identified the region from residues N209-N215 in ATGL as essential for coactivation by CGI-58. ATGL variants with amino acids exchanges in this region were still able to hydrolyze triacylglycerol at the basal level and to interact with CGI-58, yet could not be activated by CGI-58. Our studies also demonstrate that full-length mouse ATGL showed higher tolerance to specific single amino acid exchanges in the N209-N215 region upon CGI-58 coactivation compared to C-terminally truncated ATGL variants. The region is either directly involved in protein-protein interaction or essential for conformational changes required in the coactivation process. Three-dimensional models of the ATGL/CGI-58 complex with the artificial intelligence software AlphaFold demonstrated that a large surface area is involved in the protein-protein interaction. Mapping important amino acids for coactivation of both proteins, ATGL and CGI-58, onto the 3D model of the complex locates these essential amino acids at the predicted ATGL/CGI-58 interface thus strongly corroborating the significance of these residues in CGI-58-mediated coactivation of ATGL.
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Affiliation(s)
| | | | - Peter Hofer
- Institute of Molecular Biosciences, University of Graz, Graz, Austria
| | - Ines Kathrin Cerk
- Institute of Molecular Biosciences, University of Graz, Graz, Austria
| | - Noopur Dubey
- Institute of Molecular Biosciences, University of Graz, Graz, Austria
| | - Roland Viertlmayr
- Institute of Molecular Biosciences, University of Graz, Graz, Austria
| | - Theo Sagmeister
- Institute of Molecular Biosciences, University of Graz, Graz, Austria
| | - Tea Pavkov-Keller
- Institute of Molecular Biosciences, University of Graz, Graz, Austria; BioTechMed Graz, Graz, Austria; BioHealth Field of Excellence, University of Graz, Graz, Austria
| | - Rudolf Zechner
- Institute of Molecular Biosciences, University of Graz, Graz, Austria; BioTechMed Graz, Graz, Austria; BioHealth Field of Excellence, University of Graz, Graz, Austria
| | - Monika Oberer
- Institute of Molecular Biosciences, University of Graz, Graz, Austria; BioTechMed Graz, Graz, Austria; BioHealth Field of Excellence, University of Graz, Graz, Austria.
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11
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Quaglia A, Roberts EA, Torbenson M. Developmental and Inherited Liver Disease. MACSWEEN'S PATHOLOGY OF THE LIVER 2024:122-294. [DOI: 10.1016/b978-0-7020-8228-3.00003-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
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12
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Shankarappa B, Mahadevan J, Murthy P, Purushottam M, Viswanath B, Jain S, Devarbhavi H, Mysore V A. A study of genetic variants, genetic risk score and DNA methylation of PNPLA3 and TM6SF2 in alcohol liver cirrhosis. Indian J Gastroenterol 2023; 42:800-807. [PMID: 37589914 DOI: 10.1007/s12664-023-01420-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2023] [Accepted: 06/20/2023] [Indexed: 08/18/2023]
Abstract
BACKGROUND Genetic and epigenetic factors are associated with the development of alcohol-associated liver disease (AALD). The single nucleotide polymorphisms (SNPs), rs738409 in Patatin-like phospholipase domain-containing protein (PNPLA3) and rs58542926 in Transmembrane 6 Superfamily Member 2 (TM6SF2) are strongly associated with AALD in different global populations, Hence, we analyzed the genetic risk score for these variants and deoxyribonucleic acid (DNA) methylation levels of the PNPLA3 and TM6SF2 genes among cases (alcohol liver cirrhosis) and controls (heavy drinkers without cirrhosis). METHOD We studied patients with alcohol use disorder (AUD) with cirrhosis (AUD-C + ve, n = 136) and without cirrhosis (AUD-C-ve, n = 107) drawn from the clinical services of St. John's Medical College Hospital (SJMCH) (Gastroenterology and Psychiatry) and Centre for Addiction Medicine (CAM), National Institute of Mental Health and Neurosciences, (NIMHANS). Genotype data was generated for rs738409 (PNPLA3) and rs58542926 (TM6SF2) and used to calculate unweighted genetic risk score (uGRS) and weighted genetic risk scores (wGRS). DNA methylation levels were estimated by pyrosequencing at PNPLA3 and TM6SF2 loci. RESULTS Overall we observed a significantly higher genetic risk score (weighted genetic risk score, wGRS) in individuals with alcohol use disorder compared to control population (p = < 0.01). Further, uGRS and wGRS were associated with the diagnosis of cirrhosis, even after correcting for age of onset, quantity and frequency of drinking. We also found hypomethylation at CpG2 of TM6SF2 gene in AUD-C + ve compared to AUD-C-ve (P = 0.02). CONCLUSION We found that a genetic risk score based on SNPs in the PNPLA3 and TM6SF2 genes was significantly associated with cirrhosis in patients with AUD, suggesting a potential utility in identifying patients at risk and providing pre-emptive interventions. These may include interventions that aim to alter DNA methylation, which may be one of the mechanisms through which elevated genetic risk may influence the development of cirrhosis.
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Affiliation(s)
- Bhagyalakshmi Shankarappa
- Department of Psychiatry, St John's Medical College Hospital, Bengaluru 560 034, India
- Molecular Genetics Laboratory, Department of Psychiatry, National Institute of Mental Health and Neurosciences, Bengaluru, 560 030, India
| | - Jayant Mahadevan
- Department of Psychiatry, National Institute of Mental Health and Neurosciences, Bengaluru, 560 030, India
| | - Pratima Murthy
- Department of Psychiatry, National Institute of Mental Health and Neurosciences, Bengaluru, 560 030, India
| | - Meera Purushottam
- Molecular Genetics Laboratory, Department of Psychiatry, National Institute of Mental Health and Neurosciences, Bengaluru, 560 030, India.
| | - Biju Viswanath
- Molecular Genetics Laboratory, Department of Psychiatry, National Institute of Mental Health and Neurosciences, Bengaluru, 560 030, India
- Department of Psychiatry, National Institute of Mental Health and Neurosciences, Bengaluru, 560 030, India
| | - Sanjeev Jain
- Department of Psychiatry, National Institute of Mental Health and Neurosciences, Bengaluru, 560 030, India
| | - Harshad Devarbhavi
- Department of Gastroenterology, St John's Medical College Hospital, Bengaluru, 560 034, India
| | - Ashok Mysore V
- Department of Psychiatry, St John's Medical College Hospital, Bengaluru 560 034, India
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13
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Guo YF, Sun JY, Liu Y, Liu ZY, Huang Y, Xiao Y, Su T. lncRNA Hnscr Regulates Lipid Metabolism by Mediating Adipocyte Lipolysis. Endocrinology 2023; 164:bqad147. [PMID: 37788569 PMCID: PMC10628467 DOI: 10.1210/endocr/bqad147] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2023] [Revised: 09/26/2023] [Accepted: 09/27/2023] [Indexed: 10/05/2023]
Abstract
Obesity is a process of fat accumulation due to the imbalance between energy intake and consumption. Long noncoding RNA (lncRNA) Hnscr is crucial for metabolic regulation, but its roles in lipid metabolism during obesity are still unknown. In this article, we found that the expression of Hnscr gradually decreased in adipose tissues of diet-induced obese mice. Furthermore, the deletion of Hnscr promoted an increase in body weight and adipose tissue weight by upregulating the expression of lipogenesis genes and downregulating lipolysis genes in inguinal white adipose tissue (iWAT) and brown adipose tissue. In vitro knockdown of Hnscr in adipocytes resulted in reduced lipolysis of adipocytes. Overexpression of Hnscr by adenovirus or drug mimics showed the opposite. Mechanistically, Hnscr regulated adipose lipid metabolism by mediating the cyclic adenosine monophosphate/protein kinase A signaling pathway. This study identifies the initial characterization of Hnscr as a critical modifier that regulates lipid metabolism, suggesting that lncRNA Hnscr is a potential target for treating obesity.
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Affiliation(s)
- Yi-Fan Guo
- Department of Endocrinology, Endocrinology Research Center, Xiangya Hospital of Central South University, Changsha, Hunan 410008, China
| | - Jing-Yi Sun
- Department of Geriatrics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Ya Liu
- Department of Endocrinology, Endocrinology Research Center, Xiangya Hospital of Central South University, Changsha, Hunan 410008, China
| | - Zhe-Yu Liu
- Department of Endocrinology, Endocrinology Research Center, Xiangya Hospital of Central South University, Changsha, Hunan 410008, China
| | - Yan Huang
- Department of Endocrinology, Endocrinology Research Center, Xiangya Hospital of Central South University, Changsha, Hunan 410008, China
| | - Yuan Xiao
- Department of Endocrinology, Endocrinology Research Center, Xiangya Hospital of Central South University, Changsha, Hunan 410008, China
| | - Tian Su
- Department of Endocrinology, Endocrinology Research Center, Xiangya Hospital of Central South University, Changsha, Hunan 410008, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital of Central South University, Changsha, Hunan 410008, China
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Sherman DJ, Liu L, Mamrosh JL, Xie J, Ferbas J, Lomenick B, Ladinsky MS, Verma R, Rulifson IC, Deshaies RJ. The fatty liver disease-causing protein PNPLA3-I148M alters lipid droplet-Golgi dynamics. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.10.13.562302. [PMID: 37873239 PMCID: PMC10592801 DOI: 10.1101/2023.10.13.562302] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 10/25/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD), recently renamed metabolic dysfunction-associated steatotic liver disease (MASLD), is a progressive metabolic disorder that begins with aberrant triglyceride accumulation in the liver and can lead to cirrhosis and cancer. A common variant in the gene PNPLA3, encoding the protein PNPLA3-I148M, is the strongest known genetic risk factor for MASLD to date. Despite its discovery twenty years ago, the function of PNPLA3, and now the role of PNPLA3-I148M, remain unclear. In this study, we sought to dissect the biogenesis of PNPLA3 and PNPLA3-I148M and characterize changes induced by endogenous expression of the disease-causing variant. Contrary to bioinformatic predictions and prior studies with overexpressed proteins, we demonstrate here that PNPLA3 and PNPLA3-I148M are not endoplasmic reticulum-resident transmembrane proteins. To identify their intracellular associations, we generated a paired set of isogenic human hepatoma cells expressing PNPLA3 and PNPLA3-I148M at endogenous levels. Both proteins were enriched in lipid droplet, Golgi, and endosomal fractions. Purified PNPLA3 and PNPLA3-I148M proteins associated with phosphoinositides commonly found in these compartments. Despite a similar fractionation pattern as the wild-type variant, PNPLA3-I148M induced morphological changes in the Golgi apparatus, including increased lipid droplet-Golgi contact sites, which were also observed in I148M-expressing primary human patient hepatocytes. In addition to lipid droplet accumulation, PNPLA3-I148M expression caused significant proteomic and transcriptomic changes that resembled all stages of liver disease. Cumulatively, we validate an endogenous human cellular system for investigating PNPLA3-I148M biology and identify the Golgi apparatus as a central hub of PNPLA3-I148M-driven cellular change.
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Affiliation(s)
| | - Lei Liu
- Amgen Research, South San Francisco, CA 94080, USA
| | | | | | - John Ferbas
- Amgen Research, Thousand Oaks, CA 91320, USA
| | - Brett Lomenick
- Proteome Exploration Laboratory, California Institute of Technology, Pasadena, CA 91125, USA
| | - Mark S. Ladinsky
- Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA
| | - Rati Verma
- Amgen Research, Thousand Oaks, CA 91320, USA
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15
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Johnson S, Bao H, McMahon C, Chen Y, Burr S, Anderson A, Madeyski-Bengtson K, Lindén D, Han X, Liu J. Substrate-Specific Function of PNPLA3 Facilitates Hepatic VLDL-Triglyceride Secretion During Stimulated Lipogenesis. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.08.30.553213. [PMID: 37693552 PMCID: PMC10491159 DOI: 10.1101/2023.08.30.553213] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/12/2023]
Abstract
The I148M variant of PNPLA3 is strongly linked to hepatic steatosis. Evidence suggests a gain-of-function role for the I148M mutant as an ATGL inhibitor, leaving the physiological relevance of wild-type PNPLA3 undefined. Here we show that PNPLA3 selectively degrades triglycerides (TGs) enriched in polyunsaturated fatty acids (PUFAs) independently of ATGL in cultured cells and mice. Lipidomics and metabolite tracing analyses demonstrated that PNPLA3 mobilizes PUFAs from intracellular TGs for phospholipid desaturation, supporting hepatic secretion of TG-rich lipoproteins. Consequently, mice with liver-specific knockout or acute knockdown of PNPLA3 both exhibited aggravated liver steatosis and concomitant decreases in plasma VLDL-TG, phenotypes that manifest only under lipogenic conditions. I148M-knockin mice similarly displayed impaired hepatic TG secretion during lipogenic stimulation. Our results highlight a specific context whereby PNPLA3 facilitates the balance between hepatic TG storage and secretion and suggest the potential contributions of I148M variant loss-of-function to the development of hepatic steatosis in humans. Summary Statement We define the physiological role of wild type PNPLA3 in maintaining hepatic VLDL-TG secretion.
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16
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Samarasinghe SM, Hewage AS, Siriwardana RC, Tennekoon KH, Niriella MA, De Silva S. Genetic and metabolic aspects of non-alcoholic fatty liver disease (NAFLD) pathogenicity. EGYPTIAN JOURNAL OF MEDICAL HUMAN GENETICS 2023; 24:53. [DOI: 10.1186/s43042-023-00433-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2023] [Accepted: 08/21/2023] [Indexed: 01/03/2025] Open
Abstract
Abstract
Background
Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease showing a rising prevalence globally. Genetic predisposition plays a key role in the development and progression of the disease pathogenicity.
Main body
This paper summarizes genetic associations based on their influence on several metabolic aspects such as lipid metabolism, glucose metabolism, hepatic iron accumulation and cholesterol metabolism toward the NAFLD pathogenicity. Furthermore, we present variations in some epigenetic characters and the microRNA profile with regard to NAFLD.
Conclusion
As reported in many studies, the PNPLA3 rs738409 variant seems to be significantly associated with NAFLD susceptibility. Other gene variants like TM6SF2 rs58542926, MBOAT7 rs641738 and GCKR variants also appear to be more prevalent among NAFLD patients. We believe these genetic variants may provide insights into new trends in developing noninvasive biomarkers and identify their suitability in clinical practice in the future.
Graphical abstract
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Kimura T, Kimura AK, Epand RM. Systematic crosstalk in plasmalogen and diacyl lipid biosynthesis for their differential yet concerted molecular functions in the cell. Prog Lipid Res 2023; 91:101234. [PMID: 37169310 DOI: 10.1016/j.plipres.2023.101234] [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: 03/03/2023] [Revised: 04/29/2023] [Accepted: 05/05/2023] [Indexed: 05/13/2023]
Abstract
Plasmalogen is a major phospholipid of mammalian cell membranes. Recently it is becoming evident that the sn-1 vinyl-ether linkage in plasmalogen, contrasting to the ester linkage in the counterpart diacyl glycerophospholipid, yields differential molecular characteristics for these lipids especially related to hydrocarbon-chain order, so as to concertedly regulate biological membrane processes. A role played by NMR in gaining information in this respect, ranging from molecular to tissue levels, draws particular attention. We note here that a broad range of enzymes in de novo synthesis pathway of plasmalogen commonly constitute that of diacyl glycerophospholipid. This fact forms the basis for systematic crosstalk that not only controls a quantitative balance between these lipids, but also senses a defect causing loss of lipid in either pathway for compensation by increase of the counterpart lipid. However, this inherent counterbalancing mechanism paradoxically amplifies imbalance in differential effects of these lipids in a diseased state on membrane processes. While sharing of enzymes has been recognized, it is now possible to overview the crosstalk with growing information for specific enzymes involved. The overview provides a fundamental clue to consider cell and tissue type-dependent schemes in regulating membrane processes by plasmalogen and diacyl glycerophospholipid in health and disease.
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Affiliation(s)
- Tomohiro Kimura
- Department of Chemistry & Department of Biochemistry and Molecular Biophysics, Kansas State University, Manhattan, Kansas 66506, USA.
| | - Atsuko K Kimura
- Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario L8S 4K1, Canada
| | - Richard M Epand
- Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario L8S 4K1, Canada
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Lulić AM, Katalinić M. The PNPLA family of enzymes: characterisation and biological role. Arh Hig Rada Toksikol 2023; 74:75-89. [PMID: 37357879 PMCID: PMC10291501 DOI: 10.2478/aiht-2023-74-3723] [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: 02/01/2023] [Revised: 02/01/2023] [Accepted: 05/01/2023] [Indexed: 06/27/2023] Open
Abstract
This paper brings a brief review of the human patatin-like phospholipase domain-containing protein (PNPLA) family. Even though it consists of only nine members, their physiological roles and mechanisms of their catalytic activity are not fully understood. However, the results of a number of knock-out and gain- or loss-of-function research models suggest that these enzymes have an important role in maintaining the homeostasis and integrity of organelle membranes, in cell growth, signalling, cell death, and the metabolism of lipids such as triacylglycerol, phospholipids, ceramides, and retinyl esters. Research has also revealed a connection between PNPLA family member mutations or irregular catalytic activity and the development of various diseases. Here we summarise important findings published so far and discuss their structure, localisation in the cell, distribution in the tissues, specificity for substrates, and their potential physiological role, especially in view of their potential as drug targets.
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Affiliation(s)
- Ana-Marija Lulić
- Institute for Medical Research and Occupational Health, Biochemistry and Organic Analytical Chemistry Unit, Zagreb, Croatia
| | - Maja Katalinić
- Institute for Medical Research and Occupational Health, Biochemistry and Organic Analytical Chemistry Unit, Zagreb, Croatia
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19
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Guerrero-Santoro J, Morizane M, Oh SY, Mishima T, Goff JP, Bildirici I, Sadovsky E, Ouyang Y, Tyurin VA, Tyurina YY, Kagan VE, Sadovsky Y. The lipase cofactor CGI58 controls placental lipolysis. JCI Insight 2023; 8:168717. [PMID: 37212279 DOI: 10.1172/jci.insight.168717] [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: 01/10/2023] [Accepted: 04/12/2023] [Indexed: 05/23/2023] Open
Abstract
In eutherians, the placenta plays a critical role in the uptake, storage, and metabolism of lipids. These processes govern the availability of fatty acids to the developing fetus, where inadequate supply has been associated with substandard fetal growth. Whereas lipid droplets are essential for the storage of neutral lipids in the placenta and many other tissues, the processes that regulate placental lipid droplet lipolysis remain largely unknown. To assess the role of triglyceride lipases and their cofactors in determining placental lipid droplet and lipid accumulation, we assessed the role of patatin like phospholipase domain containing 2 (PNPLA2) and comparative gene identification-58 (CGI58) in lipid droplet dynamics in the human and mouse placenta. While both proteins are expressed in the placenta, the absence of CGI58, not PNPLA2, markedly increased placental lipid and lipid droplet accumulation. These changes were reversed upon restoration of CGI58 levels selectively in the CGI58-deficient mouse placenta. Using co-immunoprecipitation, we found that, in addition to PNPLA2, PNPLA9 interacts with CGI58. PNPLA9 was dispensable for lipolysis in the mouse placenta yet contributed to lipolysis in human placental trophoblasts. Our findings establish a crucial role for CGI58 in placental lipid droplet dynamics and, by extension, in nutrient supply to the developing fetus.
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Affiliation(s)
- Jennifer Guerrero-Santoro
- Magee-Womens Research Institute, Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Mayumi Morizane
- Magee-Womens Research Institute, Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Soo-Young Oh
- Magee-Womens Research Institute, Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Takuya Mishima
- Magee-Womens Research Institute, Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Julie P Goff
- Magee-Womens Research Institute, Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Ibrahim Bildirici
- Department of Obstetrics and Gynecology, Washington University School of Medicine in St. Louis, St. Louis, Missouri, USA
| | - Elena Sadovsky
- Magee-Womens Research Institute, Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Yingshi Ouyang
- Magee-Womens Research Institute, Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Vladimir A Tyurin
- Center for Free Radical and Antioxidant Health, Department of Environmental and Occupational Health
| | - Yulia Y Tyurina
- Center for Free Radical and Antioxidant Health, Department of Environmental and Occupational Health
| | - Valerian E Kagan
- Center for Free Radical and Antioxidant Health, Department of Environmental and Occupational Health
- Department of Chemistry
- Department of Pharmacology and Chemical Biology
- Department of Radiation Oncology; and
| | - Yoel Sadovsky
- Magee-Womens Research Institute, Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
- Department of Microbiology and Molecular Genetics, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
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20
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Zhao X, Amevor FK, Cui Z, Wan Y, Xue X, Peng C, Li Y. Steatosis in metabolic diseases: A focus on lipolysis and lipophagy. Biomed Pharmacother 2023; 160:114311. [PMID: 36764133 DOI: 10.1016/j.biopha.2023.114311] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2022] [Revised: 01/23/2023] [Accepted: 01/26/2023] [Indexed: 02/11/2023] Open
Abstract
Fatty acids (FAs), as part of lipids, are involved in cell membrane composition, cellular energy storage, and cell signaling. FAs can also be toxic when their concentrations inside and/or outside the cell exceed physiological levels, which is called "lipotoxicity", and steatosis is a form of lipotoxity. To facilitate the storage of large quantities of FAs in cells, they undergo a process called lipolysis or lipophagy. This review focuses on the effects of lipolytic enzymes including cytoplasmic "neutral" lipolysis, lysosomal "acid" lipolysis, and lipophagy. Moreover, the impact of related lipolytic enzymes on lipid metabolism homeostasis and energy conservation, as well as their role in lipid-related metabolic diseases. In addition, we describe how they affect lipid metabolism homeostasis and energy conservation in lipid-related metabolic diseases with a focus on hepatic steatosis and cancer and the pathogenesis and therapeutic targets of AMPK/SIRTs/FOXOs, PI3K/Akt, PPARs/PGC-1α, MAPK/ERK1/2, TLR4/NF-κB, AMPK/mTOR/TFEB, Wnt/β-catenin through immune inflammation, oxidative stress and autophagy-related pathways. As well as the current application of lipolytic enzyme inhibitors (especially Monoacylglycerol lipase (MGL) inhibitors) to provide new strategies for future exploration of metabolic programming in metabolic diseases.
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Affiliation(s)
- Xingtao Zhao
- State Key Laboratory of Southwestern Chinese Medicine Resources, Ministry of Education, Chengdu 611137, China; School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China.
| | - Felix Kwame Amevor
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, China.
| | - Zhifu Cui
- College of Animal Science and Technology, Southwest University, Chongqing 400715, China.
| | - Yan Wan
- State Key Laboratory of Southwestern Chinese Medicine Resources, Ministry of Education, Chengdu 611137, China; School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China.
| | - Xinyan Xue
- State Key Laboratory of Southwestern Chinese Medicine Resources, Ministry of Education, Chengdu 611137, China; School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China.
| | - Cheng Peng
- State Key Laboratory of Southwestern Chinese Medicine Resources, Ministry of Education, Chengdu 611137, China; School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China.
| | - Yunxia Li
- State Key Laboratory of Southwestern Chinese Medicine Resources, Ministry of Education, Chengdu 611137, China; School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China.
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21
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Ragavendran PV, Tripathi V, Gandotra S. Structure prediction-based insights into the patatin family of Mycobacterium tuberculosis. MICROBIOLOGY (READING, ENGLAND) 2022; 168. [PMID: 36748562 DOI: 10.1099/mic.0.001270] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Despite its genome sequencing more than two decades ago, the majority of the genes of Mycobacterium tuberculosis remain functionally uncharacterized. Patatins are one such class of proteins that, despite undergoing an expansion in this pathogenic species compared to their non-pathogenic cousins, remain largely unstudied. Recent advances in protein structure prediction using machine learning tools such as AlphaFold2 have provided high-confidence predicted structures for all M. tuberculosis proteins. Here we present detailed analyses of the patatin family of M. tuberculosis using AlphaFold-predicted structures, providing insights into likely modes of regulation, membrane interaction and substrate binding. Regulatory domains within this family of proteins include cyclic nucleotide binding, lid-like domains and other helical domains. Using structural homologues, we identified the likely membrane localization mechanisms and substrate-binding sites. These analyses reveal diversity in their regulatory capacity, mechanisms of membrane binding and likely length of fatty acid substrates. Together, this analysis suggests unique roles for the eight predicted patatins of M. tuberculosis.
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Affiliation(s)
- P V Ragavendran
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh- 201 002, India.,Immunology and Infectious Disease, CSIR-Institute of Genomics and Integrative Biology, New Delhi, India, New Delhi, India
| | - Vaishnavi Tripathi
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh- 201 002, India.,Immunology and Infectious Disease, CSIR-Institute of Genomics and Integrative Biology, New Delhi, India, New Delhi, India
| | - Sheetal Gandotra
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh- 201 002, India.,Immunology and Infectious Disease, CSIR-Institute of Genomics and Integrative Biology, New Delhi, India, New Delhi, India
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Schratter M, Lass A, Radner FPW. ABHD5-A Regulator of Lipid Metabolism Essential for Diverse Cellular Functions. Metabolites 2022; 12:1015. [PMID: 36355098 PMCID: PMC9694394 DOI: 10.3390/metabo12111015] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2022] [Revised: 10/19/2022] [Accepted: 10/23/2022] [Indexed: 11/12/2023] Open
Abstract
The α/β-Hydrolase domain-containing protein 5 (ABHD5; also known as comparative gene identification-58, or CGI-58) is the causative gene of the Chanarin-Dorfman syndrome (CDS), a disorder mainly characterized by systemic triacylglycerol accumulation and a severe defect in skin barrier function. The clinical phenotype of CDS patients and the characterization of global and tissue-specific ABHD5-deficient mouse strains have demonstrated that ABHD5 is a crucial regulator of lipid and energy homeostasis in various tissues. Although ABHD5 lacks intrinsic hydrolase activity, it functions as a co-activating enzyme of the patatin-like phospholipase domain-containing (PNPLA) protein family that is involved in triacylglycerol and glycerophospholipid, as well as sphingolipid and retinyl ester metabolism. Moreover, ABHD5 interacts with perilipins (PLINs) and fatty acid-binding proteins (FABPs), which are important regulators of lipid homeostasis in adipose and non-adipose tissues. This review focuses on the multifaceted role of ABHD5 in modulating the function of key enzymes in lipid metabolism.
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Affiliation(s)
- Margarita Schratter
- Institute of Molecular Biosciences, NAWI Graz, University of Graz, 8010 Graz, Austria
| | - Achim Lass
- Institute of Molecular Biosciences, NAWI Graz, University of Graz, 8010 Graz, Austria
- BioTechMed-Graz, 8010 Graz, Austria
- Field of Excellence BioHealth, 8010 Graz, Austria
| | - Franz P. W. Radner
- Institute of Molecular Biosciences, NAWI Graz, University of Graz, 8010 Graz, Austria
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23
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Mobilia M, Whitus C, Karakashian A, Lu HS, Daugherty A, Gordon SM. Dennd5b-Deficient Mice are Resistant to PCSK9-Induced Hypercholesterolemia and Diet-Induced Hepatic Steatosis. J Lipid Res 2022; 63:100296. [PMID: 36243100 PMCID: PMC9685390 DOI: 10.1016/j.jlr.2022.100296] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2022] [Revised: 09/01/2022] [Accepted: 09/10/2022] [Indexed: 11/07/2022] Open
Abstract
Dennd5b plays a pivotal role in intestinal absorption of dietary lipids in mice and is associated with body mass index in humans. This study examined the impact of whole-body Dennd5b deletion on plasma lipid concentrations, atherosclerosis, and hepatic lipid metabolism in mice. Hypercholesterolemia was induced in Dennd5b-/- mice by infection with an adeno-associated virus expressing the proprotein convertase subtilisin/kexin type 9 serine protease (PCSK9) gain-of-function mutation (PCSK9D377Y) and feeding a Western diet for 12 weeks. Body weight and plasma lipid concentrations were monitored over 12 weeks, and then aortic atherosclerosis and hepatic lipid content were quantified. Compared to Dennd5b+/+ mice, Dennd5b-/- mice were resistant to diet-induced weight gain and PCSK9-induced hypercholesterolemia. Atherosclerosis quantified by en face analysis and in aortic root sections, revealed significantly smaller lesions in Dennd5b-/- compared to Dennd5b+/+ mice. Additionally, Dennd5b-/- mice had significantly less hepatic lipid content (triglyceride and cholesterol) compared to Dennd5b+/+ mice. To gain insight into the basis for reduced hepatic lipids, quantitative PCR was used to measure mRNA abundance of genes involved in hepatic lipid metabolism. Key genes involved in hepatic lipid metabolism and lipid storage were differentially expressed in Dennd5b-/- liver including Pparg, Cd36, and Pnpla3. These findings demonstrate a significant impact of Dennd5b on plasma and hepatic lipid concentrations and resistance to PCSK9-induced hypercholesterolemia in the absence of Dennd5b.
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Affiliation(s)
- Maura Mobilia
- Saha Cardiovascular Research Center, University of Kentucky, Lexington, KY, USA
| | - Callie Whitus
- Saha Cardiovascular Research Center, University of Kentucky, Lexington, KY, USA
| | | | - Hong S. Lu
- Saha Cardiovascular Research Center, University of Kentucky, Lexington, KY, USA,Department of Physiology, University of Kentucky, Lexington, KY, USA
| | - Alan Daugherty
- Saha Cardiovascular Research Center, University of Kentucky, Lexington, KY, USA,Department of Physiology, University of Kentucky, Lexington, KY, USA
| | - Scott M. Gordon
- Saha Cardiovascular Research Center, University of Kentucky, Lexington, KY, USA,Department of Physiology, University of Kentucky, Lexington, KY, USA,For correspondence: Scott M. Gordon
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24
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Meriin AB, Zaarur N, Roy D, Kandror KV. Egr1 plays a major role in the transcriptional response of white adipocytes to insulin and environmental cues. Front Cell Dev Biol 2022; 10:1003030. [PMID: 36246998 PMCID: PMC9554007 DOI: 10.3389/fcell.2022.1003030] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Accepted: 09/08/2022] [Indexed: 11/18/2022] Open
Abstract
It is believed that insulin regulates metabolic functions of white adipose tissue primarily at the post-translational level via the PI3K-Akt-mediated pathway. Still, changes in transcription also play an important role in the response of white adipocytes to insulin and environmental signals. One transcription factor that is dramatically and rapidly induced in adipocytes by insulin and nutrients is called Early Growth Response 1, or Egr1. Among other functions, it directly binds to promoters of leptin and ATGL stimulating the former and inhibiting the latter. Furthermore, expression of Egr1 in adipocytes demonstrates cell autonomous circadian pattern suggesting that Egr1 not only mediates the effect of insulin and nutrients on lipolysis and leptin production but also, coordinates insulin action with endogenous circadian rhythms of adipose tissue.
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Affiliation(s)
- A. B. Meriin
- Department of Biochemistry, Boston University School of Medicine, Boston, MA, United States
| | - N. Zaarur
- Department of Biochemistry, Boston University School of Medicine, Boston, MA, United States
| | - D. Roy
- Department of Neuroscience, The Ohio State University, Columbus, OH, United States
| | - K. V. Kandror
- Department of Biochemistry, Boston University School of Medicine, Boston, MA, United States
- *Correspondence: K. V. Kandror,
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25
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Kabbani M, Michailidis E, Steensels S, Fulmer CG, Luna JM, Le Pen J, Tardelli M, Razooky B, Ricardo-Lax I, Zou C, Zeck B, Stenzel AF, Quirk C, Foquet L, Ashbrook AW, Schneider WM, Belkaya S, Lalazar G, Liang Y, Pittman M, Devisscher L, Suemizu H, Theise ND, Chiriboga L, Cohen DE, Copenhaver R, Grompe M, Meuleman P, Ersoy BA, Rice CM, de Jong YP. Human hepatocyte PNPLA3-148M exacerbates rapid non-alcoholic fatty liver disease development in chimeric mice. Cell Rep 2022; 40:111321. [PMID: 36103835 PMCID: PMC11587767 DOI: 10.1016/j.celrep.2022.111321] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2020] [Revised: 05/11/2022] [Accepted: 08/16/2022] [Indexed: 11/28/2022] Open
Abstract
Advanced non-alcoholic fatty liver disease (NAFLD) is a rapidly emerging global health problem associated with pre-disposing genetic polymorphisms, most strikingly an isoleucine to methionine substitution in patatin-like phospholipase domain-containing protein 3 (PNPLA3-I148M). Here, we study how human hepatocytes with PNPLA3 148I and 148M variants engrafted in the livers of broadly immunodeficient chimeric mice respond to hypercaloric diets. As early as four weeks, mice developed dyslipidemia, impaired glucose tolerance, and steatosis with ballooning degeneration selectively in the human graft, followed by pericellular fibrosis after eight weeks of hypercaloric feeding. Hepatocytes with the PNPLA3-148M variant, either from a homozygous 148M donor or overexpressed in a 148I donor background, developed microvesicular and severe steatosis with frequent ballooning degeneration, resulting in more active steatohepatitis than 148I hepatocytes. We conclude that PNPLA3-148M in human hepatocytes exacerbates NAFLD. These models will facilitate mechanistic studies into human genetic variant contributions to advanced fatty liver diseases.
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Affiliation(s)
- Mohammad Kabbani
- Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY 10065, USA; Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Eleftherios Michailidis
- Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY 10065, USA; Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University, Atlanta, GA 30322, USA
| | - Sandra Steensels
- Division of Gastroenterology and Hepatology, Weill Cornell Medicine, 413 East 69th Street, BB626, New York, NY 10065, USA
| | - Clifton G Fulmer
- Department of Pathology, Weill Cornell Medicine, New York, NY 10065, USA; Robert J. Tomsich Pathology and Laboratory Medicine Institute, The Cleveland Clinic, Cleveland, OH 44195, USA
| | - Joseph M Luna
- Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY 10065, USA
| | - Jérémie Le Pen
- Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY 10065, USA
| | - Matteo Tardelli
- Division of Gastroenterology and Hepatology, Weill Cornell Medicine, 413 East 69th Street, BB626, New York, NY 10065, USA
| | - Brandon Razooky
- Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY 10065, USA
| | - Inna Ricardo-Lax
- Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY 10065, USA
| | - Chenhui Zou
- Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY 10065, USA; Division of Gastroenterology and Hepatology, Weill Cornell Medicine, 413 East 69th Street, BB626, New York, NY 10065, USA
| | - Briana Zeck
- Department of Pathology, NYU Langone, New York, NY 10028, USA
| | - Ansgar F Stenzel
- Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY 10065, USA; Department of Infectious Diseases, Molecular Virology, Heidelberg University, Heidelberg, Germany
| | - Corrine Quirk
- Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY 10065, USA
| | | | - Alison W Ashbrook
- Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY 10065, USA
| | - William M Schneider
- Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY 10065, USA
| | - Serkan Belkaya
- St. Giles Laboratory of Human Genetics of Infectious Diseases, The Rockefeller University, New York, NY 10065, USA
| | - Gadi Lalazar
- Division of Gastroenterology and Hepatology, Weill Cornell Medicine, 413 East 69th Street, BB626, New York, NY 10065, USA; Laboratory of Cellular Biophysics, The Rockefeller University, New York, NY 10065, USA
| | - Yupu Liang
- Center for Clinical and Translational Science, The Rockefeller University, New York, NY 10065, USA
| | - Meredith Pittman
- Department of Pathology, Weill Cornell Medicine, New York, NY 10065, USA
| | - Lindsey Devisscher
- Department of Basic and Applied Medical Sciences, Gut-Liver Immunopharmacology Unit, Ghent University, Ghent, Belgium
| | | | - Neil D Theise
- Department of Pathology, NYU Langone, New York, NY 10028, USA
| | - Luis Chiriboga
- Department of Pathology, NYU Langone, New York, NY 10028, USA
| | - David E Cohen
- Division of Gastroenterology and Hepatology, Weill Cornell Medicine, 413 East 69th Street, BB626, New York, NY 10065, USA
| | | | - Markus Grompe
- Yecuris Corporation, Tualatin, OR 97062, USA; Department of Pediatrics, Oregon Stem Cell Center, Oregon Health and Science University, Portland, OR 97239, USA
| | - Philip Meuleman
- Laboratory of Liver Infectious Diseases, Ghent University, Ghent, Belgium
| | - Baran A Ersoy
- Division of Gastroenterology and Hepatology, Weill Cornell Medicine, 413 East 69th Street, BB626, New York, NY 10065, USA
| | - Charles M Rice
- Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY 10065, USA
| | - Ype P de Jong
- Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY 10065, USA; Division of Gastroenterology and Hepatology, Weill Cornell Medicine, 413 East 69th Street, BB626, New York, NY 10065, USA.
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26
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Liu ZG, Hu YQ, Li K, Mu YL, Wu TW. Pnpla5-knockout rats exhibit reduced expression levels of proteins involved in steroid metabolism and wound healing compared to wild-type rats. BMC Genomics 2022; 23:583. [PMID: 35962316 PMCID: PMC9375266 DOI: 10.1186/s12864-022-08835-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2022] [Accepted: 08/09/2022] [Indexed: 12/02/2022] Open
Abstract
Background Patatin-like phospholipase domain containing 5 (PNPLA5) is a newly-discovered lipase. Although the PNPLA family plays critical roles in diverse biological processes, the biological functions of PNPLA5 mostly unknown. We previously found that the deletion of Pnpla5 in rats causes a variety of phenotypic abnormalities. In this study, we further explored the effects of Pnpla5 knockout (KO) on male rats. Results The body weight and testicular or epididymal tissue weight of three to six 3-month-old Pnpla5 KO or wild-type (WT) male Sprague–Dawley rats were measured. The protein expression levels were also measured via western blotting and iTRAQ (isobaric tags for relative and absolute quantitation) analyses. No significant difference between Pnpla5 KO and WT rats, regarding body weight, testicular or epididymal tissue weight, or hormone levels, were found. However, the relative testicular tissue weight of the KO (Pnpla5−/−) rats was higher (P < 0.05) than that of WT rats. Significant increases in apoptotic cells numbers (P < 0.001) and BAX and Caspase-9 expression levels were observed in the testicular tissue of Pnpla5−/− rats. Moreover, iTRAQ analysis revealed that the levels of proteins involved in steroid metabolism and wound healing were significantly decreased in Pnpla5−/− rats. Conclusion This study revealed that Pnpla5 knockout induced apoptosis in rat testes. We also ascertained that Pnpla5 plays an important role in lipid metabolism, wound healing, and affects reproductive organs negatively, providing new target genes and pathways that can be analyzed to unravel the biological function of Pnpla5. Supplementary Information The online version contains supplementary material available at 10.1186/s12864-022-08835-8.
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Affiliation(s)
- Zhi-Guo Liu
- State Key Laboratory of Animal Nutrition, Key Laboratory of Animal Genetics Breeding and Reproduction of Ministry of Agriculture and Rural Affairs of China, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing, 100193, China
| | - Yan-Qing Hu
- State Key Laboratory of Animal Nutrition, Key Laboratory of Animal Genetics Breeding and Reproduction of Ministry of Agriculture and Rural Affairs of China, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing, 100193, China
| | - Kui Li
- State Key Laboratory of Animal Nutrition, Key Laboratory of Animal Genetics Breeding and Reproduction of Ministry of Agriculture and Rural Affairs of China, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing, 100193, China.,Genome Analysis Laboratory of the Ministry of Agriculture and Rural Affairs, Agricultural Genomics Institute at Shenzhen, Chinese Academy of Agricultural Sciences, Shenzhen, 518120, China
| | - Yu-Lian Mu
- State Key Laboratory of Animal Nutrition, Key Laboratory of Animal Genetics Breeding and Reproduction of Ministry of Agriculture and Rural Affairs of China, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing, 100193, China
| | - Tian-Wen Wu
- State Key Laboratory of Animal Nutrition, Key Laboratory of Animal Genetics Breeding and Reproduction of Ministry of Agriculture and Rural Affairs of China, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing, 100193, China.
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27
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Patsenker E, Thangapandi VR, Knittelfelder O, Palladini A, Hefti M, Beil-Wagner J, Rogler G, Buch T, Shevchenko A, Hampe J, Stickel F. The Pnpla3 Variant I148M Reveals Protective Effects Towards Hepatocellular Carcinoma in Mice via Restoration of Omega-3 Polyunsaturated Fats. J Nutr Biochem 2022; 108:109081. [PMID: 35691594 DOI: 10.1016/j.jnutbio.2022.109081] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2021] [Revised: 02/02/2022] [Accepted: 05/03/2022] [Indexed: 12/02/2022]
Abstract
Alcohol consumption and high caloric diet are leading causes of progressive fatty liver disease. Genetic variant rs738409 in patatin-like phospholipase domain-containing protein 3 (PNPLA3 rs738409 C>G) has been repeatedly described as one of the major risk loci for alcoholic liver cirrhosis (ALC) and hepatocellular carcinoma (HCC) in humans, however, the mechanism behind this association is incompletely understood. We generated mice carrying the rs738409 variant (PNPLA3 I148M) in order to detect genotype-phenotype relationships in mice upon chow and alcohol-high fat/high sugar diet (EtOH/WD). We could clearly demonstrate that the presence of rs738409 per se is sufficient to induce spontaneous development of steatosis after one year in mice on a chow diet, whereas in the setting of unhealthy diet feeding, PNPLA3 I148M did not affect hepatic inflammation or fibrosis, but induced a striking lipid remodelling, microvesicular steatosis and protected from HCC formation. Using shot gun lipidomics, we detected a striking restoration of reduced long chain-polyunsaturated fatty acids (LC-PUFA)-containing TGs, docosapentaenoic acid (C22:5 n3) and omega-3-derived eicosanoids (5-HEPE, 20-HEPE, 19,20-EDP, 21-HDHA) in PNPLA3 I148M mice upon EtOH/WD. At the molecular level, PNPLA3 I148M modulated enzymes for fatty acid and TG transport and metabolism. These findings suggest (dietary) lipids as an important and independent driver of hepatic tumorigenesis. Genetic variant in PNPLA3 exerted protective effects in mice, conflicting with findings in humans. Species-related differences in physiology and metabolism should be taken into account when modelling unhealthy human lifestyle, as genetic mouse models may not always allow for translation of insight gained in humans.
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Affiliation(s)
- Eleonora Patsenker
- Department of Gastroenterology and Hepatology, University of Zurich, 8091 Zurich, Switzerland.
| | - Veera Raghavan Thangapandi
- Department of Gastroenterology and Hepatology, Universitätsklinikum Dresden, 01304 Dresden, Germany; Center for Regenerative Therapies, TU Dresden, 01307 Dresden, Germany
| | - Oskar Knittelfelder
- Max Plank Institute of Molecular Cell Biology and Genetics, 01307 Dresden, Germany
| | - Alessandra Palladini
- Paul Langerhans Institute Dresden of the Helmholtz Zentrum München at the University Hospital and Faculty of Medicine Carl Gustav Carus, TU Dresden, 01307 Dresden, Germany; German Center for Diabetes Research, 85764 Neuherberg, Germany
| | - Michaela Hefti
- Department of Gastroenterology and Hepatology, University of Zurich, 8091 Zurich, Switzerland
| | - Jane Beil-Wagner
- Institute of Laboratory Animal Science, University of Zurich, 8952 Schlieren, Switzerland
| | - Gerhard Rogler
- Department of Gastroenterology and Hepatology, University of Zurich, 8091 Zurich, Switzerland
| | - Thorsten Buch
- Institute of Laboratory Animal Science, University of Zurich, 8952 Schlieren, Switzerland
| | - Andrej Shevchenko
- Max Plank Institute of Molecular Cell Biology and Genetics, 01307 Dresden, Germany
| | - Jochen Hampe
- Department of Gastroenterology and Hepatology, Universitätsklinikum Dresden, 01304 Dresden, Germany; Center for Regenerative Therapies, TU Dresden, 01307 Dresden, Germany
| | - Felix Stickel
- Department of Gastroenterology and Hepatology, University of Zurich, 8091 Zurich, Switzerland
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28
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Hua Y, Zhang J, Liu Q, Su J, Zhao Y, Zheng G, Yang Z, Zhuo D, Ma C, Fan G. The Induction of Endothelial Autophagy and Its Role in the Development of Atherosclerosis. Front Cardiovasc Med 2022; 9:831847. [PMID: 35402552 PMCID: PMC8983858 DOI: 10.3389/fcvm.2022.831847] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2021] [Accepted: 02/08/2022] [Indexed: 12/29/2022] Open
Abstract
Increasing attention is now being paid to the important role played by autophagic flux in maintaining normal blood vessel walls. Endothelial cell dysfunction initiates the development of atherosclerosis. In the endothelium, a variety of critical triggers ranging from shear stress to circulating blood lipids promote autophagy. Furthermore, emerging evidence links autophagy to a range of important physiological functions such as redox homeostasis, lipid metabolism, and the secretion of vasomodulatory substances that determine the life and death of endothelial cells. Thus, the promotion of autophagy in endothelial cells may have the potential for treating atherosclerosis. This paper reviews the role of endothelial cells in the pathogenesis of atherosclerosis and explores the molecular mechanisms involved in atherosclerosis development.
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Affiliation(s)
- Yunqing Hua
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
- Tianjin State Key Laboratory of Component-Based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Jing Zhang
- Tianjin State Key Laboratory of Component-Based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Qianqian Liu
- Tianjin State Key Laboratory of Component-Based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Jing Su
- Tianjin State Key Laboratory of Component-Based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Yun Zhao
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
- Tianjin State Key Laboratory of Component-Based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Guobin Zheng
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
| | - Zhihui Yang
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
- Tianjin State Key Laboratory of Component-Based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Danping Zhuo
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
- Tianjin State Key Laboratory of Component-Based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Chuanrui Ma
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
- Tianjin State Key Laboratory of Component-Based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Guanwei Fan
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
- Tianjin State Key Laboratory of Component-Based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
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29
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Expression and production of pigment epithelium-derived factor (PEDF) and PEDF receptor variants from mammalian and bacterial cells. Protein Expr Purif 2022; 194:106072. [PMID: 35181508 DOI: 10.1016/j.pep.2022.106072] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2021] [Revised: 02/11/2022] [Accepted: 02/11/2022] [Indexed: 11/22/2022]
Abstract
Human SERPINF1 gene codes for pigment epithelium-derived factor (PEDF), a secreted glycoprotein and member of the SERPIN superfamily. To obtain large amounts of recombinant PEDF proteins, we subcloned the coding sequence of human SERPINF1 mutated versions into the pCEP4 vector and generated stably transfected HEK.Ebna cells. The cells produced and secreted recombinant PEDF proteins into the culturing media. The recombinant PEDF proteins were purified by ion-exchange column chromatography and milligram amounts of highly purified protein were recovered. PEDF has affinity for PEDF-receptor (PEDF-R), a membrane-linked lipase encoded by the PNPLA2 gene. Recombinant PEDF-R truncated versions were obtained from Escherichia coli containing expression vectors with human PNPLA2 cDNAs with 3'end deletions and by induction with isopropyl β-d-1-thiogalactopyranoside. The bacterially derived PEDF-R proteins in insoluble inclusion bodies were solubilized with urea and purified by cation-exchange column chromatography. C-terminally truncated PEDF-R versions containing the ligand binding region retained the ability to bind PEDF. The data demonstrate that mammalian-derived recombinant PEDF and bacterially derived recombinant PEDF-R can be produced and purified in large amounts for further use in structural and biological studies.
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30
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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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31
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Ahmad F, Ahmed I, Alam Q, Ahmad T, Khan A, Ahmad I, Bilal M, Hayat A, Khan A, Waqas A, Rafeeq MM, Sain ZM, Umair M. Variants in the PNPLA1 Gene in Families with Autosomal Recessive Congenital Ichthyosis Reveal Clinical Significance. Mol Syndromol 2021; 12:351-361. [PMID: 34899144 DOI: 10.1159/000516943] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Accepted: 04/28/2021] [Indexed: 01/13/2023] Open
Abstract
The term autosomal recessive congenital ichthyosis (ARCI) is the subgroup of ichthyosis, which describes a highly heterogeneous group of genetic disorders of the skin characterized by cornification and defective keratinocytes differentiation associated with mutations in at least 14 genes including PNPLA1. To study the molecular basis of the Pakistani kindreds (A and B) affected by ARCI, whole-exome sequencing (WES) in the DNA samples of affected members was performed followed by Sanger sequencing of the candidate gene to hunt down the disease-causing sequence variant/s. WES data analysis led to the identification of a novel nonsense sequence variant (c.892C>T; p.Arg298*, family A) and a recurrent missense variant (c.102C>A; p.Asp34Glu, family B) in PNPLA1 mapped to the ARCI locus in chromosome 6p21.31. Validation and cosegregation analysis of the variants in the remaining family members of the respective families were confirmed by Sanger sequencing. The current investigation expands the spectrum of PNPLA1 mutations and helps establish the proper clinico-genetic diagnosis and correct genotype-phenotype correlation.
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Affiliation(s)
- Farooq Ahmad
- Department of Chemistry, Women University Swabi, Swabi, Pakistan.,Department of Biochemistry, Faculty of Biological Sciences, Quaid-i-Azam University (QAU), Islamabad, Pakistan
| | | | - Qamre Alam
- Medical Genomics Research Department, King Abdullah International Medical Research Center (KAIMRC), King Saud bin Abdulaziz University for Health Science, Ministry of National Guard-Health Affairs (MNGHA), Riyadh, Saudi Arabia
| | - Tanveer Ahmad
- Department of Biotechnology, Faculty of Chemical and Life Sciences, Abdul Wali Khan University (AWKUM), Mardan, Pakistan
| | - Ammara Khan
- Department of Chemistry, Women University Swabi, Swabi, Pakistan
| | - Ijaz Ahmad
- Department of Biochemistry, Faculty of Biological Sciences, Quaid-i-Azam University (QAU), Islamabad, Pakistan
| | - Muhammad Bilal
- Department of Biochemistry, Faculty of Biological Sciences, Quaid-i-Azam University (QAU), Islamabad, Pakistan
| | - Amir Hayat
- Department Biochemistry, Abdul Wali Khan University, Mardan, Pakistan
| | - Amjad Khan
- Laboratoire d'ImmunoRhumatologie Moléculaire, Plateforme GENOMAX, INSERM UMR_S 1109, Faculté de Médecine, Fédération Hospitalo-Universitaire OMICARE, Fédération de Médecine Translationnelle de Strasbourg (FMTS), LabEx TRANSPLANTEX, Université de Strasbourg, Strasbourg, France
| | - Ahmed Waqas
- Division of Science and Technology, Department of Zoology, University of Education Lahore, Multan Campus, Multan, Pakistan
| | - Misbahuddin M Rafeeq
- Department of Pharmacology, Faculty of Medicine, Rabigh, King Abduaziz University, Jeddah, Saudi Arabia
| | - Ziaullah M Sain
- Department of Microbiology, Faculty of Medicine, Rabigh, King Abduaziz University, Jeddah, Saudi Arabia
| | - Muhammad Umair
- Medical Genomics Research Department, King Abdullah International Medical Research Center (KAIMRC), King Saud bin Abdulaziz University for Health Science, Ministry of National Guard-Health Affairs (MNGHA), Riyadh, Saudi Arabia.,Department of Life Sciences, School of Science, University of Management and Technology (UMT), Lahore, Pakistan
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32
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Tilson SG, Morell CM, Lenaerts A, Park SB, Hu Z, Jenkins B, Koulman A, Liang TJ, Vallier L. Modeling PNPLA3-Associated NAFLD Using Human-Induced Pluripotent Stem Cells. Hepatology 2021; 74:2998-3017. [PMID: 34288010 PMCID: PMC11497257 DOI: 10.1002/hep.32063] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2020] [Revised: 06/28/2021] [Accepted: 07/06/2021] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIMS NAFLD is a growing public health burden. However, the pathogenesis of NAFLD has not yet been fully elucidated, and the importance of genetic factors has only recently been appreciated. Genomic studies have revealed a strong association between NAFLD progression and the I148M variant in patatin-like phospholipase domain-containing protein 3 (PNPLA3). Nonetheless, very little is known about the mechanisms by which this gene and its variants can influence disease development. To investigate these mechanisms, we have developed an in vitro model that takes advantage of the unique properties of human-induced pluripotent stem cells (hiPSCs) and the CRISPR/CAS9 gene editing technology. APPROACH AND RESULTS We used isogenic hiPSC lines with either a knockout (PNPLA3KO ) of the PNPLA3 gene or with the I148M variant (PNPLA3I148M ) to model PNPLA3-associated NAFLD. The resulting hiPSCs were differentiated into hepatocytes, treated with either unsaturated or saturated free fatty acids to induce NAFLD-like phenotypes, and characterized by various functional, transcriptomic, and lipidomic assays. PNPLA3KO hepatocytes showed higher lipid accumulation as well as an altered pattern of response to lipid-induced stress. Interestingly, loss of PNPLA3 also caused a reduction in xenobiotic metabolism and predisposed PNPLA3KO cells to be more susceptible to ethanol-induced and methotrexate-induced toxicity. The PNPLA3I148M cells exhibited an intermediate phenotype between the wild-type and PNPLA3KO cells. CONCLUSIONS Together, these results indicate that the I148M variant induces a loss of function predisposing to steatosis and increased susceptibility to hepatotoxins.
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Affiliation(s)
- Samantha G. Tilson
- Wellcome Sanger InstituteHinxtonUnited Kingdom
- Wellcome Medical Research Council Cambridge Stem Cell InstituteUniversity of CambridgeCambridgeUnited Kingdom
- Liver Diseases BranchNational Institute of Diabetes and Digestive and Kidney DiseasesNational Institutes of HealthBethesdaMD
| | - Carola M. Morell
- Wellcome Medical Research Council Cambridge Stem Cell InstituteUniversity of CambridgeCambridgeUnited Kingdom
| | - An‐Sofie Lenaerts
- Wellcome Medical Research Council Cambridge Stem Cell InstituteUniversity of CambridgeCambridgeUnited Kingdom
| | - Seung Bum Park
- Liver Diseases BranchNational Institute of Diabetes and Digestive and Kidney DiseasesNational Institutes of HealthBethesdaMD
| | - Zongyi Hu
- Liver Diseases BranchNational Institute of Diabetes and Digestive and Kidney DiseasesNational Institutes of HealthBethesdaMD
| | - Benjamin Jenkins
- Wellcome Medical Research Council Institute of Metabolic ScienceUniversity of CambridgeCambridgeUnited Kingdom
| | - Albert Koulman
- Wellcome Medical Research Council Institute of Metabolic ScienceUniversity of CambridgeCambridgeUnited Kingdom
| | - T. Jake Liang
- Liver Diseases BranchNational Institute of Diabetes and Digestive and Kidney DiseasesNational Institutes of HealthBethesdaMD
| | - Ludovic Vallier
- Wellcome Medical Research Council Cambridge Stem Cell InstituteUniversity of CambridgeCambridgeUnited Kingdom
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Elevated ATGL in colon cancer cells and cancer stem cells promotes metabolic and tumorigenic reprogramming reinforced by obesity. Oncogenesis 2021; 10:82. [PMID: 34845203 PMCID: PMC8630180 DOI: 10.1038/s41389-021-00373-4] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2021] [Revised: 09/26/2021] [Accepted: 11/01/2021] [Indexed: 12/24/2022] Open
Abstract
Obesity is a worldwide epidemic associated with increased risk and progression of colon cancer. Here, we aimed to determine the role of adipose triglyceride lipase (ATGL), responsible for intracellular lipid droplet (LD) utilization, in obesity-driven colonic tumorigenesis. In local colon cancer patients, significantly increased ATGL levels in tumor tissue, compared to controls, were augmented in obese individuals. Elevated ATGL levels in human colon cancer cells (CCC) relative to non-transformed were augmented by an obesity mediator, oleic acid (OA). In CCC and colonospheres, enriched in colon cancer stem cells (CCSC), inhibition of ATGL prevented LDs utilization and inhibited OA-stimulated growth through retinoblastoma-mediated cell cycle arrest. Further, transcriptomic analysis of CCC, with inhibited ATGL, revealed targeted pathways driving tumorigenesis, and high-fat-diet obesity facilitated tumorigenic pathways. Inhibition of ATGL in colonospheres revealed targeted pathways in human colonic tumor crypt base cells (enriched in CCSC) derived from colon cancer patients. In CCC and colonospheres, we validated selected transcripts targeted by ATGL inhibition, some with emerging roles in colonic tumorigeneses (ATG2B, PCK2, PGAM1, SPTLC2, IGFBP1, and ABCC3) and others with established roles (MYC and MUC2). These findings demonstrate obesity-promoted, ATGL-mediated colonic tumorigenesis and establish the therapeutic significance of ATGL in obesity-reinforced colon cancer progression.
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34
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Correlations between PNPLA3 Gene Polymorphisms and NAFLD in Type 2 Diabetic Patients. MEDICINA (KAUNAS, LITHUANIA) 2021; 57:medicina57111249. [PMID: 34833467 PMCID: PMC8620174 DOI: 10.3390/medicina57111249] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Revised: 11/03/2021] [Accepted: 11/12/2021] [Indexed: 12/20/2022]
Abstract
Background and Objectives: Non-alcoholic fatty liver disease is a worldwide significant public health problem, particularly in patients with type 2 diabetes mellitus. Identifying possible risk factors for the disease is mandatory for a better understandingand management of this condition. Patatin-like phospholipase domain-containing protein 3 (PNPLA3) has been linked to the development and evolution of fatty liver but not to insulin resistance. The aim of this study isto evaluate the relationships between PNPLA3 and fatty liver, metabolic syndrome and subclinical atherosclerosis. Materials and Methods: The study group consisted of patients with type 2 diabetes mellitus without insulin treatment. The degree of liver fat loading was assessed by ultrasonography, and subclinical atherosclerosis was assessed using carotid intima-media thickness (CIMT). PNPLA3 rs738409 genotype determination was performed by high-resolution melting analysis that allowed three standard genotypes: CC, CG, and GG. Results: Among the 92 patients, more than 90% showed various degrees of hepatic steatosis, almost 62% presented values over the normal limit for the CIMT. The majority of the included subjects met the criteria for metabolic syndrome. Genotyping of PNPLA3 in 68 patients showed that the difference between subjects without steatosis and subjects with hepatic steatosis was due to the higher frequency of genotype GG. The CC genotype was the most common in the group we studied and was significantly more frequent in the group of subjects with severe steatosis; the GG genotype was significantly more frequent in subjects with moderate steatosis; the frequency of the CG genotype was not significantly different among the groups.When we divided the group of subjects into two groups: those with no or mild steatosis and those with moderate or severe steatosis it was shown that the frequency of the GG genotype was significantly higher in the group of subjects with moderate or severe steatosis. PNPLA3 genotypes were not associated with metabolic syndrome, subclinical atherosclerosis, or insulin resistance. Conclusions: Our results suggest that PNPLA3 does not independently influence cardiovascular risk in patients with type 2 diabetes mellitus. The hypothesis that PNPLA3 may have a cardioprotective effect requires future confirmation.
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35
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Grabner GF, Xie H, Schweiger M, Zechner R. Lipolysis: cellular mechanisms for lipid mobilization from fat stores. Nat Metab 2021; 3:1445-1465. [PMID: 34799702 DOI: 10.1038/s42255-021-00493-6] [Citation(s) in RCA: 364] [Impact Index Per Article: 91.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2021] [Accepted: 10/15/2021] [Indexed: 12/13/2022]
Abstract
The perception that intracellular lipolysis is a straightforward process that releases fatty acids from fat stores in adipose tissue to generate energy has experienced major revisions over the last two decades. The discovery of new lipolytic enzymes and coregulators, the demonstration that lipophagy and lysosomal lipolysis contribute to the degradation of cellular lipid stores and the characterization of numerous factors and signalling pathways that regulate lipid hydrolysis on transcriptional and post-transcriptional levels have revolutionized our understanding of lipolysis. In this review, we focus on the mechanisms that facilitate intracellular fatty-acid mobilization, drawing on canonical and noncanonical enzymatic pathways. We summarize how intracellular lipolysis affects lipid-mediated signalling, metabolic regulation and energy homeostasis in multiple organs. Finally, we examine how these processes affect pathogenesis and how lipolysis may be targeted to potentially prevent or treat various diseases.
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Affiliation(s)
- Gernot F Grabner
- Institute of Molecular Biosciences, University of Graz, Graz, Austria
| | - Hao Xie
- Institute of Molecular Biosciences, University of Graz, Graz, Austria
| | - Martina Schweiger
- Institute of Molecular Biosciences, University of Graz, Graz, Austria.
- BioTechMed-Graz, Graz, Austria.
| | - Rudolf Zechner
- Institute of Molecular Biosciences, University of Graz, Graz, Austria.
- BioTechMed-Graz, Graz, Austria.
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36
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Ma X, Zhi Z, Zhang S, Zhou C, Mechler A, Liu P. Validating an artificial organelle: Studies of lipid droplet-specific proteins on adiposome platform. iScience 2021; 24:102834. [PMID: 34368652 PMCID: PMC8326204 DOI: 10.1016/j.isci.2021.102834] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2021] [Revised: 06/28/2021] [Accepted: 07/08/2021] [Indexed: 10/25/2022] Open
Abstract
New strategies are urgently needed to characterize the functions of the lipid droplet (LD). Here, adiposome, an artificial LD mimetic platform, was validated by comparative in vitro bioassays. Scatchard analysis found that the binding of perilipin 2 (PLIN2) to the adiposome surface was saturable. Phosphatidylinositol (PtdIns) was found to inhibit PLIN2 binding while it did not impede perilipin 3 (PLIN3). Structural analysis combined with mutagenesis revealed that the 73rd glutamic acid of PLIN2 is significant for the effect of PtdIns on the PLIN2 binding. Furthermore, adiposome was also found to be an ideal platform for in situ enzymatic activity measurement of adipose triglyceride lipase (ATGL). The significant serine mutants of ATGL were found to cause the loss of lipase activity. Our study demonstrates the adiposome as a powerful, manipulatable model system that mimics the function of LD for binding and enzymatic activity studies of LD proteins in vitro.
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Affiliation(s)
- Xuejing Ma
- National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Zelun Zhi
- Department of Chemistry and Physics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, 3086, Australia
| | - Shuyan Zhang
- National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China
| | - Chang Zhou
- National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China
| | - Adam Mechler
- Department of Chemistry and Physics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, 3086, Australia
| | - Pingsheng Liu
- National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
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37
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López-Bautista F, Posadas-Sánchez R, Vargas-Alarcón G. Association of the IL-37 Polymorphisms with Transaminases and Alkaline Phosphatase Levels in Premature Coronary Artery Disease Patients and Healthy Controls. Results of the Genetics of Atherosclerotic (GEA) Mexican Study. Diagnostics (Basel) 2021; 11:diagnostics11061018. [PMID: 34199391 PMCID: PMC8227963 DOI: 10.3390/diagnostics11061018] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2021] [Revised: 05/28/2021] [Accepted: 05/29/2021] [Indexed: 11/16/2022] Open
Abstract
Interleukin 37 (IL-37) is an anti-inflammatory cytokine expressed in foam cells located in the atherosclerosis plaques. The present study aimed to evaluate the association of the IL-37 polymorphisms with premature coronary artery disease (pCAD), cardiovascular risk factors, metabolic parameters, and levels of liver enzymes. Three IL-37 polymorphisms (rs6717710, rs2708961, and rs2708947) were determined in 1161 patients with pCAD and 951 healthy controls. IL-37 polymorphisms were not associated with the presence of pCAD. The association of the polymorphisms with cardiovascular risk factors, metabolic parameters, and levels of liver enzymes was evaluated independently in pCAD and healthy controls. In pCAD patients, under different models, the rs6717710 was associated with low risk of having elevated alkaline phosphatase (ALP) (padditive = 0.020; pdominant = 0.02; pheterozygous = 0.04; pcodominant1 = 0.040). On the other hand, in healthy controls, the rs6717710 was associated with low risk of having elevated levels of alanine aminotransferase (ALT) (padditive = 0.04, precessive = 0.01, pcodominant2 = 0.01) and aspartate aminotransferase (AST) (padditive = 0.02, pdominant = 0.02). The IL-37 polymorphisms were not associated with the risk of pCAD. In pCAD patients, the rs6717710 was associated with low risk of having elevated ALP levels, whereas in controls was associated with low risk of having elevated ALT and AST levels.
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Affiliation(s)
- Fabiola López-Bautista
- Department of Molecular Biology, Instituto Nacional de Cardiología Ignacio Chávez, Ciudad de México 14080, Mexico;
| | - Rosalinda Posadas-Sánchez
- Department of Endocrinology, Instituto Nacional de Cardiología Ignacio Chávez, Ciudad de México 14080, Mexico;
| | - Gilberto Vargas-Alarcón
- Department of Molecular Biology, Instituto Nacional de Cardiología Ignacio Chávez, Ciudad de México 14080, Mexico;
- Correspondence: ; Tel.: +52-5573-2911 (ext. 20134)
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Zhao R, Xiang B, Dolinsky VW, Xia M, Shen GX. Saskatoon berry powder reduces hepatic steatosis and insulin resistance in high fat-high sucrose diet-induced obese mice. J Nutr Biochem 2021; 95:108778. [PMID: 34004342 DOI: 10.1016/j.jnutbio.2021.108778] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2020] [Revised: 11/27/2020] [Accepted: 05/07/2021] [Indexed: 12/19/2022]
Abstract
Non-alcoholic fatty liver disease is a common metabolic disorder associated with insulin resistance and lacks a specific treatment. Our previous studies demonstrated that freeze-dried Saskatoon berry powder (SBp) reduced high fat-high sucrose (HFHS) diet-induced hyperglycemia and insulin resistance in mice. The present study examined the effect of SBp and one of its active components, cyanidin-3-glucoside (C3G), on hepatic steatosis in mice fed with HFHS diet for 10 weeks. HFHS diet significantly increased fasting plasma glucose, cholesterol, triglycerides, insulin resistance, inflammatory markers (tumor necrosis factor-α, monocyte chemotactic protein-1, plasminogen activator inbitor-1), alanine aminotransferase activity, and monocyte adhesion compared to control diet. In the liver, HFHS diet increased steatosis, lipid accumulation, collagen deposition, and the abundance of patatin-like phospholipase domain-containing 3, CCAAT-enhancer-binding protein homologous protein, toll-like receptor-4, and macrophage marker. Supplementation with SBp (5%) or C3G in an amount corresponding to that in 5% SBp to HFHS diet had similar effects to reduced fasting plasma glucose, liver steatosis, enzyme activity, lipid, collagen and macrophage deposition, hyperglycemia, hyperlipidemia, insulin resistance, monocyte adhesion, markers related to liver steatosis, inflammation, oxidative or endoplasmic reticulum stress in the peripheral circulation and/or liver compared to mice fed with HFHS diet alone. No significant difference in the studied variables was detected between mice treated with HFHS+SBp and C3G diet. The results suggest that SBp or C3G administration attenuates HFHS diet-induced liver steatosis in addition to insulin resistance and chronic inflammation in mice. C3G may contribute to the beneficial effects of SBp.
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Affiliation(s)
- Ruozhi Zhao
- Department of Internal Medicine, University of Manitoba, Winnipeg, Canada
| | - Bo Xiang
- Pharmacology and Therapeutics, University of Manitoba, Winnipeg, Canada
| | - Vernon W Dolinsky
- Pharmacology and Therapeutics, University of Manitoba, Winnipeg, Canada
| | - Min Xia
- School of Public Health, Sun Yat-sen University, Guangzhou, China
| | - Garry X Shen
- Department of Internal Medicine, University of Manitoba, Winnipeg, Canada.
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Dixon ED, Nardo AD, Claudel T, Trauner M. The Role of Lipid Sensing Nuclear Receptors (PPARs and LXR) and Metabolic Lipases in Obesity, Diabetes and NAFLD. Genes (Basel) 2021; 12:genes12050645. [PMID: 33926085 PMCID: PMC8145571 DOI: 10.3390/genes12050645] [Citation(s) in RCA: 45] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Revised: 04/23/2021] [Accepted: 04/23/2021] [Indexed: 12/11/2022] Open
Abstract
Obesity and type 2 diabetes mellitus (T2DM) are metabolic disorders characterized by metabolic inflexibility with multiple pathological organ manifestations, including non-alcoholic fatty liver disease (NAFLD). Nuclear receptors are ligand-dependent transcription factors with a multifaceted role in controlling many metabolic activities, such as regulation of genes involved in lipid and glucose metabolism and modulation of inflammatory genes. The activity of nuclear receptors is key in maintaining metabolic flexibility. Their activity depends on the availability of endogenous ligands, like fatty acids or oxysterols, and their derivatives produced by the catabolic action of metabolic lipases, most of which are under the control of nuclear receptors. For example, adipose triglyceride lipase (ATGL) is activated by peroxisome proliferator-activated receptor γ (PPARγ) and conversely releases fatty acids as ligands for PPARα, therefore, demonstrating the interdependency of nuclear receptors and lipases. The diverse biological functions and importance of nuclear receptors in metabolic syndrome and NAFLD has led to substantial effort to target them therapeutically. This review summarizes recent findings on the roles of lipases and selected nuclear receptors, PPARs, and liver X receptor (LXR) in obesity, diabetes, and NAFLD.
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Affiliation(s)
| | | | | | - Michael Trauner
- Correspondence: ; Tel.: +43-140-4004-7410; Fax: +43-14-0400-4735
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40
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Tardelli M, Bruschi FV, Fuchs CD, Claudel T, Auer N, Kunczer V, Ronda OAHO, Verkade HJ, Stojakovic T, Scharnagl H, Trauner M. Absence of Adiponutrin (PNPLA3) and Monoacylglycerol Lipase Synergistically Increases Weight Gain and Aggravates Steatohepatitis in Mice. Int J Mol Sci 2021; 22:2126. [PMID: 33672787 PMCID: PMC7924608 DOI: 10.3390/ijms22042126] [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: 01/12/2021] [Revised: 01/29/2021] [Accepted: 02/02/2021] [Indexed: 12/11/2022] Open
Abstract
Altered lipid metabolic pathways including hydrolysis of triglycerides are key players in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). Whether adiponutrin (patatin-like phospholipase domain containing protein-3-PNPLA3) and monoacylglycerol lipase (MGL) synergistically contribute to disease progression remains unclear. We generated double knockout (DKO) mice lacking both Mgl and Pnpla3; DKO mice were compared to Mgl-/- after a challenge by high-fat diet (HFD) for 12 weeks to induce steatosis. Serum biochemistry, liver transaminases as well as histology were analyzed. Fatty acid (FA) profiling was assessed in liver and adipose tissue by gas chromatography. Markers of inflammation and lipid metabolism were analyzed. Bone marrow derived macrophages (BMDMs) were isolated and treated with oleic acid. Combined deficiency of Mgl and Pnpla3 resulted in weight gain on a chow diet; when challenged by HFD, DKO mice showed increased hepatic FA synthesis and diminished beta-oxidation compared to Mgl-/-.DKO mice exhibited more pronounced hepatic steatosis with inflammation and recruitment of immune cells to the liver associated with accumulation of saturated FAs. Primary BMDMs isolated from the DKO mice showed increased inflammatory activities, which could be reversed by oleic acid supplementation. Pnpla3 deficiency aggravates the effects of Mgl deletion on steatosis and inflammation in the liver under HFD challenge.
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Affiliation(s)
- Matteo Tardelli
- Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, 1090 Vienna, Austria; (M.T.); (F.V.B.); (C.D.F.); (T.C.); (N.A.); (V.K.)
| | - Francesca V. Bruschi
- Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, 1090 Vienna, Austria; (M.T.); (F.V.B.); (C.D.F.); (T.C.); (N.A.); (V.K.)
| | - Claudia D. Fuchs
- Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, 1090 Vienna, Austria; (M.T.); (F.V.B.); (C.D.F.); (T.C.); (N.A.); (V.K.)
| | - Thierry Claudel
- Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, 1090 Vienna, Austria; (M.T.); (F.V.B.); (C.D.F.); (T.C.); (N.A.); (V.K.)
| | - Nicole Auer
- Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, 1090 Vienna, Austria; (M.T.); (F.V.B.); (C.D.F.); (T.C.); (N.A.); (V.K.)
| | - Victoria Kunczer
- Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, 1090 Vienna, Austria; (M.T.); (F.V.B.); (C.D.F.); (T.C.); (N.A.); (V.K.)
| | - Onne A. H. O. Ronda
- Center for Liver, Digestive and Metabolic Diseases, Departments of Pediatrics, University Medical Center Groningen, 9712 Groningen, The Netherlands; (O.A.H.O.R.); (H.J.V.)
| | - Henkjan J. Verkade
- Center for Liver, Digestive and Metabolic Diseases, Departments of Pediatrics, University Medical Center Groningen, 9712 Groningen, The Netherlands; (O.A.H.O.R.); (H.J.V.)
| | - Tatjana Stojakovic
- Clinical Institute of Medical and Chemical Laboratory Diagnostics, University Hospital Graz, 8036 Graz, Austria;
| | - Hubert Scharnagl
- Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, 8036 Graz, Austria;
| | - Michael Trauner
- Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, 1090 Vienna, Austria; (M.T.); (F.V.B.); (C.D.F.); (T.C.); (N.A.); (V.K.)
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41
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Brejchova K, Radner FPW, Balas L, Paluchova V, Cajka T, Chodounska H, Kudova E, Schratter M, Schreiber R, Durand T, Zechner R, Kuda O. Distinct roles of adipose triglyceride lipase and hormone-sensitive lipase in the catabolism of triacylglycerol estolides. Proc Natl Acad Sci U S A 2021; 118:e2020999118. [PMID: 33372146 PMCID: PMC7812821 DOI: 10.1073/pnas.2020999118] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Branched esters of palmitic acid and hydroxy stearic acid are antiinflammatory and antidiabetic lipokines that belong to a family of fatty acid (FA) esters of hydroxy fatty acids (HFAs) called FAHFAs. FAHFAs themselves belong to oligomeric FA esters, known as estolides. Glycerol-bound FAHFAs in triacylglycerols (TAGs), named TAG estolides, serve as metabolite reservoir of FAHFAs mobilized by lipases upon demand. Here, we characterized the involvement of two major metabolic lipases, adipose triglyceride lipase (ATGL) and hormone-sensitive lipase (HSL), in TAG estolide and FAHFA degradation. We synthesized a library of 20 TAG estolide isomers with FAHFAs varying in branching position, chain length, saturation grade, and position on the glycerol backbone and developed an in silico mass spectra library of all predicted catabolic intermediates. We found that ATGL alone or coactivated by comparative gene identification-58 efficiently liberated FAHFAs from TAG estolides with a preference for more compact substrates where the estolide branching point is located near the glycerol ester bond. ATGL was further involved in transesterification and remodeling reactions leading to the formation of TAG estolides with alternative acyl compositions. HSL represented a much more potent estolide bond hydrolase for both TAG estolides and free FAHFAs. FAHFA and TAG estolide accumulation in white adipose tissue of mice lacking HSL argued for a functional role of HSL in estolide catabolism in vivo. Our data show that ATGL and HSL participate in the metabolism of estolides and TAG estolides in distinct manners and are likely to affect the lipokine function of FAHFAs.
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Affiliation(s)
- Kristyna Brejchova
- Institute of Physiology, Czech Academy of Sciences, 142 20 Prague 4, Czech Republic
| | | | - Laurence Balas
- Institut des Biomolécules Max Mousseron, UMR 5247, CNRS, École Nationale Supérieure de Chimie de Montpellier, Faculté de Pharmacie, Université de Montpellier, 34093 Montpellier, France
| | - Veronika Paluchova
- Institute of Physiology, Czech Academy of Sciences, 142 20 Prague 4, Czech Republic
| | - Tomas Cajka
- Institute of Physiology, Czech Academy of Sciences, 142 20 Prague 4, Czech Republic
| | - Hana Chodounska
- Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, 166 10 Prague 6, Czech Republic
| | - Eva Kudova
- Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, 166 10 Prague 6, Czech Republic
| | | | - Renate Schreiber
- Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria
| | - Thierry Durand
- Institut des Biomolécules Max Mousseron, UMR 5247, CNRS, École Nationale Supérieure de Chimie de Montpellier, Faculté de Pharmacie, Université de Montpellier, 34093 Montpellier, France
| | - Rudolf Zechner
- Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria;
- BioTechMed-Graz, 8010 Graz, Austria
| | - Ondrej Kuda
- Institute of Physiology, Czech Academy of Sciences, 142 20 Prague 4, Czech Republic;
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Valcin JA, Udoh US, Swain TM, Andringa KK, Patel CR, Al Diffalha S, Baker PRS, Gamble KL, Bailey SM. Alcohol and Liver Clock Disruption Increase Small Droplet Macrosteatosis, Alter Lipid Metabolism and Clock Gene mRNA Rhythms, and Remodel the Triglyceride Lipidome in Mouse Liver. Front Physiol 2020; 11:1048. [PMID: 33013449 PMCID: PMC7504911 DOI: 10.3389/fphys.2020.01048] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2020] [Accepted: 07/30/2020] [Indexed: 12/12/2022] Open
Abstract
Heavy alcohol drinking dysregulates lipid metabolism, promoting hepatic steatosis – the first stage of alcohol-related liver disease (ALD). The molecular circadian clock plays a major role in synchronizing daily rhythms in behavior and metabolism and clock disruption can cause pathology, including liver disease. Previous studies indicate that alcohol consumption alters liver clock function, but the impact alcohol or clock disruption, or both have on the temporal control of hepatic lipid metabolism and injury remains unclear. Here, we undertook studies to determine whether genetic disruption of the liver clock exacerbates alterations in lipid metabolism and worsens steatosis in alcohol-fed mice. To address this question, male liver-specific Bmal1 knockout (LKO) and flox/flox (Fl/Fl) control mice were fed a control or alcohol-containing diet for 5 weeks. Alcohol significantly dampened diurnal rhythms of mRNA levels in clock genes Bmal1 and Dbp, phase advanced Nr1d1/REV-ERBα, and induced arrhythmicity in Clock, Noct, and Nfil3/E4BP4, with further disruption in livers of LKO mice. Alcohol-fed LKO mice exhibited higher plasma triglyceride (TG) and different time-of-day patterns of hepatic TG and macrosteatosis, with elevated levels of small droplet macrosteatosis compared to alcohol-fed Fl/Fl mice. Diurnal rhythms in mRNA levels of lipid metabolism transcription factors (Srebf1, Nr1h2, and Ppara) were significantly altered by alcohol and clock disruption. Alcohol and/or clock disruption significantly altered diurnal rhythms in mRNA levels of fatty acid (FA) synthesis and oxidation (Acaca/b, Mlycd, Cpt1a, Fasn, Elovl5/6, and Fads1/2), TG turnover (Gpat1, Agpat1/2, Lpin1/2, Dgat2, and Pnpla2/3), and lipid droplet (Plin2/5, Lipe, Mgll, and Abdh5) genes, along with protein abundances of p-ACC, MCD, and FASN. Lipidomics analyses showed that alcohol, clock disruption, or both significantly altered FA saturation and remodeled the FA composition of the hepatic TG pool, with higher percentages of several long and very long chain FA in livers of alcohol-fed LKO mice. In conclusion, these results show that the liver clock is important for maintaining temporal control of hepatic lipid metabolism and that disrupting the liver clock exacerbates alcohol-related hepatic steatosis.
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Affiliation(s)
- Jennifer A Valcin
- Division of Molecular and Cellular Pathology, Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Uduak S Udoh
- Division of Molecular and Cellular Pathology, Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Telisha M Swain
- Division of Molecular and Cellular Pathology, Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Kelly K Andringa
- Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Chirag R Patel
- Division of Anatomic Pathology, Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Sameer Al Diffalha
- Division of Anatomic Pathology, Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, United States
| | | | - Karen L Gamble
- Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Shannon M Bailey
- Division of Molecular and Cellular Pathology, Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, United States
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43
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Qadri S, Lallukka-Brück S, Luukkonen PK, Zhou Y, Gastaldelli A, Orho-Melander M, Sammalkorpi H, Juuti A, Penttilä AK, Perttilä J, Hakkarainen A, Lehtimäki TE, Orešič M, Hyötyläinen T, Hodson L, Olkkonen VM, Yki-Järvinen H. The PNPLA3-I148M variant increases polyunsaturated triglycerides in human adipose tissue. Liver Int 2020; 40:2128-2138. [PMID: 32386450 DOI: 10.1111/liv.14507] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2020] [Revised: 04/23/2020] [Accepted: 05/02/2020] [Indexed: 12/11/2022]
Abstract
BACKGROUND & AIMS The I148M variant in PNPLA3 is the major genetic risk factor for non-alcoholic fatty liver disease (NAFLD). The liver is enriched with polyunsaturated triglycerides (PUFA-TGs) in PNPLA3-I148M carriers. Gene expression data indicate that PNPLA3 is liver-specific in humans, but whether it functions in adipose tissue (AT) is unknown. We investigated whether PNPLA3-I148M modifies AT metabolism in human NAFLD. METHODS Profiling of the AT lipidome and fasting serum non-esterified fatty acid (NEFA) composition was conducted in 125 volunteers (PNPLA3148MM/MI , n = 63; PNPLA3148II , n = 62). AT fatty acid composition was determined in 50 volunteers homozygous for the variant (PNPLA3148MM , n = 25) or lacking the variant (PNPLA3148II , n = 25). Whole-body insulin sensitivity of lipolysis was determined using [2 H5 ]glycerol, and PNPLA3 mRNA and protein levels were measured in subcutaneous AT and liver biopsies in a subset of the volunteers. RESULTS PUFA-TGs were significantly increased in AT in carriers versus non-carriers of PNPLA3-I148M. The variant did not alter the rate of lipolysis or the composition of fasting serum NEFAs. PNPLA3 mRNA was 33-fold higher in the liver than in AT (P < .0001). In contrast, PNPLA3 protein levels per tissue protein were three-fold higher in AT than the liver (P < .0001) and nine-fold higher when related to whole-body AT and liver tissue masses (P < .0001). CONCLUSIONS Contrary to previous assumptions, PNPLA3 is highly abundant in AT. PNPLA3-I148M locally remodels AT TGs to become polyunsaturated as it does in the liver, without affecting lipolysis or composition of serum NEFAs. Changes in AT metabolism do not contribute to NAFLD in PNPLA3-I148M carriers.
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Affiliation(s)
- Sami Qadri
- Department of Medicine, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.,Minerva Foundation Institute for Medical Research, Helsinki, Finland
| | - Susanna Lallukka-Brück
- Department of Medicine, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.,Minerva Foundation Institute for Medical Research, Helsinki, Finland
| | - Panu K Luukkonen
- Department of Medicine, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.,Minerva Foundation Institute for Medical Research, Helsinki, Finland
| | - You Zhou
- Minerva Foundation Institute for Medical Research, Helsinki, Finland.,Systems Immunity University Research Institute and Division of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, UK
| | - Amalia Gastaldelli
- Institute of Clinical Physiology, National Research Council, Pisa, Italy
| | | | - Henna Sammalkorpi
- Department of Gastrointestinal Surgery, Abdominal Center, Helsinki University Hospital, Helsinki, Finland
| | - Anne Juuti
- Department of Gastrointestinal Surgery, Abdominal Center, Helsinki University Hospital, Helsinki, Finland
| | - Anne K Penttilä
- Department of Gastrointestinal Surgery, Abdominal Center, Helsinki University Hospital, Helsinki, Finland
| | - Julia Perttilä
- Minerva Foundation Institute for Medical Research, Helsinki, Finland
| | - Antti Hakkarainen
- HUS Medical Imaging Center, Helsinki University Hospital, Helsinki, Finland
| | - Tiina E Lehtimäki
- HUS Medical Imaging Center, Helsinki University Hospital, Helsinki, Finland
| | - Matej Orešič
- Department of Chemistry, Örebro University, Örebro, Sweden
| | | | - Leanne Hodson
- Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK.,National Institute for Health Research Oxford Biomedical Research Centre, Oxford University Hospitals Foundation Trust, Oxford, UK
| | - Vesa M Olkkonen
- Minerva Foundation Institute for Medical Research, Helsinki, Finland
| | - Hannele Yki-Järvinen
- Department of Medicine, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.,Minerva Foundation Institute for Medical Research, Helsinki, Finland
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44
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Mancina RM, Spagnuolo R. Cross talk between liver and adipose tissue: A new role for PNPLA3? Liver Int 2020; 40:2074-2075. [PMID: 32930522 DOI: 10.1111/liv.14561] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2020] [Accepted: 06/08/2020] [Indexed: 02/13/2023]
Affiliation(s)
- Rosellina M Mancina
- Department of Molecular and Clinical Medicine, Wallenberg Laboratory, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
| | - Rocco Spagnuolo
- Dipartimento di Medicina Sperimentale e Clinica, Universitá Magna Graecia, Catanzaro, Italy
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45
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Carlsson B, Lindén D, Brolén G, Liljeblad M, Bjursell M, Romeo S, Loomba R. Review article: the emerging role of genetics in precision medicine for patients with non-alcoholic steatohepatitis. Aliment Pharmacol Ther 2020; 51:1305-1320. [PMID: 32383295 PMCID: PMC7318322 DOI: 10.1111/apt.15738] [Citation(s) in RCA: 122] [Impact Index Per Article: 24.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2019] [Revised: 01/13/2020] [Accepted: 03/29/2020] [Indexed: 12/12/2022]
Abstract
BACKGROUND Non-alcoholic steatohepatitis (NASH) is a severe form of non-alcoholic fatty liver disease (NAFLD) characterised by liver fat accumulation, inflammation and progressive fibrosis. Emerging data indicate that genetic susceptibility increases risks of NAFLD, NASH and NASH-related cirrhosis. AIMS To review NASH genetics and discuss the potential for precision medicine approaches to treatment. METHOD PubMed search and inclusion of relevant literature. RESULTS Single-nucleotide polymorphisms in PNPLA3, TM6SF2, GCKR, MBOAT7 and HSD17B13 are clearly associated with NASH development or progression. These genetic variants are common and have moderate-to-large effect sizes for development of NAFLD, NASH and hepatocellular carcinoma (HCC). The genes play roles in lipid remodelling in lipid droplets, hepatic very low-density lipoprotein (VLDL) secretion and de novo lipogenesis. The PNPLA3 I148M variant (rs738409) has large effects, with approximately twofold increased odds of NAFLD and threefold increased odds of NASH and HCC per allele. Obesity interacts with PNPLA3 I148M to elevate liver fat content and increase rates of NASH. Although the isoleucine-to-methionine substitution at amino acid position 148 of the PNPLA3 enzyme inactivates its lipid remodelling activity, the effect of PNPLA3 I148M results from trans-repression of another lipase (ATGL/PNPLA2) by sequestration of a shared cofactor (CGI-58/ABHD5), leading to decreased hepatic lipolysis and VLDL secretion. In homozygous Pnpla3 I148M knock-in rodent models of NAFLD, targeted PNPLA3 mRNA knockdown reduces hepatic steatosis, inflammation and fibrosis. CONCLUSION The emerging genetic and molecular understanding of NASH paves the way for novel interventions, including precision medicines that can modulate the activity of specific genes associated with NASH.
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Affiliation(s)
- Björn Carlsson
- Research and Early DevelopmentCardiovascular, Renal and MetabolismBioPharmaceuticals R&DAstraZenecaGothenburgSweden
| | - Daniel Lindén
- Research and Early DevelopmentCardiovascular, Renal and MetabolismBioPharmaceuticals R&DAstraZenecaGothenburgSweden,Division of EndocrinologyDepartment of Neuroscience and PhysiologySahlgrenska AcademyUniversity of GothenburgGothenburgSweden
| | - Gabriella Brolén
- Precision MedicineCardiovascular, Renal and MetabolismR&DAstraZenecaGothenburgSweden
| | - Mathias Liljeblad
- Research and Early DevelopmentCardiovascular, Renal and MetabolismBioPharmaceuticals R&DAstraZenecaGothenburgSweden
| | - Mikael Bjursell
- Research and Early DevelopmentCardiovascular, Renal and MetabolismBioPharmaceuticals R&DAstraZenecaGothenburgSweden
| | - Stefano Romeo
- Department of Molecular and Clinical MedicineUniversity of GothenburgGothenburgSweden,Clinical Nutrition UnitDepartment of Medical and Surgical SciencesMagna Graecia UniversityCatanzaroItaly,Cardiology DepartmentSahlgrenska University HospitalGothenburgSweden
| | - Rohit Loomba
- NAFLD Research CenterDivision of GastroenterologyUniversity of California San DiegoSan DiegoCAUSA
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46
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Wagner C, Hois V, Pajed L, Pusch LM, Wolinski H, Trauner M, Zimmermann R, Taschler U, Lass A. Lysosomal acid lipase is the major acid retinyl ester hydrolase in cultured human hepatic stellate cells but not essential for retinyl ester degradation. Biochim Biophys Acta Mol Cell Biol Lipids 2020; 1865:158730. [PMID: 32361002 PMCID: PMC7279957 DOI: 10.1016/j.bbalip.2020.158730] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2019] [Revised: 04/22/2020] [Accepted: 04/25/2020] [Indexed: 02/07/2023]
Abstract
Vitamin A is stored as retinyl esters (REs) in lipid droplets of hepatic stellate cells (HSCs). To date, two different pathways are known to facilitate the breakdown of REs: (i) Hydrolysis of REs by neutral lipases, and (ii) whole lipid droplet degradation in autolysosomes by acid hydrolysis. In this study, we evaluated the contribution of neutral and acid RE hydrolases to the breakdown of REs in human HSCs. (R)-Bromoenol lactone (R-BEL), inhibitor of adipose triglyceride lipase (ATGL) and patatin-like phospholipase domain-containing 3 (PNPLA3), the hormone-sensitive lipase (HSL) inhibitor 76-0079, as well as the serine-hydrolase inhibitor Orlistat reduced neutral RE hydrolase activity of LX-2 cell-lysates between 20 and 50%. Interestingly, in pulse-chase experiments, R-BEL, 76-0079, as well as Orlistat exerted little to no effect on cellular RE breakdown of LX-2 cells as well as primary human HSCs. In contrast, Lalistat2, a specific lysosomal acid lipase (LAL) inhibitor, virtually blunted acid in vitro RE hydrolase activity of LX-2 cells. Accordingly, HSCs isolated from LAL-deficient mice showed RE accumulation and were virtually devoid of acidic RE hydrolase activity. In pulse-chase experiments however, LAL-deficient HSCs, similar to LX-2 cells and primary human HSCs, were not defective in degrading REs. In summary, results demonstrate that ATGL, PNPLA3, and HSL contribute to neutral RE hydrolysis of human HSCs. LAL is the major acid RE hydrolase in HSCs. Yet, LAL is not limiting for RE degradation under serum-starvation. Together, results suggest that RE breakdown of HSCs is facilitated by (a) so far unknown, non-Orlistat inhibitable RE-hydrolase(s).
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Affiliation(s)
- Carina Wagner
- Institute of Molecular Biosciences, NAWI Graz, University of Graz, Heinrichstraße 31/II, A-8010 Graz, Austria
| | - Victoria Hois
- Institute of Molecular Biosciences, NAWI Graz, University of Graz, Heinrichstraße 31/II, A-8010 Graz, Austria
| | - Laura Pajed
- Institute of Molecular Biosciences, NAWI Graz, University of Graz, Heinrichstraße 31/II, A-8010 Graz, Austria
| | - Lisa-Maria Pusch
- Institute of Molecular Biosciences, NAWI Graz, University of Graz, Heinrichstraße 31/II, A-8010 Graz, Austria
| | - Heimo Wolinski
- Institute of Molecular Biosciences, NAWI Graz, University of Graz, Heinrichstraße 31/II, A-8010 Graz, Austria
| | - Michael Trauner
- Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria
| | - Robert Zimmermann
- Institute of Molecular Biosciences, NAWI Graz, University of Graz, Heinrichstraße 31/II, A-8010 Graz, Austria; BioTechMed-Graz, Graz, Austria
| | - Ulrike Taschler
- Institute of Molecular Biosciences, NAWI Graz, University of Graz, Heinrichstraße 31/II, A-8010 Graz, Austria.
| | - Achim Lass
- Institute of Molecular Biosciences, NAWI Graz, University of Graz, Heinrichstraße 31/II, A-8010 Graz, Austria; BioTechMed-Graz, Graz, Austria.
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47
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Paluchova V, Oseeva M, Brezinova M, Cajka T, Bardova K, Adamcova K, Zacek P, Brejchova K, Balas L, Chodounska H, Kudova E, Schreiber R, Zechner R, Durand T, Rossmeisl M, Abumrad NA, Kopecky J, Kuda O. Lipokine 5-PAHSA Is Regulated by Adipose Triglyceride Lipase and Primes Adipocytes for De Novo Lipogenesis in Mice. Diabetes 2020; 69:300-312. [PMID: 31806624 PMCID: PMC7118252 DOI: 10.2337/db19-0494] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2019] [Accepted: 11/30/2019] [Indexed: 12/18/2022]
Abstract
Branched esters of palmitic acid and hydroxystearic acid (PAHSA) are anti-inflammatory and antidiabetic lipokines that connect glucose and lipid metabolism. We aimed to characterize involvement of the 5-PAHSA regioisomer in the adaptive metabolic response of white adipose tissue (WAT) to cold exposure (CE) in mice, exploring the cross talk between glucose utilization and lipid metabolism. CE promoted local production of 5- and 9-PAHSAs in WAT. Metabolic labeling of de novo lipogenesis (DNL) using 2H2O revealed that 5-PAHSA potentiated the effects of CE and stimulated triacylglycerol (TAG)/fatty acid (FA) cycling in WAT through impacting lipogenesis and lipolysis. Adipocyte lipolytic products were altered by 5-PAHSA through selective FA re-esterification. The impaired lipolysis in global adipose triglyceride lipase (ATGL) knockout mice reduced free PAHSA levels and uncovered a metabolite reservoir of TAG-bound PAHSAs (TAG estolides) in WAT. Utilization of 13C isotope tracers and dynamic metabolomics documented that 5-PAHSA primes adipocytes for glucose metabolism in a different way from insulin, promoting DNL and impeding TAG synthesis. In summary, our data reveal new cellular and physiological mechanisms underlying the beneficial effects of 5-PAHSA and its relation to insulin action in adipocytes and independently confirm a PAHSA metabolite reservoir linked to ATGL-mediated lipolysis.
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Affiliation(s)
- Veronika Paluchova
- Institute of Physiology of the Czech Academy of Sciences, Prague, Czech Republic
| | - Marina Oseeva
- Institute of Physiology of the Czech Academy of Sciences, Prague, Czech Republic
| | - Marie Brezinova
- Institute of Physiology of the Czech Academy of Sciences, Prague, Czech Republic
| | - Tomas Cajka
- Institute of Physiology of the Czech Academy of Sciences, Prague, Czech Republic
| | - Kristina Bardova
- Institute of Physiology of the Czech Academy of Sciences, Prague, Czech Republic
| | - Katerina Adamcova
- Institute of Physiology of the Czech Academy of Sciences, Prague, Czech Republic
| | - Petr Zacek
- Proteomics Core Facility, Faculty of Science, Charles University, Division BIOCEV, Vestec, Czech Republic
| | - Kristyna Brejchova
- Institute of Physiology of the Czech Academy of Sciences, Prague, Czech Republic
| | - Laurence Balas
- Institut des Biomolécules Max Mousseron, UMR 5247, CNRS, Université Montpellier, and Faculté de Pharmacie, ENSCM, Montpellier, France
| | - Hana Chodounska
- Neurosteroids, Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Prague, Czech Republic
| | - Eva Kudova
- Neurosteroids, Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Prague, Czech Republic
| | - Renate Schreiber
- Institute of Molecular Biosciences, University of Graz, Graz, Austria
| | - Rudolf Zechner
- Institute of Molecular Biosciences, University of Graz, Graz, Austria
| | - Thierry Durand
- Institut des Biomolécules Max Mousseron, UMR 5247, CNRS, Université Montpellier, and Faculté de Pharmacie, ENSCM, Montpellier, France
| | - Martin Rossmeisl
- Institute of Physiology of the Czech Academy of Sciences, Prague, Czech Republic
| | - Nada A Abumrad
- Department of Medicine, Washington University School of Medicine, St. Louis, MO
| | - Jan Kopecky
- Institute of Physiology of the Czech Academy of Sciences, Prague, Czech Republic
| | - Ondrej Kuda
- Institute of Physiology of the Czech Academy of Sciences, Prague, Czech Republic
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48
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Dong XC. PNPLA3-A Potential Therapeutic Target for Personalized Treatment of Chronic Liver Disease. Front Med (Lausanne) 2019; 6:304. [PMID: 31921875 PMCID: PMC6927947 DOI: 10.3389/fmed.2019.00304] [Citation(s) in RCA: 40] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2019] [Accepted: 12/02/2019] [Indexed: 01/10/2023] Open
Abstract
Patatin-like phospholipase domain-containing protein 3 (PNPLA3) is a lipid droplet-associated protein that has been shown to have hydrolase activity toward triglycerides and retinyl esters. The first evidence of PNPLA3 being associated with fatty liver disease was revealed by a genome-wide association study (GWAS) of Hispanic, African American, and European American individuals in the Dallas Heart Study back in 2008. Since then, numerous GWAS reports have shown that PNPLA3 rs738409[G] (148M) variant is associated with hepatic triglyceride accumulation (steatosis), inflammation, fibrosis, cirrhosis, and even hepatocellular carcinoma regardless of etiologies including alcohol- or obesity-related and others. The frequency of PNPLA3(148M) variant ranges from 17% in African Americans, 23% in European Americans, to 49% in Hispanics in the Dallas Heart Study. Due to high prevalence of obesity and alcohol consumption in modern societies, the PNPLA3(148M) gene variant and environment interaction poses a serious concern for public health, especially chronic liver diseases including alcohol-related liver disease (ALD) and nonalcoholic fatty liver disease (NAFLD). Therefore, PNPLA3(148M) variant is a potential therapeutic target for chronic liver disease in the rs738409 allele carriers. Currently, there is no approved drug specifically targeting the PNPLA3(148M) variant yet. With additional mechanistic studies, novel therapeutic strategies are expected to be developed for the treatment of the PNPLA3(148M) variant-associated chronic liver diseases in the near future.
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Affiliation(s)
- Xiaocheng Charlie Dong
- Center for Diabetes and Metabolic Diseases, Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, United States
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49
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Abstract
Fatty liver disease (FLD) affects more than one-third of the population in the western world and an increasing number of children in the United States. It is a leading cause of obesity and liver transplantation. Mechanistic insights into the causes of FLD are urgently needed since no therapeutic intervention has proven to be effective. A sequence variation in patatin like phospholipase domain-containing protein 3 (PNPLA3), rs 738409, is strongly associated with the progression of fatty liver disease. The resulting mutant causes a substitution of isoleucine to methionine at position 148. The underlying mechanism of this disease remains unsolved although several studies have illuminated key insights into its pathogenesis. This review highlights the progress in our understanding of PNPLA3 function in lipid droplet dynamics and explores possible therapeutic interventions to ameliorate this human health hazard.
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Affiliation(s)
- Soumik Basu Ray
- Eugene McDermott Center for Human Growth and Development, Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX, USA
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50
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Genes Potentially Associated with Familial Hypercholesterolemia. Biomolecules 2019; 9:biom9120807. [PMID: 31795497 PMCID: PMC6995538 DOI: 10.3390/biom9120807] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2019] [Revised: 11/24/2019] [Accepted: 11/26/2019] [Indexed: 12/21/2022] Open
Abstract
This review addresses the contribution of some genes to the phenotype of familial hypercholesterolemia. At present, it is known that the pathogenesis of this disease involves not only a pathological variant of low-density lipoprotein receptor and its ligands (apolipoprotein B, proprotein convertase subtilisin/kexin type 9 or low-density lipoprotein receptor adaptor protein 1), but also lipids, including sphingolipids, fatty acids, and sterols. The genetic cause of familial hypercholesterolemia is unknown in 20%–40% of the cases. The genes STAP1 (signal transducing adaptor family member 1), CYP7A1 (cytochrome P450 family 7 subfamily A member 1), LIPA (lipase A, lysosomal acid type), ABCG5 (ATP binding cassette subfamily G member 5), ABCG8 (ATP binding cassette subfamily G member 8), and PNPLA5 (patatin like phospholipase domain containing 5), which can cause aberrations of lipid metabolism, are being evaluated as new targets for the diagnosis and personalized management of familial hypercholesterolemia.
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