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Zheng B, Zhang X, Kong X, Li J, Huang B, Li H, Ji Z, Wei X, Tao S, Shan Z, Ling Z, Liu J, Chen J, Zhao F. S1P regulates intervertebral disc aging by mediating endoplasmic reticulum-mitochondrial calcium ion homeostasis. JCI Insight 2024; 9:e177789. [PMID: 39316443 PMCID: PMC11601718 DOI: 10.1172/jci.insight.177789] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2023] [Accepted: 09/18/2024] [Indexed: 09/26/2024] Open
Abstract
As the aging process progresses, age-related intervertebral disc degeneration (IVDD) is becoming an emerging public health issue. Site-1 protease (S1P) has recently been found to be associated with abnormal spinal development in patients with mutations and has multiple biological functions. Here, we discovered a reduction of S1P in degenerated and aging intervertebral discs, primarily regulated by DNA methylation. Furthermore, through drug treatment and siRNA-mediated S1P knockdown, nucleus pulposus cells were more prone to exhibit degenerative and aging phenotypes. Conditional KO of S1P in mice resulted in spinal developmental abnormalities and premature aging. Mechanistically, S1P deficiency impeded COP II-mediated transport vesicle formation, which leads to protein retention in the endoplasmic reticulum (ER) and subsequently ER distension. ER distension increased the contact between the ER and mitochondria, disrupting ER-to-mitochondria calcium flow and resulting in mitochondrial dysfunction and energy metabolism disturbance. Finally, using 2-APB to inhibit calcium ion channels and the senolytic drug dasatinib and quercetin (D + Q) partially rescued the aging and degenerative phenotypes caused by S1P deficiency. In conclusion, our findings suggest that S1P is a critical factor in causing IVDD in the process of aging and highlight the potential of targeting S1P as a therapeutic approach for age-related IVDD.
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Affiliation(s)
- Bingjie Zheng
- Department of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province, Hangzhou, Zhejiang, China
- The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
| | - Xuyang Zhang
- Department of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province, Hangzhou, Zhejiang, China
| | - Xiangxi Kong
- Department of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province, Hangzhou, Zhejiang, China
| | - Jie Li
- Department of Orthopaedic Surgery, Ningbo Medical Center Li Huili Hospital, Ningbo, China
| | - Bao Huang
- Department of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province, Hangzhou, Zhejiang, China
| | - Hui Li
- Department of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province, Hangzhou, Zhejiang, China
| | - Zhongyin Ji
- Department of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province, Hangzhou, Zhejiang, China
| | - Xiaoan Wei
- Department of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province, Hangzhou, Zhejiang, China
| | - Siyue Tao
- Department of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province, Hangzhou, Zhejiang, China
| | - Zhi Shan
- Department of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province, Hangzhou, Zhejiang, China
| | - Zemin Ling
- Shenzhen Key Laboratory of Bone Tissue Repair and Translational Research, Department of Orthopaedic Surgery, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
| | - Junhui Liu
- Department of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province, Hangzhou, Zhejiang, China
| | - Jian Chen
- Department of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province, Hangzhou, Zhejiang, China
- Department of Wound Healing, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Fengdong Zhao
- Department of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province, Hangzhou, Zhejiang, China
- Department of Wound Healing, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
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Chung MY, Kim BH. Fatty acids and epigenetics in health and diseases. Food Sci Biotechnol 2024; 33:3153-3166. [PMID: 39328231 PMCID: PMC11422405 DOI: 10.1007/s10068-024-01664-3] [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: 03/04/2024] [Revised: 07/08/2024] [Accepted: 07/17/2024] [Indexed: 09/28/2024] Open
Abstract
Lipids are crucial for human health and reproduction and include diverse fatty acids (FAs), notably polyunsaturated FAs (PUFAs) and short-chain FAs (SCFAs) that are known for their health benefits. Bioactivities of PUFAs, including ω-6 and ω-3 FAs as well as SCFAs, have been widely studied in various tissues and diseases. Epigenetic regulation has been suggested as a significant mechanism affecting the progression of various diseases, including cancers and metabolic and inflammatory diseases. Epigenetics encompasses the reversible modulation of gene expression without altering the DNA sequence itself, mediated by mechanisms such as DNA methylation, histone acetylation, and chromatin remodeling. Bioactive FAs have been demonstrated to regulate gene expression via epigenetic modifications that are potentially important for modulating metabolic control and disease risk. This review paper discusses the evidence in support of bioactive FAs, including ω-6 and ω-3 FAs and SCFAs, eliciting various disease prevention via epigenetic regulation including methylation or acetylation. Graphical abstract
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Affiliation(s)
- Min-Yu Chung
- Department of Food and Nutrition, Gangseo University, Seoul, 07661 Republic of Korea
| | - Byung Hee Kim
- Department of Food and Nutrition, Sookmyung Women’s University, Seoul, 04310 Republic of Korea
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Hendrix S, Dartigue V, Hall H, Bawaria S, Kingma J, Bajaj B, Zelcer N, Kober DL. SPRING licenses S1P-mediated cleavage of SREBP2 by displacing an inhibitory pro-domain. Nat Commun 2024; 15:5732. [PMID: 38977690 PMCID: PMC11231238 DOI: 10.1038/s41467-024-50068-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2024] [Accepted: 06/28/2024] [Indexed: 07/10/2024] Open
Abstract
Site-one protease (S1P) conducts the first of two cleavage events in the Golgi to activate Sterol regulatory element binding proteins (SREBPs) and upregulate lipogenic transcription. S1P is also required for a wide array of additional signaling pathways. A zymogen serine protease, S1P matures through autoproteolysis of two pro-domains, with one cleavage event in the endoplasmic reticulum (ER) and the other in the Golgi. We recently identified the SREBP regulating gene, (SPRING), which enhances S1P maturation and is necessary for SREBP signaling. Here, we report the cryo-EM structures of S1P and S1P-SPRING at sub-2.5 Å resolution. SPRING activates S1P by dislodging its inhibitory pro-domain and stabilizing intra-domain contacts. Functionally, SPRING licenses S1P to cleave its cognate substrate, SREBP2. Our findings reveal an activation mechanism for S1P and provide insights into how spatial control of S1P activity underpins cholesterol homeostasis.
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Affiliation(s)
- Sebastian Hendrix
- Department of Medical Biochemistry, Amsterdam UMC, Amsterdam Cardiovascular Sciences and Gastroenterology and Metabolism, University of Amsterdam, Meibergdreef 9, 1105AZ, Amsterdam, the Netherlands
| | - Vincent Dartigue
- Department of Biochemistry, The University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA
| | - Hailee Hall
- Department of Biochemistry, The University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA
| | - Shrankhla Bawaria
- Department of Biochemistry, The University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA
| | - Jenina Kingma
- Department of Medical Biochemistry, Amsterdam UMC, Amsterdam Cardiovascular Sciences and Gastroenterology and Metabolism, University of Amsterdam, Meibergdreef 9, 1105AZ, Amsterdam, the Netherlands
| | - Bilkish Bajaj
- Department of Biochemistry, The University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA
| | - Noam Zelcer
- Department of Medical Biochemistry, Amsterdam UMC, Amsterdam Cardiovascular Sciences and Gastroenterology and Metabolism, University of Amsterdam, Meibergdreef 9, 1105AZ, Amsterdam, the Netherlands.
| | - Daniel L Kober
- Department of Biochemistry, The University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.
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4
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Hendrix S, Tan JME, Ndoj K, Kingma J, Valiloo M, Zijlstra LF, Ottenhoff R, Seidah NG, Loregger A, Kober DL, Zelcer N. SPRING is a Dedicated Licensing Factor for SREBP-Specific Activation by S1P. Mol Cell Biol 2024; 44:123-137. [PMID: 38747374 PMCID: PMC11110692 DOI: 10.1080/10985549.2024.2348711] [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: 07/11/2023] [Accepted: 04/10/2024] [Indexed: 05/18/2024] Open
Abstract
SREBP transcription factors are central regulators of lipid metabolism. Their proteolytic activation requires ER to the Golgi translocation and subsequent cleavage by site-1-protease (S1P). Produced as a proprotein, S1P undergoes autocatalytic cleavage from its precursor S1PA to mature S1PC form. Here, we report that SPRING (previously C12ORF29) and S1P interact through their ectodomains, and that this facilitates the autocatalytic cleavage of S1PA into its mature S1PC form. Reciprocally, we identified a S1P recognition-motif in SPRING and demonstrate that S1P-mediated cleavage leads to secretion of the SPRING ectodomain in cells, and in liver-specific Spring knockout (LKO) mice transduced with AAV-mSpring. By reconstituting SPRING variants into SPRINGKO cells we show that the SPRING ectodomain supports proteolytic maturation of S1P and SREBP signaling, but that S1P-mediated SPRING cleavage is not essential for these processes. Absence of SPRING modestly diminishes proteolytic maturation of S1PA→C and trafficking of S1PC to the Golgi. However, despite reaching the Golgi in SPRINGKO cells, S1PC fails to rescue SREBP signaling. Remarkably, whereas SREBP signaling was severely attenuated in SPRINGKO cells and LKO mice, that of ATF6, another S1P substrate, was unaffected in these models. Collectively, our study positions SPRING as a dedicated licensing factor for SREBP-specific activation by S1P.
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Affiliation(s)
- Sebastian Hendrix
- Department of Medical Biochemistry, Amsterdam UMC, Amsterdam Cardiovascular Sciences and Gastroenterology and Metabolism, University of Amsterdam, Amsterdam, The Netherlands
| | - Josephine M. E. Tan
- Department of Medical Biochemistry, Amsterdam UMC, Amsterdam Cardiovascular Sciences and Gastroenterology and Metabolism, University of Amsterdam, Amsterdam, The Netherlands
| | - Klevis Ndoj
- Department of Medical Biochemistry, Amsterdam UMC, Amsterdam Cardiovascular Sciences and Gastroenterology and Metabolism, University of Amsterdam, Amsterdam, The Netherlands
| | - Jenina Kingma
- Department of Medical Biochemistry, Amsterdam UMC, Amsterdam Cardiovascular Sciences and Gastroenterology and Metabolism, University of Amsterdam, Amsterdam, The Netherlands
| | - Masoud Valiloo
- Department of Medical Biochemistry, Amsterdam UMC, Amsterdam Cardiovascular Sciences and Gastroenterology and Metabolism, University of Amsterdam, Amsterdam, The Netherlands
| | - Lobke F. Zijlstra
- Department of Medical Biochemistry, Amsterdam UMC, Amsterdam Cardiovascular Sciences and Gastroenterology and Metabolism, University of Amsterdam, Amsterdam, The Netherlands
| | - Roelof Ottenhoff
- Department of Medical Biochemistry, Amsterdam UMC, Amsterdam Cardiovascular Sciences and Gastroenterology and Metabolism, University of Amsterdam, Amsterdam, The Netherlands
| | - Nabil G. Seidah
- Laboratory of Biochemical Neuroendocrinology, Montreal Clinical Research Institute (IRCM), University of Montreal, Montréal, Québec, Canada
| | - Anke Loregger
- Department of Medical Biochemistry, Amsterdam UMC, Amsterdam Cardiovascular Sciences and Gastroenterology and Metabolism, University of Amsterdam, Amsterdam, The Netherlands
| | - Daniel L. Kober
- Department of Biochemistry, The University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Noam Zelcer
- Department of Medical Biochemistry, Amsterdam UMC, Amsterdam Cardiovascular Sciences and Gastroenterology and Metabolism, University of Amsterdam, Amsterdam, The Netherlands
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Liaqat K, Treat K, Mantcheva L, Nasir A, Weaver DD, Conboy E, Vetrini F. A case of MBTPS1-related disorder due to compound heterozygous variants in MBTPS1 gene: Genotype-phenotype expansion and the emergence of a novel syndrome. Am J Med Genet A 2024; 194:e63499. [PMID: 38135440 DOI: 10.1002/ajmg.a.63499] [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: 10/18/2023] [Revised: 11/23/2023] [Accepted: 11/28/2023] [Indexed: 12/24/2023]
Abstract
MBTPS1 (NM_003791.4) encodes Site-1 protease, a serine protease that functions sequentially with Site-2 protease regulating cholesterol homeostasis and endoplasmic reticulum stress response. MBTPS1 pathogenic variants are associated with spondyloepiphyseal dysplasia, Kondo-Fu type (MIM:618392; cataract, alopecia, oral mucosal disorder, and psoriasis-like syndrome, and Silver-Russell-like syndrome). In this report, we describe a 14-year-old female with a complex medical history including white matter volume loss, early-onset cataracts, retrognathia, laryngomalacia, inguinal hernia, joint hypermobility, feeding dysfunction, and speech delay. Additionally, features of ectodermal dysplasia that she has include decreased sweating, heat intolerance, dysplastic nails, chronically dry skin, and abnormal hair growth issues. Exome sequencing analysis identified compound heterozygous variants in the MBTPS1 gene: c.2255G > T p.(Gly752Val) predicted to affect important function of the protein, which was inherited from the mother, and a splice site variant c.2831 + 5G > T, which was inherited from the father. The RNA-seq analysis of the splice variant showed skipping of exon 21, predicted to result in frameshifting p.(Ser901fs28*) leading to non-sense mediated decay. To our knowledge, only eight studies have been published that described the MBPTS1-related disorders. Interestingly, we observed the features of ectodermal dysplasia in our patient that further expands the phenotypic spectrum of MBTPS1 gene-related disorders.
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Affiliation(s)
- Khurram Liaqat
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana, USA
- Undiagnosed Rare Disease Clinic (URDC), Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Kayla Treat
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana, USA
- Undiagnosed Rare Disease Clinic (URDC), Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Lili Mantcheva
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana, USA
- Undiagnosed Rare Disease Clinic (URDC), Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Abdul Nasir
- Department of Anesthesiology, Second Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - David D Weaver
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Erin Conboy
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana, USA
- Undiagnosed Rare Disease Clinic (URDC), Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Francesco Vetrini
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana, USA
- Undiagnosed Rare Disease Clinic (URDC), Indiana University School of Medicine, Indianapolis, Indiana, USA
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Mohammadpour-Asl S, Roshan-Milani B, Roshan-Milani S, Saboory E, Ghobadian B, Chodari L. Endoplasmic reticulum stress PERK-ATF4-CHOP pathway is involved in non-alcoholic fatty liver disease in type 1 diabetic rats: The rescue effect of treatment exercise and insulin-like growth factor I. Heliyon 2024; 10:e27225. [PMID: 38468961 PMCID: PMC10926145 DOI: 10.1016/j.heliyon.2024.e27225] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2023] [Revised: 02/23/2024] [Accepted: 02/26/2024] [Indexed: 03/13/2024] Open
Abstract
Endoplasmic Reticulum Stress (ERS) is a key factor in the development of Non-Alcoholic Fatty Liver Disease (NAFLD) in diabetes. The current study aimed to examine the effects of exercise and IGF-I on ERS markers in liver tissue. Rats were divided into five groups (n = 8 per group), including control (CON), diabetes (DIA), diabetes + exercise (DIA + EX), diabetes + IGF-I (DIA + IGF-I), and diabetes + exercise + IGF-I (DIA + EX + IGF-I). Type 1 diabetes was induced by an I.P. injection of streptozotocin (60 mg/kg). After 30 days of treatment with exercise or IGF-I alone or in combination, liver tissue was assessed for caspase 12, 8, and CHOP protein levels, and expression of ERS markers (ATF-6, PERK, IRE-1A) and lipid metabolism-involved genes (FAS, FXR, SREBP-1c) by western immunoblotting. In addition, for the evaluation of histopathological changes in the liver, Hematoxylin - Eosin and Masson's Trichrome staining were done. Compared to the control group, diabetes significantly caused liver fibrosis, induced ERS, increased caspase 12 and 8 levels in the liver, and changed expression levels of genes associated with lipid metabolism, including FAS, FXR, and SREBP-1c. Treatment with either exercise or IGF-I reduced fibrosis levels suppressed ER stress markers and apoptosis, and improved expression of genes associated with lipid metabolism. In addition, simultaneous treatment with exercise and IGF-I showed a synergistic effect compared to DIA + E and DIA + IGF-I. The results suggest that IGF-1 and exercise reduced liver fibrosis possibly by reducing ERS, creating adaptive ER stress status, and improving protein folding.
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Affiliation(s)
- Shadi Mohammadpour-Asl
- Student Research Committee, Urmia University of Medical Sciences, Urmia, Iran
- Department of Physiology, School of Medicine, Urmia University of Medical Sciences, Urmia, Iran
| | | | - Shiva Roshan-Milani
- Department of Physiology, School of Medicine, Urmia University of Medical Sciences, Urmia, Iran
- Neurophysiology Research Center, Cellular and Molecular Medicine Research Institute, Urmia University of Medical Sciences, Urmia, Iran
| | - Ehsan Saboory
- Department of Addiction Studies, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Bijan Ghobadian
- Zanjan Metabolic Diseases Research Center, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Leila Chodari
- Department of Physiology, School of Medicine, Urmia University of Medical Sciences, Urmia, Iran
- Neurophysiology Research Center, Cellular and Molecular Medicine Research Institute, Urmia University of Medical Sciences, Urmia, Iran
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Raggio V, Rodríguez S, Feder S, Gueçaimburú R, Spangenberg L. Exome Sequencing Reveals Biallelic Mutations in MBTPS1 Gene in a Girl with a Very Rare Skeletal Dysplasia. Diagnostics (Basel) 2024; 14:313. [PMID: 38337829 PMCID: PMC10855125 DOI: 10.3390/diagnostics14030313] [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: 11/23/2023] [Revised: 12/28/2023] [Accepted: 01/03/2024] [Indexed: 02/12/2024] Open
Abstract
The Kondo-Fu type of spondyloepiphyseal dysplasia (SEDKF) is a rare skeletal dysplasia caused by homozygous or compound heterozygous mutations in the MBTPS1 gene. The MBTPS1 gene encodes a protein that is involved in the regulation of cholesterol and fatty acid metabolism. Mutations in MBTPS1 can lead to reduced levels of these lipids, which can have a number of effects on development, including skeletal anomalies, growth retardation, and elevated levels of blood lysosomal enzymes. This work reports the case of a 5-year-old girl with SEDKF. The patient had a severely short stature and a number of skeletal anomalies, including kyphosis, pectus carinatum, and reduced bone mineral density. She also had early onset cataracts and inguinal hernias. Genetic testing revealed two novel compound heterozygous variants in the MBTPS1 gene. These variants are predicted to disrupt the function of the MBTPS1 protein, which is consistent with the patient's clinical presentation. This case report adds to the growing body of evidence that mutations in the MBTPS1 gene are causal of SEDKF. We summarized the features of previous reported cases (with age ranges from 4 to 24 years) and identified that 80% had low stature, 70% low weight, 80% had bilateral cataracts and 70% showed Spondyloepiphyseal dysplasia on X-rays. The findings of this study suggest that SEDKF is a clinically heterogeneous disorder that can present with a variety of features. Further studies are needed to better understand the underlying mechanisms of SEDKF and to develop more effective treatments.
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Affiliation(s)
- Víctor Raggio
- Departamento de Genética, Facultad de Medicina, Universidad de la República, Montevideo 11800, Uruguay; (V.R.); (S.R.)
| | - Soledad Rodríguez
- Departamento de Genética, Facultad de Medicina, Universidad de la República, Montevideo 11800, Uruguay; (V.R.); (S.R.)
| | - Sandra Feder
- Laboratorio de Genética Clínica Genodiagnosis, Montevideo 11600, Uruguay;
| | - Rosario Gueçaimburú
- Centro de Referencia Nacional de Defectos Congénitos y Enfermedades Raras (CRENADECER), Av. Agraciada 2989, Montevideo 11800, Uruguay;
- Hospital Británico, Av. Italia 2420, Montevideo 11600, Uruguay
| | - Lucía Spangenberg
- Departamento Básico de Medicina, Hospital de Clínicas, Facultad de Medicina, Universidad de la República, Montevideo 11600, Uruguay
- Bioinformatics Unit, Institut Pasteur de Montevideo, Montevideo 11400, Uruguay
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Bao X, Liang Y, Chang H, Cai T, Feng B, Gordon K, Zhu Y, Shi H, He Y, Xie L. Targeting proprotein convertase subtilisin/kexin type 9 (PCSK9): from bench to bedside. Signal Transduct Target Ther 2024; 9:13. [PMID: 38185721 PMCID: PMC10772138 DOI: 10.1038/s41392-023-01690-3] [Citation(s) in RCA: 28] [Impact Index Per Article: 28.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2023] [Revised: 09/27/2023] [Accepted: 10/27/2023] [Indexed: 01/09/2024] Open
Abstract
Proprotein convertase subtilisin/kexin type 9 (PCSK9) has evolved as a pivotal enzyme in lipid metabolism and a revolutionary therapeutic target for hypercholesterolemia and its related cardiovascular diseases (CVD). This comprehensive review delineates the intricate roles and wide-ranging implications of PCSK9, extending beyond CVD to emphasize its significance in diverse physiological and pathological states, including liver diseases, infectious diseases, autoimmune disorders, and notably, cancer. Our exploration offers insights into the interaction between PCSK9 and low-density lipoprotein receptors (LDLRs), elucidating its substantial impact on cholesterol homeostasis and cardiovascular health. It also details the evolution of PCSK9-targeted therapies, translating foundational bench discoveries into bedside applications for optimized patient care. The advent and clinical approval of innovative PCSK9 inhibitory therapies (PCSK9-iTs), including three monoclonal antibodies (Evolocumab, Alirocumab, and Tafolecimab) and one small interfering RNA (siRNA, Inclisiran), have marked a significant breakthrough in cardiovascular medicine. These therapies have demonstrated unparalleled efficacy in mitigating hypercholesterolemia, reducing cardiovascular risks, and have showcased profound value in clinical applications, offering novel therapeutic avenues and a promising future in personalized medicine for cardiovascular disorders. Furthermore, emerging research, inclusive of our findings, unveils PCSK9's potential role as a pivotal indicator for cancer prognosis and its prospective application as a transformative target for cancer treatment. This review also highlights PCSK9's aberrant expression in various cancer forms, its association with cancer prognosis, and its crucial roles in carcinogenesis and cancer immunity. In conclusion, this synthesized review integrates existing knowledge and novel insights on PCSK9, providing a holistic perspective on its transformative impact in reshaping therapeutic paradigms across various disorders. It emphasizes the clinical value and effect of PCSK9-iT, underscoring its potential in advancing the landscape of biomedical research and its capabilities in heralding new eras in personalized medicine.
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Affiliation(s)
- Xuhui Bao
- Institute of Therapeutic Cancer Vaccines, Fudan University Pudong Medical Center, Shanghai, China.
- Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai, China.
- Department of Oncology, Fudan University Pudong Medical Center, Shanghai, China.
- Center for Clinical Research, Fudan University Pudong Medical Center, Shanghai, China.
- Clinical Research Center for Cell-based Immunotherapy, Fudan University, Shanghai, China.
- Department of Pathology, Duke University Medical Center, Durham, NC, USA.
| | - Yongjun Liang
- Center for Medical Research and Innovation, Fudan University Pudong Medical Center, Shanghai, China
| | - Hanman Chang
- Institute for Food Safety and Health, Illinois Institute of Technology, Chicago, IL, USA
| | - Tianji Cai
- Department of Sociology, University of Macau, Taipa, Macau, China
| | - Baijie Feng
- Department of Oncology, Fudan University Pudong Medical Center, Shanghai, China
| | - Konstantin Gordon
- Medical Institute, Peoples' Friendship University of Russia, Moscow, Russia
- A. Tsyb Medical Radiological Research Center, Obninsk, Russia
| | - Yuekun Zhu
- Department of Colorectal Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Hailian Shi
- Shanghai Key Laboratory of Compound Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Zhangjiang Hi-tech Park, Shanghai, China
| | - Yundong He
- Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai, China.
| | - Liyi Xie
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
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9
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Hendrix S, Zelcer N. A new SPRING in lipid metabolism. Curr Opin Lipidol 2023; 34:201-207. [PMID: 37548386 DOI: 10.1097/mol.0000000000000894] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 08/08/2023]
Abstract
PURPOSE OF REVIEW The SREBP transcription factors are master regulators of lipid homeostasis owing to their role in controlling cholesterol and fatty acid metabolism. The core machinery required to promote their trafficking and proteolytic activation has been established close to 20 years ago. In this review, we summarize the current understanding of a newly identified regulator of SREBP signaling, SPRING (formerly C12ORF49), its proposed mechanism of action, and its role in lipid metabolism. RECENT FINDINGS Using whole-genome functional genetic screens we, and others, have recently identified SPRING as a novel regulator of SREBP signaling. SPRING is a Golgi-resident single-pass transmembrane protein that is required for proteolytic activation of SREBPs in this compartment. Mechanistic studies identified regulation of S1P, the protease that cleaves SREBPs, and control of retrograde trafficking of the SREBP chaperone SCAP from the Golgi to the ER as processes requiring SPRING. Emerging studies suggest an important role for SPRING in regulating circulating and hepatic lipid levels in mice and potentially in humans. SUMMARY Current studies support the notion that SPRING is a novel component of the core SREBP-activating machinery. Additional studies are warranted to elucidate its role in cellular and systemic lipid metabolism.
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Affiliation(s)
- Sebastian Hendrix
- Department of Medical Biochemistry, Amsterdam UMC, Amsterdam Cardiovascular Sciences and Gastroenterology and Metabolism, University of Amsterdam, Meibergdreef 15, Amsterdam, the Netherlands
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10
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Hendrix S, Kingma J, Ottenhoff R, Valiloo M, Svecla M, Zijlstra LF, Sachdev V, Kovac K, Levels JHM, Jongejan A, de Boer JF, Kuipers F, Rimbert A, Norata GD, Loregger A, Zelcer N. Hepatic SREBP signaling requires SPRING to govern systemic lipid metabolism in mice and humans. Nat Commun 2023; 14:5181. [PMID: 37626055 PMCID: PMC10457316 DOI: 10.1038/s41467-023-40943-1] [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] [Subscribe] [Scholar Register] [Received: 04/20/2023] [Accepted: 08/11/2023] [Indexed: 08/27/2023] Open
Abstract
The sterol regulatory element binding proteins (SREBPs) are transcription factors that govern cholesterol and fatty acid metabolism. We recently identified SPRING as a post-transcriptional regulator of SREBP activation. Constitutive or inducible global ablation of Spring in mice is not tolerated, and we therefore develop liver-specific Spring knockout mice (LKO). Transcriptomics and proteomics analysis reveal attenuated SREBP signaling in livers and hepatocytes of LKO mice. Total plasma cholesterol is reduced in male and female LKO mice in both the low-density lipoprotein and high-density lipoprotein fractions, while triglycerides are unaffected. Loss of Spring decreases hepatic cholesterol and triglyceride content due to diminished biosynthesis, which coincides with reduced very-low-density lipoprotein secretion. Accordingly, LKO mice are protected from fructose diet-induced hepatosteatosis. In humans, we find common genetic SPRING variants that associate with circulating high-density lipoprotein cholesterol and ApoA1 levels. This study positions SPRING as a core component of hepatic SREBP signaling and systemic lipid metabolism in mice and humans.
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Affiliation(s)
- Sebastian Hendrix
- Department of Medical Biochemistry, Amsterdam UMC, Amsterdam Cardiovascular Sciences and Gastroenterology and Metabolism, University of Amsterdam, Meibergdreef 9, 1105AZ, Amsterdam, The Netherlands
| | - Jenina Kingma
- Department of Medical Biochemistry, Amsterdam UMC, Amsterdam Cardiovascular Sciences and Gastroenterology and Metabolism, University of Amsterdam, Meibergdreef 9, 1105AZ, Amsterdam, The Netherlands
| | - Roelof Ottenhoff
- Department of Medical Biochemistry, Amsterdam UMC, Amsterdam Cardiovascular Sciences and Gastroenterology and Metabolism, University of Amsterdam, Meibergdreef 9, 1105AZ, Amsterdam, The Netherlands
| | - Masoud Valiloo
- Department of Medical Biochemistry, Amsterdam UMC, Amsterdam Cardiovascular Sciences and Gastroenterology and Metabolism, University of Amsterdam, Meibergdreef 9, 1105AZ, Amsterdam, The Netherlands
| | - Monika Svecla
- Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Via Balzaretti 9, 20133, Milan, Italy
| | - Lobke F Zijlstra
- Department of Medical Biochemistry, Amsterdam UMC, Amsterdam Cardiovascular Sciences and Gastroenterology and Metabolism, University of Amsterdam, Meibergdreef 9, 1105AZ, Amsterdam, The Netherlands
| | - Vinay Sachdev
- Department of Medical Biochemistry, Amsterdam UMC, Amsterdam Cardiovascular Sciences and Gastroenterology and Metabolism, University of Amsterdam, Meibergdreef 9, 1105AZ, Amsterdam, The Netherlands
| | - Kristina Kovac
- Department of Medical Biochemistry, Amsterdam UMC, Amsterdam Cardiovascular Sciences and Gastroenterology and Metabolism, University of Amsterdam, Meibergdreef 9, 1105AZ, Amsterdam, The Netherlands
| | - Johannes H M Levels
- Department of Experimental Vascular Medicine, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105AZ, Amsterdam, The Netherlands
| | - Aldo Jongejan
- Department of Epidemiology and Data Science, Bioinformatics Laboratory, of Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105AZ, Amsterdam, The Netherlands
| | - Jan F de Boer
- Department of Pediatrics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
- Department of Laboratory Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Folkert Kuipers
- Department of Pediatrics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
- European Research Institute for the Biology of Ageing (ERIBA), University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Antoine Rimbert
- l'institut du thorax, Nantes Université, CNRS, INSERM, F-44000, Nantes, France
| | - Giuseppe D Norata
- Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Via Balzaretti 9, 20133, Milan, Italy
| | - Anke Loregger
- Department of Medical Biochemistry, Amsterdam UMC, Amsterdam Cardiovascular Sciences and Gastroenterology and Metabolism, University of Amsterdam, Meibergdreef 9, 1105AZ, Amsterdam, The Netherlands
- Myllia Biotechnology GmbH, Am Kanal 27, 1110, Vienna, Austria
| | - Noam Zelcer
- Department of Medical Biochemistry, Amsterdam UMC, Amsterdam Cardiovascular Sciences and Gastroenterology and Metabolism, University of Amsterdam, Meibergdreef 9, 1105AZ, Amsterdam, The Netherlands.
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11
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Jeon YG, Kim YY, Lee G, Kim JB. Physiological and pathological roles of lipogenesis. Nat Metab 2023; 5:735-759. [PMID: 37142787 DOI: 10.1038/s42255-023-00786-y] [Citation(s) in RCA: 56] [Impact Index Per Article: 28.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2022] [Accepted: 03/15/2023] [Indexed: 05/06/2023]
Abstract
Lipids are essential metabolites, which function as energy sources, structural components and signalling mediators. Most cells are able to convert carbohydrates into fatty acids, which are often converted into neutral lipids for storage in the form of lipid droplets. Accumulating evidence suggests that lipogenesis plays a crucial role not only in metabolic tissues for systemic energy homoeostasis but also in immune and nervous systems for their proliferation, differentiation and even pathophysiological roles. Thus, excessive or insufficient lipogenesis is closely associated with aberrations in lipid homoeostasis, potentially leading to pathological consequences, such as dyslipidaemia, diabetes, fatty liver, autoimmune diseases, neurodegenerative diseases and cancers. For systemic energy homoeostasis, multiple enzymes involved in lipogenesis are tightly controlled by transcriptional and post-translational modifications. In this Review, we discuss recent findings regarding the regulatory mechanisms, physiological roles and pathological importance of lipogenesis in multiple tissues such as adipose tissue and the liver, as well as the immune and nervous systems. Furthermore, we briefly introduce the therapeutic implications of lipogenesis modulation.
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Affiliation(s)
- Yong Geun Jeon
- Center for Adipocyte Structure and Function, Institute of Molecular Biology and Genetics, School of Biological Sciences, Seoul National University, Seoul, South Korea
| | - Ye Young Kim
- Center for Adipocyte Structure and Function, Institute of Molecular Biology and Genetics, School of Biological Sciences, Seoul National University, Seoul, South Korea
| | - Gung Lee
- Center for Adipocyte Structure and Function, Institute of Molecular Biology and Genetics, School of Biological Sciences, Seoul National University, Seoul, South Korea
| | - Jae Bum Kim
- Center for Adipocyte Structure and Function, Institute of Molecular Biology and Genetics, School of Biological Sciences, Seoul National University, Seoul, South Korea.
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12
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Mousa MG, Vuppaladhadiam L, Kelly MO, Pietka T, Ek S, Shen KC, Meyer GA, Finck BN, Brookheart RT. Site-1 protease inhibits mitochondrial respiration by controlling the TGF-β target gene Mss51. Cell Rep 2023; 42:112336. [PMID: 37002920 PMCID: PMC10544680 DOI: 10.1016/j.celrep.2023.112336] [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] [Subscribe] [Scholar Register] [Received: 08/29/2022] [Revised: 02/17/2023] [Accepted: 03/20/2023] [Indexed: 04/03/2023] Open
Abstract
The mitochondrial response to changes in cellular energy demand is necessary for cellular adaptation and organ function. Many genes are essential in orchestrating this response, including the transforming growth factor (TGF)-β1 target gene Mss51, an inhibitor of skeletal muscle mitochondrial respiration. Although Mss51 is implicated in the pathophysiology of obesity and musculoskeletal disease, how Mss51 is regulated is not entirely understood. Site-1 protease (S1P) is a key activator of several transcription factors required for cellular adaptation. However, the role of S1P in muscle is unknown. Here, we identify S1P as a negative regulator of muscle mass and mitochondrial respiration. S1P disruption in mouse skeletal muscle reduces Mss51 expression and increases muscle mass and mitochondrial respiration. The effects of S1P deficiency on mitochondrial activity are counteracted by overexpressing Mss51, suggesting that one way S1P inhibits respiration is by regulating Mss51. These discoveries expand our understanding of TGF-β signaling and S1P function.
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Affiliation(s)
- Muhammad G Mousa
- John T. Milliken Department of Medicine, Division of Geriatrics and Nutritional Sciences, Washington University School of Medicine, St. Louis, MO 61110, USA
| | - Lahari Vuppaladhadiam
- John T. Milliken Department of Medicine, Division of Geriatrics and Nutritional Sciences, Washington University School of Medicine, St. Louis, MO 61110, USA
| | - Meredith O Kelly
- John T. Milliken Department of Medicine, Division of Geriatrics and Nutritional Sciences, Washington University School of Medicine, St. Louis, MO 61110, USA
| | - Terri Pietka
- John T. Milliken Department of Medicine, Division of Geriatrics and Nutritional Sciences, Washington University School of Medicine, St. Louis, MO 61110, USA
| | - Shelby Ek
- John T. Milliken Department of Medicine, Division of Geriatrics and Nutritional Sciences, Washington University School of Medicine, St. Louis, MO 61110, USA
| | - Karen C Shen
- Program in Physical Therapy, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Gretchen A Meyer
- Program in Physical Therapy, Washington University School of Medicine, St. Louis, MO 63110, USA; Departments of Orthopaedic Surgery and Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Biomedical Engineering, Washington University, St. Louis, MO 63130, USA
| | - Brian N Finck
- John T. Milliken Department of Medicine, Division of Geriatrics and Nutritional Sciences, Washington University School of Medicine, St. Louis, MO 61110, USA
| | - Rita T Brookheart
- John T. Milliken Department of Medicine, Division of Geriatrics and Nutritional Sciences, Washington University School of Medicine, St. Louis, MO 61110, USA.
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13
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Zhang X, Wang L, Wang Y, He L, Xu D, Yan E, Guo J, Ma C, Zhang P, Yin J. Lack of adipocyte IP3R1 reduces diet-induced obesity and greatly improves whole-body glucose homeostasis. Cell Death Discov 2023; 9:87. [PMID: 36894534 PMCID: PMC9998023 DOI: 10.1038/s41420-023-01389-y] [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: 01/18/2023] [Revised: 02/26/2023] [Accepted: 02/27/2023] [Indexed: 03/11/2023] Open
Abstract
The normal function of skeletal muscle and adipose tissue ensures whole-body glucose homeostasis. Ca2+ release channel inositol 1,4,5-trisphosphate receptor 1 (IP3R1) plays a vital role in regulating diet-induced obesity and disorders, but its functions in peripheral tissue regulating glucose homeostasis remain unexplored. In this study, mice with Ip3r1 specific knockout in skeletal muscle or adipocytes were used for investigating the mediatory role of IP3R1 on whole-body glucose homeostasis under normal or high-fat diet. We reported that IP3R1 expression levels were increased in the white adipose tissue and skeletal muscle of diet-induced obese mice. Ip3r1 knockout in skeletal muscle improved glucose tolerance and insulin sensitivity of mice on a normal chow diet, but worsened insulin resistance in diet-induced obese mice. These changes were associated with the reduced muscle weight and compromised Akt signaling activation. Importantly, Ip3r1 deletion in adipocytes protected mice from diet-induced obesity and glucose intolerance, mainly due to the enhanced lipolysis and AMPK signaling pathway in the visceral fat. In conclusion, our study demonstrates that IP3R1 in skeletal muscle and adipocytes exerts divergent effects on systemic glucose homeostasis, and characterizes adipocyte IP3R1 as a promising target for treating obesity and type 2 diabetes.
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Affiliation(s)
- Xin Zhang
- State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, 100193, Beijing, China
- Molecular Design Breeding Frontier Science Center of the Ministry of Education, 100193, Beijing, China
| | - Lu Wang
- State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, 100193, Beijing, China
| | - Yubo Wang
- State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, 100193, Beijing, China
| | - Linjuan He
- State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, 100193, Beijing, China
| | - Doudou Xu
- State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, 100193, Beijing, China
| | - Enfa Yan
- State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, 100193, Beijing, China
| | - Jianxin Guo
- State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, 100193, Beijing, China
| | - Chenghong Ma
- State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, 100193, Beijing, China
| | - Pengguang Zhang
- State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, 100193, Beijing, China
| | - Jingdong Yin
- State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, 100193, Beijing, China.
- Molecular Design Breeding Frontier Science Center of the Ministry of Education, 100193, Beijing, China.
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14
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Essalmani R, Andréo U, Evagelidis A, Le Dévéhat M, Pereira Ramos OH, Fruchart Gaillard C, Susan-Resiga D, Cohen ÉA, Seidah NG. SKI-1/S1P Facilitates SARS-CoV-2 Spike Induced Cell-to-Cell Fusion via Activation of SREBP-2 and Metalloproteases, Whereas PCSK9 Enhances the Degradation of ACE2. Viruses 2023; 15:v15020360. [PMID: 36851576 PMCID: PMC9959508 DOI: 10.3390/v15020360] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Revised: 01/23/2023] [Accepted: 01/24/2023] [Indexed: 01/31/2023] Open
Abstract
Proprotein convertases activate various envelope glycoproteins and participate in cellular entry of many viruses. We recently showed that the convertase furin is critical for the infectivity of SARS-CoV-2, which requires cleavage of its spike protein (S) at two sites: S1/S2 and S2'. This study investigates the implication of the two cholesterol-regulating convertases SKI-1 and PCSK9 in SARS-CoV-2 entry. The assays used were cell-to-cell fusion in HeLa cells and pseudoparticle entry into Calu-3 cells. SKI-1 increased cell-to-cell fusion by enhancing the activation of SREBP-2, whereas PCSK9 reduced cell-to-cell fusion by promoting the cellular degradation of ACE2. SKI-1 activity led to enhanced S2' formation, which was attributed to increased metalloprotease activity as a response to enhanced cholesterol levels via activated SREBP-2. However, high metalloprotease activity resulted in the shedding of S2' into a new C-terminal fragment (S2″), leading to reduced cell-to-cell fusion. Indeed, S-mutants that increase S2″ formation abolished S2' and cell-to-cell fusion, as well as pseudoparticle entry, indicating that the formation of S2″ prevents SARS-CoV-2 cell-to-cell fusion and entry. We next demonstrated that PCSK9 enhanced the cellular degradation of ACE2, thereby reducing cell-to-cell fusion. However, different from the LDLR, a canonical target of PCSK9, the C-terminal CHRD domain of PCSK9 is dispensable for the PCSK9-induced degradation of ACE2. Molecular modeling suggested the binding of ACE2 to the Pro/Catalytic domains of mature PCSK9. Thus, both cholesterol-regulating convertases SKI-1 and PCSK9 can modulate SARS-CoV-2 entry via two independent mechanisms.
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Affiliation(s)
- Rachid Essalmani
- Laboratory of Biochemical Neuroendocrinology, Montreal Clinical Research Institute (IRCM), Université de Montréal, Montreal, QC H2W 1R7, Canada
| | - Ursula Andréo
- Laboratory of Biochemical Neuroendocrinology, Montreal Clinical Research Institute (IRCM), Université de Montréal, Montreal, QC H2W 1R7, Canada
| | - Alexandra Evagelidis
- Laboratory of Biochemical Neuroendocrinology, Montreal Clinical Research Institute (IRCM), Université de Montréal, Montreal, QC H2W 1R7, Canada
| | - Maïlys Le Dévéhat
- Laboratory of Biochemical Neuroendocrinology, Montreal Clinical Research Institute (IRCM), Université de Montréal, Montreal, QC H2W 1R7, Canada
| | - Oscar Henrique Pereira Ramos
- Département Médicaments et Technologies pour la Santé (DMTS), Université Paris-Saclay, CEA, INRAE, SI-MoS, 91191 Gif-sur-Yvette, France
| | - Carole Fruchart Gaillard
- Département Médicaments et Technologies pour la Santé (DMTS), Université Paris-Saclay, CEA, INRAE, SI-MoS, 91191 Gif-sur-Yvette, France
| | - Delia Susan-Resiga
- Laboratory of Biochemical Neuroendocrinology, Montreal Clinical Research Institute (IRCM), Université de Montréal, Montreal, QC H2W 1R7, Canada
| | - Éric A. Cohen
- Laboratory of Human Retrovirology, Montreal Clinical Research Institute (IRCM), Université de Montréal, 110 Pine Ave West, Montreal, QC H2W 1R7, Canada
- Department of Microbiology, Infectiology and Immunology, Université de Montréal, Montreal, QC H3C 3J7, Canada
| | - Nabil G. Seidah
- Laboratory of Biochemical Neuroendocrinology, Montreal Clinical Research Institute (IRCM), Université de Montréal, Montreal, QC H2W 1R7, Canada
- Correspondence: ; Tel.: +1-514-987-5609
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15
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Kim JY, Wang LQ, Sladky VC, Oh TG, Liu J, Trinh K, Eichin F, Downes M, Hosseini M, Jacotot ED, Evans RM, Villunger A, Karin M. PIDDosome-SCAP crosstalk controls high-fructose-diet-dependent transition from simple steatosis to steatohepatitis. Cell Metab 2022; 34:1548-1560.e6. [PMID: 36041455 PMCID: PMC9547947 DOI: 10.1016/j.cmet.2022.08.005] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2021] [Revised: 06/17/2022] [Accepted: 08/07/2022] [Indexed: 02/06/2023]
Abstract
Sterol deficiency triggers SCAP-mediated SREBP activation, whereas hypernutrition together with ER stress activates SREBP1/2 via caspase-2. Whether these pathways interact and how they are selectively activated by different dietary cues are unknown. Here, we reveal regulatory crosstalk between the two pathways that controls the transition from hepatosteatosis to steatohepatitis. Hepatic ER stress elicited by NASH-inducing diets activates IRE1 and induces expression of the PIDDosome subunits caspase-2, RAIDD, and PIDD1, along with INSIG2, an inhibitor of SCAP-dependent SREBP activation. PIDDosome assembly activates caspase-2 and sustains IRE1 activation. PIDDosome ablation or IRE1 inhibition blunt steatohepatitis and diminish INSIG2 expression. Conversely, while inhibiting simple steatosis, SCAP ablation amplifies IRE1 and PIDDosome activation and liver damage in NASH-diet-fed animals, effects linked to ER disruption and preventable by IRE1 inhibition. Thus, the PIDDosome and SCAP pathways antagonistically modulate nutrient-induced hepatic ER stress to control non-linear transition from simple steatosis to hepatitis, a key step in NASH pathogenesis.
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Affiliation(s)
- Ju Youn Kim
- Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, School of Medicine, University of California San Diego, La Jolla, CA 92093, USA.
| | - Lily Q Wang
- Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, School of Medicine, University of California San Diego, La Jolla, CA 92093, USA
| | - Valentina C Sladky
- Institute for Developmental Immunology, Biocenter, Medical University of Innsbruck, Innsbruck, Austria
| | - Tae Gyu Oh
- Gene Expression Laboratory, Salk Institute of Biological Studies, La Jolla, CA 9037, USA
| | - Junlai Liu
- Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, School of Medicine, University of California San Diego, La Jolla, CA 92093, USA
| | - Kaitlyn Trinh
- Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, School of Medicine, University of California San Diego, La Jolla, CA 92093, USA
| | - Felix Eichin
- Institute for Developmental Immunology, Biocenter, Medical University of Innsbruck, Innsbruck, Austria
| | - Michael Downes
- Gene Expression Laboratory, Salk Institute of Biological Studies, La Jolla, CA 9037, USA
| | - Mojgan Hosseini
- Department of Pathology, University of California San Diego, La Jolla, CA 92037, USA
| | - Etienne D Jacotot
- INSERM U1164 Sorbonne Université, Campus Pierre et Marie Curie, Paris 75005, France; Department of Pathology & Cell Biology and the Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Medical Center, New York, NY 10033, USA
| | - Ronald M Evans
- Gene Expression Laboratory, Salk Institute of Biological Studies, La Jolla, CA 9037, USA
| | - Andreas Villunger
- Institute for Developmental Immunology, Biocenter, Medical University of Innsbruck, Innsbruck, Austria; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
| | - Michael Karin
- Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, School of Medicine, University of California San Diego, La Jolla, CA 92093, USA.
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16
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Abstract
This article reviews the discovery of PCSK9, its structure-function characteristics, and its presently known and proposed novel biological functions. The major critical function of PCSK9 deduced from human and mouse studies, as well as cellular and structural analyses, is its role in increasing the levels of circulating low-density lipoprotein (LDL)-cholesterol (LDLc), via its ability to enhance the sorting and escort of the cell surface LDL receptor (LDLR) to lysosomes. This implicates the binding of the catalytic domain of PCSK9 to the EGF-A domain of the LDLR. This also requires the presence of the C-terminal Cys/His-rich domain, its binding to the secreted cytosolic cyclase associated protein 1, and possibly another membrane-bound "protein X". Curiously, in PCSK9-deficient mice, an alternative to the downregulation of the surface levels of the LDLR by PCSK9 is taking place in the liver of female mice in a 17β-estradiol-dependent manner by still an unknown mechanism. Recent studies have extended our understanding of the biological functions of PCSK9, namely its implication in septic shock, vascular inflammation, viral infections (Dengue; SARS-CoV-2) or immune checkpoint modulation in cancer via the regulation of the cell surface levels of the T-cell receptor and MHC-I, which govern the antitumoral activity of CD8+ T cells. Because PCSK9 inhibition may be advantageous in these processes, the availability of injectable safe PCSK9 inhibitors that reduces by 50% to 60% LDLc above the effect of statins is highly valuable. Indeed, injectable PCSK9 monoclonal antibody or small interfering RNA could be added to current immunotherapies in cancer/metastasis.
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Affiliation(s)
- Nabil G Seidah
- Laboratory of Biochemical Neuroendocrinology, Montreal Clinical Research Institute (IRCM, affiliated to the University of Montreal), Montreal, QC, Canada
| | - Annik Prat
- Laboratory of Biochemical Neuroendocrinology, Montreal Clinical Research Institute (IRCM, affiliated to the University of Montreal), Montreal, QC, Canada
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17
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Chen F, Ni C, Wang X, Cheng R, Pan C, Wang Y, Liang J, Zhang J, Cheng J, Chin YE, Zhou Y, Wang Z, Guo Y, Chen S, Htun S, Mathes EF, de Alba Campomanes AG, Slavotinek AM, Zhang S, Li M, Yao Z. S1P defects cause a new entity of cataract, alopecia, oral mucosal disorder, and psoriasis-like syndrome. EMBO Mol Med 2022; 14:e14904. [PMID: 35362222 PMCID: PMC9081911 DOI: 10.15252/emmm.202114904] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2021] [Revised: 02/28/2022] [Accepted: 03/08/2022] [Indexed: 11/17/2022] Open
Abstract
In this report, we discovered a new entity named cataract, alopecia, oral mucosal disorder, and psoriasis‐like (CAOP) syndrome in two unrelated and ethnically diverse patients. Furthermore, patient 1 failed to respond to regular treatment. We found that CAOP syndrome was caused by an autosomal recessive defect in the mitochondrial membrane‐bound transcription factor peptidase/site‐1 protease (MBTPS1, S1P). Mitochondrial abnormalities were observed in patient 1 with CAOP syndrome. Furthermore, we found that S1P is a novel mitochondrial protein that forms a trimeric complex with ETFA/ETFB. S1P enhances ETFA/ETFB flavination and maintains its stability. Patient S1P variants destabilize ETFA/ETFB, impair mitochondrial respiration, decrease fatty acid β‐oxidation activity, and shift mitochondrial oxidative phosphorylation (OXPHOS) to glycolysis. Mitochondrial dysfunction and inflammatory lesions in patient 1 were significantly ameliorated by riboflavin supplementation, which restored the stability of ETFA/ETFB. Our study discovered that mutations in MBTPS1 resulted in a new entity of CAOP syndrome and elucidated the mechanism of the mutations in the new disease.
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Affiliation(s)
- Fuying Chen
- Department of Dermatology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.,Institute of Dermatology, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Cheng Ni
- Department of Dermatology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.,Institute of Dermatology, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Xiaoxiao Wang
- Department of Dermatology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.,Institute of Dermatology, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Ruhong Cheng
- Department of Dermatology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.,Institute of Dermatology, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Chaolan Pan
- Department of Dermatology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.,Institute of Dermatology, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Yumeng Wang
- Department of Dermatology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.,Institute of Dermatology, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Jianying Liang
- Department of Dermatology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Jia Zhang
- Department of Dermatology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Jinke Cheng
- Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Department of Biochemistry and Molecular Cell Biology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Y Eugene Chin
- Instituteof Health Sciences, Chinese Academy of Sciences, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Yi Zhou
- Department of gastroenterology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Zhen Wang
- Department of Dermatology, Children's Hospital of Shanghai Jiaotong University, Shanghai, China
| | - Yiran Guo
- Center for Data Driven Discovery in Biomedicine, Children's Hospital of Philadelphia, PA, USA
| | - She Chen
- NHC Key Laboratory of Glycoconjugate Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Stephanie Htun
- Division of Genetics, Department of Pediatrics, University of California San Francisco, San Francisco, CA, USA
| | - Erin F Mathes
- Departments of Dermatology and Pediatrics, University California, San Francisco, CA, USA
| | | | - Anne M Slavotinek
- Division of Genetics, Department of Pediatrics, University of California San Francisco, San Francisco, CA, USA
| | - Si Zhang
- NHC Key Laboratory of Glycoconjugate Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Ming Li
- Department of Dermatology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.,Institute of Dermatology, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Zhirong Yao
- Department of Dermatology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.,Institute of Dermatology, Shanghai Jiaotong University School of Medicine, Shanghai, China
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Jia L, Ma Y, Haywood J, Jiang L, Xue B, Shi H, Dawson PA, Yu L. NPC1L1 Deficiency Suppresses Ileal Fibroblast Growth Factor 15 Expression and Increases Bile Acid Pool Size in High-Fat-Diet-Fed Mice. Cells 2021; 10:3468. [PMID: 34943976 PMCID: PMC8700447 DOI: 10.3390/cells10123468] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Revised: 12/06/2021] [Accepted: 12/07/2021] [Indexed: 02/04/2023] Open
Abstract
Niemann-Pick C1-like 1 (NPC1L1) mediates intestinal uptake of dietary and biliary cholesterol and is the target of ezetimibe, a cholesterol absorption inhibitor used to treat hypercholesterolemia. Genetic deletion of NPC1L1 or ezetimibe treatment protects mice from high-fat diet (HFD)-induced obesity; however, the molecular mechanisms responsible for this therapeutic benefit remain unknown. A major metabolic fate of cholesterol is its conversion to bile acids. We found that NPC1L1 knockout (L1-KO) mice fed an HFD had increased energy expenditure, bile acid pool size, and fecal bile acid excretion rates. The elevated bile acid pool in the HFD-fed L1-KO mice was enriched with tauro-β-muricholic acid. These changes in the L1-KO mice were associated with reduced ileal mRNA expression of fibroblast growth factor 15 (FGF15) and increased hepatic mRNA expression of cholesterol 7α-hydroxylase (Cyp7A1) and mitochondrial sterol 27-hydroxylase (Cyp27A1). In addition, mRNA expression of the membrane bile acid receptor Takeda G protein-coupled receptor 5 (TGR5) and type 2 iodothyronine deiodinase (Dio2) were elevated in brown adipose tissue of L1-KO mice, which is known to promote energy expenditure. Thus, altered bile acid homeostasis and signaling may play a role in protecting L1-KO mice against HFD-induced obesity.
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Affiliation(s)
- Lin Jia
- Department of Pathology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA; (L.J.); (Y.M.); (J.H.); (P.A.D.)
- Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA
- Department of Biological Sciences, The University of Texas at Dallas, 800 W, Campbell Road, Richardson, TX 75080, USA
| | - Yinyan Ma
- Department of Pathology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA; (L.J.); (Y.M.); (J.H.); (P.A.D.)
- Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA
| | - Jamie Haywood
- Department of Pathology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA; (L.J.); (Y.M.); (J.H.); (P.A.D.)
| | - Long Jiang
- Division of Endocrinology, Diabetes and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA;
| | - Bingzhong Xue
- Department of Endocrinology and Metabolism, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA;
- Department of Biology, Georgia State University, Atlanta, GA 30303, USA;
| | - Hang Shi
- Department of Biology, Georgia State University, Atlanta, GA 30303, USA;
- Internal Medicine Section on Gerontology and Geriatric Medicine, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA
| | - Paul A. Dawson
- Department of Pathology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA; (L.J.); (Y.M.); (J.H.); (P.A.D.)
- Department of Pediatrics, Division of Gastroenterology, Hepatology, and Nutrition, Emory University, Atlanta, GA 30322, USA
| | - Liqing Yu
- Department of Pathology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA; (L.J.); (Y.M.); (J.H.); (P.A.D.)
- Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA
- Division of Endocrinology, Diabetes and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA;
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Seidah NG. The PCSK9 discovery, an inactive protease with varied functions in hypercholesterolemia, viral infections, and cancer. J Lipid Res 2021; 62:100130. [PMID: 34606887 PMCID: PMC8551645 DOI: 10.1016/j.jlr.2021.100130] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Revised: 08/19/2021] [Accepted: 08/21/2021] [Indexed: 01/06/2023] Open
Abstract
In 2003, the sequences of mammalian proprotein convertase subtilisin/kexin type 9 (PCSK9) were reported. Radiolabeling pulse-chase analyses demonstrated that PCSK9 was synthesized as a precursor (proPCSK9) that undergoes autocatalytic cleavage in the endoplasmic reticulum into PCSK9, which is then secreted as an inactive enzyme in complex with its inhibitory prodomain. Its high mRNA expression in liver hepatocytes and its gene localization on chromosome 1p32, a third locus associated with familial hypercholesterolemia, other than LDLR or APOB, led us to identify three patient families expressing the PCSK9 variants S127R or F216L. Although Pcsk9 and Ldlr were downregulated in mice that were fed a cholesterol-rich diet, PCSK9 overexpression led to the degradation of the LDLR. This led to the demonstration that gain-of-function and loss-of-function variations in PCSK9 modulate its bioactivity, whereby PCSK9 binds the LDLR in a nonenzymatic fashion to induce its degradation in endosomes/lysosomes. PCSK9 was also shown to play major roles in targeting other receptors for degradation, thereby regulating various processes, including hypercholesterolemia and associated atherosclerosis, vascular inflammation, viral infections, and immune checkpoint regulation in cancer. Injectable PCSK9 monoclonal antibody or siRNA is currently used in clinics worldwide to treat hypercholesterolemia and could be combined with current therapies in cancer/metastasis. In this review, we present the critical information that led to the discovery of PCSK9 and its implication in LDL-C metabolism. We further analyze the underlying functional mechanism(s) in the regulation of LDL-C, as well as the evolving novel roles of PCSK9 in both health and disease states.
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Affiliation(s)
- Nabil G Seidah
- Laboratory of Biochemical Neuroendocrinology, Montreal Clinical Research Institute (IRCM, affiliated to the University of Montreal), 110 Pine Ave West, Montreal, QC, H2W 1R7, Canada.
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20
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Site-1 protease controls osteoclastogenesis by mediating LC3 transcription. Cell Death Differ 2021; 28:2001-2018. [PMID: 33469231 PMCID: PMC8184842 DOI: 10.1038/s41418-020-00731-6] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Accepted: 12/29/2020] [Indexed: 01/30/2023] Open
Abstract
Site-1 protease (S1P) is a Golgi-located protein that activates unique membrane-bound latent transcription factors, and it plays an indispensable role in endoplasmic reticulum stress, lipid metabolism, inflammatory response and lysosome function. A patient with S1P mutation exhibits severe skeletal dysplasia with kyphoscoliosis, dysmorphic facial features and pectus carinatum. However, whether S1P regulates bone remodeling by affecting osteoclastogenesis remains elusive. Here, we show that S1P is indeed a positive regulator of osteoclastogenesis. S1P ablation in mice led to significant osteosclerosis compared with wild-type littermates. Mechanistically, S1P showed upregulated during osteoclastogenesis and was identified as a direct target of miR-9-5p. S1P deletion in bone marrow monocytes (BMMs) inhibited ATF6 and SREBP2 maturation, which subsequently impeded CHOP/SREBP2-complex-induced LC3 expression and autophagy flux. Consistently, transfection of LC3 adenovirus evidently rescued osteoclastogenesis in S1P-deficient BMMs. We then identified the interaction regions between CHOP and SREBP2 by Co-immunoprecipitation (Co-IP) and molecular docking. Furthermore, S1P deletion or inhibitor efficaciously rescued ovariectomized (OVX)- and LPS-induced bone loss in vivo. Collectively, we showed that S1P regulates osteoclast differentiation in a LC3 dependent manner and so is a potential therapy target for osteoporosis.
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21
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Wali JA, Solon-Biet SM, Freire T, Brandon AE. Macronutrient Determinants of Obesity, Insulin Resistance and Metabolic Health. BIOLOGY 2021; 10:336. [PMID: 33923531 PMCID: PMC8072595 DOI: 10.3390/biology10040336] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/23/2021] [Accepted: 04/07/2021] [Indexed: 01/18/2023]
Abstract
Obesity caused by the overconsumption of calories has increased to epidemic proportions. Insulin resistance is often associated with an increased adiposity and is a precipitating factor in the development of cardiovascular disease, type 2 diabetes, and altered metabolic health. Of the various factors contributing to metabolic impairments, nutrition is the major modifiable factor that can be targeted to counter the rising prevalence of obesity and metabolic diseases. However, the macronutrient composition of a nutritionally balanced "healthy diet" are unclear, and so far, no tested dietary intervention has been successful in achieving long-term compliance and reductions in body weight and associated beneficial health outcomes. In the current review, we briefly describe the role of the three major macronutrients, carbohydrates, fats, and proteins, and their role in metabolic health, and provide mechanistic insights. We also discuss how an integrated multi-dimensional approach to nutritional science could help in reconciling apparently conflicting findings.
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Affiliation(s)
- Jibran A Wali
- Charles Perkins Centre, University of Sydney, Sydney, NSW 2006, Australia
- School of Life and Environmental Sciences, Faculty of Science, University of Sydney, Sydney, NSW 2006, Australia
| | - Samantha M Solon-Biet
- Charles Perkins Centre, University of Sydney, Sydney, NSW 2006, Australia
- School of Medical Sciences, Faculty of Medicine and Health, University of Sydney, Sydney, NSW 2006, Australia
| | - Therese Freire
- Charles Perkins Centre, University of Sydney, Sydney, NSW 2006, Australia
- School of Medical Sciences, Faculty of Medicine and Health, University of Sydney, Sydney, NSW 2006, Australia
| | - Amanda E Brandon
- Charles Perkins Centre, University of Sydney, Sydney, NSW 2006, Australia
- School of Medical Sciences, Faculty of Medicine and Health, University of Sydney, Sydney, NSW 2006, Australia
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22
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Inhibitory Effects of Thymol Isolated from Curcuma longa L. on Adipogenesis in HepG2 Cells. Processes (Basel) 2020. [DOI: 10.3390/pr8091191] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a disease associated with metabolic syndromes such as diabetes and obesity, regardless of alcohol consumption, and refers to the accumulation of triacylglycerols in the liver. Thymol (THY) is a vegetable essential oil that is naturally contained in the Zingiberaceae and Lamiaceae families. THY was isolated from Curcuma longa L. The rhizomes of Curcuma longa L. were dried, sliced and extracted with 50% ethanol and then isolated through repeated column chromatography. This study was conducted to investigate the inhibitory effect of THY, even in non-alcoholic fatty liver disease, in relation to the inhibiting hyperlipidemia effect of THY, which was demonstrated in previous studies. Hepatocytes were treated with oleate (OA) containing THY to observe lipid accumulation by Oil Red O staining (ORO). We also tested the effect of THY on triacylglycerols (TG) and total cholesterol (TC) in HepG2 cells. Western blot and real-time RT-PCR using sterol regulatory element-binding protein-1c (SREBP-1c), fatty acid synthase (FAS), acetyl-CoA carboxylase (ACC), CCAAT-enhancer-binding protein (C/EBP), proliferator-activated receptor γ (PPARγ), and adenosine monophosphate (AMP)-activated protein kinase (AMPK) expressions were carried out. Consequently, inhibition of lipogenesis by THY (100 μM or 200 μM) in NAFLD treated with OA in HepG2 cells was confirmed. The results of TG and TC experiments confirmed a decrease in the degree of fat accumulation in the liver. Furthermore, inhibition of the SREBP-1c, FAS, ACC, C/EBP and PPARγ expressions that mediated fat accumulation and increased AMPK phosphorylation was observed. Taken together, THY is proposed as a potential natural constituent for the treatment of NAFLD.
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23
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Podszun MC, Alawad AS, Lingala S, Morris N, Huang WCA, Yang S, Schoenfeld M, Rolt A, Ouwerkerk R, Valdez K, Umarova R, Ma Y, Fatima SZ, Lin DD, Mahajan LS, Samala N, Violet PC, Levine M, Shamburek R, Gharib AM, Kleiner DE, Garraffo HM, Cai H, Walter PJ, Rotman Y. Vitamin E treatment in NAFLD patients demonstrates that oxidative stress drives steatosis through upregulation of de-novo lipogenesis. Redox Biol 2020; 37:101710. [PMID: 32920226 PMCID: PMC7494510 DOI: 10.1016/j.redox.2020.101710] [Citation(s) in RCA: 61] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2020] [Revised: 08/23/2020] [Accepted: 08/27/2020] [Indexed: 02/08/2023] Open
Abstract
Oxidative stress (OS) in non-alcoholic fatty liver disease (NAFLD) promotes liver injury and inflammation. Treatment with vitamin E (α-tocopherol, αT), a lipid-soluble antioxidant, improves liver injury but also decreases steatosis, thought to be upstream of OS, through an unknown mechanism. To elucidate the mechanism, we combined a mechanistic human trial interrogating pathways of intrahepatic triglyceride (IHTG) accumulation and in vitro experiments. 50% of NAFLD patients (n = 20) treated with αT (200-800 IU/d) for 24 weeks had a ≥ 25% relative decrease in IHTG by magnetic resonance spectroscopy. Paired liver biopsies at baseline and week 4 of treatment revealed a decrease in markers of hepatic de novo lipogenesis (DNL) that strongly predicted week 24 response. In vitro, using HepG2 cells and primary human hepatocytes, αT inhibited glucose-induced DNL by decreasing SREBP-1 processing and lipogenic gene expression. This mechanism is dependent on the antioxidant capacity of αT, as redox-silenced methoxy-αT is unable to inhibit DNL in vitro. OS by itself was sufficient to increase S2P expression in vitro, and S2P is upregulated in NAFLD livers. In summary, we utilized αT to demonstrate a vicious cycle in which NAFLD generates OS, which feeds back to augment DNL and increases steatosis. Clinicaltrials.gov: NCT01792115.
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Affiliation(s)
- Maren C Podszun
- Liver and Energy Metabolism Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA; Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Ahmad S Alawad
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Shilpa Lingala
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Nevitt Morris
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Wen-Chun A Huang
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Shanna Yang
- Nutrition Department, NIH Clinical Center, National Institutes of Health, Bethesda, MD, USA
| | - Megan Schoenfeld
- Nutrition Department, NIH Clinical Center, National Institutes of Health, Bethesda, MD, USA
| | - Adam Rolt
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Ronald Ouwerkerk
- Biomedical and Metabolic Imaging Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Kristin Valdez
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Regina Umarova
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Yanling Ma
- Liver and Energy Metabolism Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA; Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Syeda Zaheen Fatima
- Liver and Energy Metabolism Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA; Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Dennis D Lin
- Liver and Energy Metabolism Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA; Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Lakshmi S Mahajan
- Liver and Energy Metabolism Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA; Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Niharika Samala
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Pierre-Christian Violet
- Molecular and Clinical Nutrition Section, Digestive Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Mark Levine
- Molecular and Clinical Nutrition Section, Digestive Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Robert Shamburek
- Cardiovascular Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA
| | - Ahmed M Gharib
- Biomedical and Metabolic Imaging Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
| | - David E Kleiner
- Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - H Martin Garraffo
- Clinical Mass Spectrometry Core, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Hongyi Cai
- Clinical Mass Spectrometry Core, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Peter J Walter
- Clinical Mass Spectrometry Core, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Yaron Rotman
- Liver and Energy Metabolism Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA; Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA.
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Patra D, Kim J, Zhang Q, Tycksen E, Sandell LJ. Site-1 protease ablation in the osterix-lineage in mice results in bone marrow neutrophilia and hematopoietic stem cell alterations. Biol Open 2020; 9:bio052993. [PMID: 32576566 PMCID: PMC7328000 DOI: 10.1242/bio.052993] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2020] [Accepted: 04/24/2020] [Indexed: 01/03/2023] Open
Abstract
Site-1 protease (S1P) ablation in the osterix-lineage in mice drastically reduces bone development and downregulates bone marrow-derived skeletal stem cells. Here we show that these mice also suffer from spina bifida occulta with a characteristic lack of bone fusion in the posterior neural arches. Molecular analysis of bone marrow-derived non-red blood cell cells, via single-cell RNA-Seq and protein mass spectrometry, demonstrate that these mice have a much-altered bone marrow with a significant increase in neutrophils and Ly6C-expressing leukocytes. The molecular composition of bone marrow neutrophils is also different as they express more and additional members of the stefin A (Stfa) family of proteins. In vitro, recombinant Stfa1 and Stfa2 proteins have the ability to drastically inhibit osteogenic differentiation of bone marrow stromal cells, with no effect on adipogenic differentiation. FACS analysis of hematopoietic stem cells show that despite a decrease in hematopoietic stem cells, S1P ablation results in an increased production of granulocyte-macrophage progenitors, the precursors to neutrophils. These observations indicate that S1P has a role in the lineage specification of hematopoietic stem cells and/or their progenitors for development of a normal hematopoietic niche. Our study designates a fundamental requirement of S1P for maintaining a balanced regenerative capacity of the bone marrow niche.
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Affiliation(s)
- Debabrata Patra
- Department of Orthopaedic Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Joongho Kim
- Department of Orthopaedic Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Qiang Zhang
- Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Eric Tycksen
- McDonnell Genome Institute, Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Linda J Sandell
- Department of Orthopaedic Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA
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Liu M, Zhang G, Wu S, Song M, Wang J, Cai W, Mi S, Liu C. Schaftoside alleviates HFD-induced hepatic lipid accumulation in mice via upregulating farnesoid X receptor. JOURNAL OF ETHNOPHARMACOLOGY 2020; 255:112776. [PMID: 32205261 DOI: 10.1016/j.jep.2020.112776] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/07/2019] [Revised: 03/06/2020] [Accepted: 03/17/2020] [Indexed: 06/10/2023]
Abstract
ETHNOPHARMACOLOGY RELEVANCE The farnesoid X receptor (FXR) is a therapeutic target of for the treatment of non-alcoholic fatty liver disease (NAFLD) owing to its regulatory role in lipid homeostasis. Schaftoside (SS) is a bioactive compound of Herba Desmodii Styracifolii, which has traditionally been used to treat hepatitis and cholelithiasis. However, the potential hepatoprotective effect of SS against NAFLD and the underlying mechanisms remain unknown. AIM OF THE STUDY We investigated whether SS could improve NAFLD-induced liver injury by decreasing lipid accumulation via the activation of FXR signalling. MATERIALS AND METHODS In vivo, the effects of SS on high-fat diet (HFD)-induced lipid accumulation in the liver of mice were evaluated by serum biochemical parameters and histopathological analysis. In vitro, the intracellular triglyceride (TG) level and Oil Red O staining were used to evaluate the lipid removal ability of SS in Huh-7 cells or FXR knockout mouse primary hepatocytes (MPHs) induced by oleic acid (OA). Moreover, FXR/sterol regulatory element-binding protein 1 (SREBP1) mRNA and protein expression levels were detected. RESULTS SS reduced HFD-induced lipid accumulation in the liver, as indicated by decreased aspartate aminotransferase (AST), cholesterol (Ch), and TG levels in serum and TG levels in liver tissue, and subsequently resulting in attenuation of liver histopathological injury. Gene expression profiles demonstrated that SS dose-dependently prevented HFD-induced decrease of FXR expression and inversely inhibited SREBP1 expression in the nucleus. Furthermore, SS significantly suppressed excessive TG accumulation and decreased intracellular TG level in Huh-7 cells or MPHs via the upregulation of FXR and inhibition of SREBP1 expression in the nucleus. CONCLUSION Our results suggest that SS ameliorates HFD-induced NAFLD by the decrease of lipid accumulation via the control of FXR-SREBP1 signalling.
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Affiliation(s)
- Meijing Liu
- Beijing Advanced Innovation Center for Big Data-Based Precision Medicine, School of Biological Science and Medical Engineering, Beihang University, Beijing, 100191, China; School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510405, China
| | - Guohui Zhang
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510405, China; Zhuhai Precision Medicine Center, Zhuhai People's Hospital, Zhuhai, 519000, China
| | - Shuangcheng Wu
- The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, 510405, China
| | - Meng Song
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510405, China
| | - Jueyu Wang
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510405, China
| | - Weibin Cai
- Guangdong Second Traditional Chinese Medicine Hospital, Guangzhou University of Chinese Medicine, Guangzhou, 510095, China
| | - Suiqing Mi
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510405, China
| | - Changhui Liu
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510405, China.
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26
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Bayraktar EC, La K, Karpman K, Unlu G, Ozerdem C, Ritter DJ, Alwaseem H, Molina H, Hoffmann HH, Millner A, Atilla-Gokcumen GE, Gamazon ER, Rushing AR, Knapik EW, Basu S, Birsoy K. Metabolic coessentiality mapping identifies C12orf49 as a regulator of SREBP processing and cholesterol metabolism. Nat Metab 2020; 2:487-498. [PMID: 32694732 PMCID: PMC7384252 DOI: 10.1038/s42255-020-0206-9] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2019] [Accepted: 04/15/2020] [Indexed: 12/14/2022]
Abstract
Coessentiality mapping has been useful to systematically cluster genes into biological pathways and identify gene functions1-3. Here, using the debiased sparse partial correlation (DSPC) method3, we construct a functional coessentiality map for cellular metabolic processes across human cancer cell lines. This analysis reveals 35 modules associated with known metabolic pathways and further assigns metabolic functions to unknown genes. In particular, we identify C12orf49 as an essential regulator of cholesterol and fatty acid metabolism in mammalian cells. Mechanistically, C12orf49 localizes to the Golgi, binds membrane-bound transcription factor peptidase, site 1 (MBTPS1, site 1 protease) and is necessary for the cleavage of its substrates, including sterol regulatory element binding protein (SREBP) transcription factors. This function depends on the evolutionarily conserved uncharacterized domain (DUF2054) and promotes cell proliferation under cholesterol depletion. Notably, c12orf49 depletion in zebrafish blocks dietary lipid clearance in vivo, mimicking the phenotype of mbtps1 mutants. Finally, in an electronic health record (EHR)-linked DNA biobank, C12orf49 is associated with hyperlipidaemia through phenome analysis. Altogether, our findings reveal a conserved role for C12orf49 in cholesterol and lipid homeostasis and provide a platform to identify unknown components of other metabolic pathways.
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Affiliation(s)
- Erol C Bayraktar
- Laboratory of Metabolic Regulation and Genetics, The Rockefeller University, New York, NY, USA
| | - Konnor La
- Laboratory of Metabolic Regulation and Genetics, The Rockefeller University, New York, NY, USA
| | - Kara Karpman
- Center for Applied Mathematics, Cornell University, Ithaca, NY, USA
| | - Gokhan Unlu
- Laboratory of Metabolic Regulation and Genetics, The Rockefeller University, New York, NY, USA
- Division of Genetic Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
- Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN, USA
| | - Ceren Ozerdem
- Laboratory of Metabolic Regulation and Genetics, The Rockefeller University, New York, NY, USA
| | - Dylan J Ritter
- Division of Genetic Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
- Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN, USA
| | - Hanan Alwaseem
- Proteomics Resource Center, The Rockefeller University, New York, NY, USA
| | - Henrik Molina
- Proteomics Resource Center, The Rockefeller University, New York, NY, USA
| | - Hans-Heinrich Hoffmann
- Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY, USA
| | - Alec Millner
- Department of Chemistry, University at Buffalo, The State University of New York (SUNY), Buffalo, NY, USA
| | - G Ekin Atilla-Gokcumen
- Department of Chemistry, University at Buffalo, The State University of New York (SUNY), Buffalo, NY, USA
| | - Eric R Gamazon
- Division of Genetic Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Amy R Rushing
- Division of Genetic Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Ela W Knapik
- Division of Genetic Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
- Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN, USA
| | - Sumanta Basu
- Department of Statistics and Data Science, Cornell University, Ithaca, NY, USA
| | - Kıvanç Birsoy
- Laboratory of Metabolic Regulation and Genetics, The Rockefeller University, New York, NY, USA.
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27
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Zhou Y, Tong Z, Jiang S, Zheng W, Zhao J, Zhou X. The Roles of Endoplasmic Reticulum in NLRP3 Inflammasome Activation. Cells 2020; 9:cells9051219. [PMID: 32423023 PMCID: PMC7291288 DOI: 10.3390/cells9051219] [Citation(s) in RCA: 76] [Impact Index Per Article: 15.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2020] [Revised: 05/11/2020] [Accepted: 05/13/2020] [Indexed: 12/26/2022] Open
Abstract
The NLRP3 (nucleotide-binding domain, leucine-rich-repeat-containing family, pyrin domain-containing 3) inflammasome senses pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs), and activates caspase-1, which provokes release of proinflammatory cytokines such as interleukin-1β (IL-1β) and IL-18 as well as pyroptosis to engage in innate immune defense. The endoplasmic reticulum (ER) is a large and dynamic endomembrane compartment, critical to cellular function of organelle networks. Recent studies have unveiled the pivotal roles of the ER in NLRP3 inflammasome activation. ER–mitochondria contact sites provide a location for NLRP3 activation, its association with ligands released from or residing in mitochondria, and rapid Ca2+ mobilization from ER stores to mitochondria. ER-stress signaling plays a critical role in NLRP3 inflammasome activation. Lipid perturbation and cholesterol trafficking to the ER activate the NLRP3 inflammasome. These findings emphasize the importance of the ER in initiation and regulation of the NLRP3 inflammasome.
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Affiliation(s)
- Yang Zhou
- College of Animal Science, Southwest University, Chongqing 402460, China; (Z.T.); (S.J.); (W.Z.); (J.Z.)
- Immunology Research Center, Medical Research Institute, Southwest University, Chongqing 402460, China
- Correspondence:
| | - Zhizi Tong
- College of Animal Science, Southwest University, Chongqing 402460, China; (Z.T.); (S.J.); (W.Z.); (J.Z.)
| | - Songhong Jiang
- College of Animal Science, Southwest University, Chongqing 402460, China; (Z.T.); (S.J.); (W.Z.); (J.Z.)
| | - Wenyan Zheng
- College of Animal Science, Southwest University, Chongqing 402460, China; (Z.T.); (S.J.); (W.Z.); (J.Z.)
| | - Jianjun Zhao
- College of Animal Science, Southwest University, Chongqing 402460, China; (Z.T.); (S.J.); (W.Z.); (J.Z.)
- Immunology Research Center, Medical Research Institute, Southwest University, Chongqing 402460, China
| | - Xiangmei Zhou
- State Key Laboratories for Agrobiotechnology, Key Laboratory of Animal Epidemiology of the Ministry of Agriculture, National Animal Transmissible Spongiform Encephalopathy Laboratory, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China;
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Beneficial Effects of SREBP Decoy Oligodeoxynucleotide in an Animal Model of Hyperlipidemia. Int J Mol Sci 2020; 21:ijms21020552. [PMID: 31952262 PMCID: PMC7014099 DOI: 10.3390/ijms21020552] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2019] [Revised: 01/08/2020] [Accepted: 01/13/2020] [Indexed: 12/15/2022] Open
Abstract
Hyperlipidemia is a chronic disorder that plays an important role in the development of cardiovascular diseases, type II diabetes, atherosclerosis, hypertension, and non-alcoholic fatty liver disease. Hyperlipidemias have created a worldwide health crisis and impose a substantial burden not only on personal health but also on societies and economies. Transcription factors in the sterol regulatory element binding protein (SREBP) family are key regulators of the lipogenic genes in the liver. SREBPs regulate lipid homeostasis by controlling the expression of a range of enzymes required for the synthesis of endogenous cholesterol, fatty acids, triacylglycerol, and phospholipids. Thereby, SREBPs have been considered as targets for the treatment of metabolic diseases. The aim of this study was to investigate the beneficial functions and the possible underlying molecular mechanisms of SREBP decoy ODN, which is a novel inhibitor of SREBPs, in high-fat diet (HFD)-fed hyperlipidemic mice. Our studies using HFD-induced hyperlipidemia animal model revealed that SREBB decoy ODN inhibited the increased expression of fatty acid synthetic pathway, such as SREBP-1c, FAS, SCD-1, ACC1, and HMGCR. In addition, SREBP decoy ODN decreased pro-inflammatory cytokines, including TNF-α, IL-1β, IL-8, and IL-6 expression. These results suggest that SREBP decoy ODN exerts its anti-hyperlipidemia effects in HFD-induced hyperlipidemia mice by regulating their lipid metabolism and inhibiting lipogenesis through inactivation of the SREPB pathway.
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29
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Koundouros N, Poulogiannis G. Reprogramming of fatty acid metabolism in cancer. Br J Cancer 2020; 122:4-22. [PMID: 31819192 PMCID: PMC6964678 DOI: 10.1038/s41416-019-0650-z] [Citation(s) in RCA: 889] [Impact Index Per Article: 177.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2019] [Revised: 10/21/2019] [Accepted: 11/01/2019] [Indexed: 02/08/2023] Open
Abstract
A common feature of cancer cells is their ability to rewire their metabolism to sustain the production of ATP and macromolecules needed for cell growth, division and survival. In particular, the importance of altered fatty acid metabolism in cancer has received renewed interest as, aside their principal role as structural components of the membrane matrix, they are important secondary messengers, and can also serve as fuel sources for energy production. In this review, we will examine the mechanisms through which cancer cells rewire their fatty acid metabolism with a focus on four main areas of research. (1) The role of de novo synthesis and exogenous uptake in the cellular pool of fatty acids. (2) The mechanisms through which molecular heterogeneity and oncogenic signal transduction pathways, such as PI3K-AKT-mTOR signalling, regulate fatty acid metabolism. (3) The role of fatty acids as essential mediators of cancer progression and metastasis, through remodelling of the tumour microenvironment. (4) Therapeutic strategies and considerations for successfully targeting fatty acid metabolism in cancer. Further research focusing on the complex interplay between oncogenic signalling and dysregulated fatty acid metabolism holds great promise to uncover novel metabolic vulnerabilities and improve the efficacy of targeted therapies.
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Affiliation(s)
- Nikos Koundouros
- Signalling and Cancer Metabolism Team, Division of Cancer Biology, The Institute of Cancer Research, 237 Fulham Road, London, SW3 6JB, UK
| | - George Poulogiannis
- Signalling and Cancer Metabolism Team, Division of Cancer Biology, The Institute of Cancer Research, 237 Fulham Road, London, SW3 6JB, UK.
- Division of Computational and Systems Medicine, Department of Surgery and Cancer, Imperial College London, London, SW7 2AZ, UK.
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30
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Schweitzer GG, Gan C, Bucelli RC, Wegner D, Schmidt RE, Shinawi M, Finck BN, Brookheart RT. A mutation in Site-1 Protease is associated with a complex phenotype that includes episodic hyperCKemia and focal myoedema. Mol Genet Genomic Med 2019; 7:e00733. [PMID: 31070020 PMCID: PMC6625134 DOI: 10.1002/mgg3.733] [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: 08/20/2018] [Revised: 01/25/2019] [Accepted: 04/04/2019] [Indexed: 01/04/2023] Open
Abstract
Background Site‐1 Protease (S1P) is a Golgi‐resident protein required for the activation of regulatory proteins that drive key cellular functions, including, the unfolded protein response (UPR) and lipid and cholesterol biosynthesis. While disruptions in S1P function have been widely characterized in animal models, to date, the implications of disrupted S1P function in human disease states are not completely known. Methods The patient and both parents underwent whole exome and mitochondrial DNA sequencing, and Sanger sequencing was used to confirm the mutation. Western blotting and immunofluorescence studies were performed on either proband‐derived fibroblasts or on an established cell line to assess protein expression and cellular localization of the mutated S1P protein. Quantitative real‐time PCR and luciferase reporter assays were used to examine activation of S1P target pathways in the context of the S1P mutation. Results We describe a female patient with a de novo heterozygous missense mutation in the transmembrane domain of S1P (p. Pro1003Ser). The patient presented to our neuromuscular clinic with episodic, activity‐induced, focal myoedema and myalgias with hyperCKemia. Her clinical phenotype was complex and included gastrointestinal hypomotility, ocular migraines, and polycystic ovary syndrome. Molecular analysis using proband‐derived fibroblasts and cell lines harboring the Pro1003Ser mutation demonstrated increased activation of UPR and lipid and cholesterol regulatory pathways and localization of S1P Pro1003Ser in the Golgi. Conclusion These findings suggest a critical function for S1P in several human organ systems and implicate an important role for S1P in various human disease states.
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Affiliation(s)
- George G Schweitzer
- John T. Milliken Department of Medicine, Division of Geriatrics and Nutritional Sciences, Washington University School of Medicine, St. Louis, Missouri
| | - Connie Gan
- John T. Milliken Department of Medicine, Division of Geriatrics and Nutritional Sciences, Washington University School of Medicine, St. Louis, Missouri
| | - Robert C Bucelli
- Department of Neurology, Washington University School of Medicine, St. Louis, Missouri
| | - Daniel Wegner
- Edward Mallinckrodt Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri
| | - Robert E Schmidt
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri
| | - Marwan Shinawi
- Edward Mallinckrodt Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri.,Division of Genetics and Genomic Medicine, Washington University School of Medicine, St. Louis, Missouri
| | - Brian N Finck
- John T. Milliken Department of Medicine, Division of Geriatrics and Nutritional Sciences, Washington University School of Medicine, St. Louis, Missouri
| | - Rita T Brookheart
- John T. Milliken Department of Medicine, Division of Geriatrics and Nutritional Sciences, Washington University School of Medicine, St. Louis, Missouri
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31
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Ding S, Yuan C, Si B, Wang M, Da S, Bai L, Wu W. Combined effects of ambient particulate matter exposure and a high-fat diet on oxidative stress and steatohepatitis in mice. PLoS One 2019; 14:e0214680. [PMID: 30921449 PMCID: PMC6438678 DOI: 10.1371/journal.pone.0214680] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2018] [Accepted: 03/18/2019] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND Chronic exposure to ambient particulate matter with aerodynamic diameters < 2.5 (PM2.5) induces oxidative injury and liver pathogenesis. The present study assessed the effect and mechanism of long-term, real-world airborne particulate matter (PM) exposure on oxidative stress and hepatic steatosis in the context of a standard chow diet (STD) and a high-fat diet (HFD); the study further explored whether a combination of PM exposure and HFD treatment exacerbates the adverse effects in mice. METHODS C57BL/6J mice fed with STD or HFD (41.26% kcal fat) were exposed to PM or filtered air (FA) for 5 months. Lipid metabolism, oxidative stress and liver pathogenesis were evaluated. Real-time PCR and western blotting were performed to determine gene expression and molecular signal transduction in liver. RESULTS Chronic airborne PM exposure impaired oxidative homeostasis, caused inflammation and induced hepatic steatosis in mice. Further investigation found that exposure to real-world PM increased the expression of hepatic Nrf2 and Nrf2-regulated antioxidant enzyme gene. The increased protein expression of the sterol regulatory element binding protein-1c (SREBP-1c) and fatty acid synthase (FAS) in the liver were also observed in PM-exposed groups. Furthermore, the combination of PM exposure and HFD treatment caused a synergistic effect on the changes of lipid accumulation oxidative stress, inflammation in the mouse liver. CONCLUSIONS Through in vivo study, we reveal that the combination of real-world ambient PM exposure and HFD treatment aggravates hepatic lipid metabolism disorders, inflammation and oxidative stress. PM exposure may accelerate the progression to non-alcoholic steatohepatitis by regulating SREBP-1c/FAS regulatory axis.
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Affiliation(s)
- Shibin Ding
- Department of nutrition and food hygiene, school of public health, Xinxiang Medical University, Xinxiang, Henan Province, PR China
- Henan Collaborative Innovation Center of Molecular Diagnosis and Laboratory Medicine, Xinxiang Medical University, Xinxiang, Henan Province, PR China
- * E-mail:
| | - Chunyan Yuan
- Department of nutrition and food hygiene, school of public health, Xinxiang Medical University, Xinxiang, Henan Province, PR China
| | - Bingjie Si
- Department of nutrition and food hygiene, school of public health, Xinxiang Medical University, Xinxiang, Henan Province, PR China
| | - Mengruo Wang
- Department of nutrition and food hygiene, school of public health, Xinxiang Medical University, Xinxiang, Henan Province, PR China
| | - Shuyan Da
- Department of nutrition and food hygiene, school of public health, Xinxiang Medical University, Xinxiang, Henan Province, PR China
| | - Lanxin Bai
- Department of nutrition and food hygiene, school of public health, Xinxiang Medical University, Xinxiang, Henan Province, PR China
| | - Weidong Wu
- Department of nutrition and food hygiene, school of public health, Xinxiang Medical University, Xinxiang, Henan Province, PR China
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32
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Sasako T, Ohsugi M, Kubota N, Itoh S, Okazaki Y, Terai A, Kubota T, Yamashita S, Nakatsukasa K, Kamura T, Iwayama K, Tokuyama K, Kiyonari H, Furuta Y, Shibahara J, Fukayama M, Enooku K, Okushin K, Tsutsumi T, Tateishi R, Tobe K, Asahara H, Koike K, Kadowaki T, Ueki K. Hepatic Sdf2l1 controls feeding-induced ER stress and regulates metabolism. Nat Commun 2019; 10:947. [PMID: 30814508 PMCID: PMC6393527 DOI: 10.1038/s41467-019-08591-6] [Citation(s) in RCA: 46] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2018] [Accepted: 01/15/2019] [Indexed: 01/11/2023] Open
Abstract
Dynamic metabolic changes occur in the liver during the transition between fasting and feeding. Here we show that transient ER stress responses in the liver following feeding terminated by Sdf2l1 are essential for normal glucose and lipid homeostasis. Sdf2l1 regulates ERAD through interaction with a trafficking protein, TMED10. Suppression of Sdf2l1 expression in the liver results in insulin resistance and increases triglyceride content with sustained ER stress. In obese and diabetic mice, Sdf2l1 is downregulated due to decreased levels of nuclear XBP-1s, whereas restoration of Sdf2l1 expression ameliorates glucose intolerance and fatty liver with decreased ER stress. In diabetic patients, insufficient induction of Sdf2l1 correlates with progression of insulin resistance and steatohepatitis. Therefore, failure to build an ER stress response in the liver may be a causal factor in obesity-related diabetes and nonalcoholic steatohepatitis, for which Sdf2l1 could serve as a therapeutic target and sensitive biomarker.
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Affiliation(s)
- Takayoshi Sasako
- Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-8655, Japan.,Translational Systems Biology and Medicine Initiative (TSBMI), The University of Tokyo, Tokyo, 113-8655, Japan.,Department of Molecular Diabetic Medicine, Diabetes Research Center, National Center for Global Health and Medicine, Tokyo, 162-8655, Japan.,Division for Health Service Promotion, The University of Tokyo, Tokyo, 113-0033, Japan.,Department of Molecular Sciences on Diabetes, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-8655, Japan
| | - Mitsuru Ohsugi
- Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-8655, Japan
| | - Naoto Kubota
- Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-8655, Japan.,Translational Systems Biology and Medicine Initiative (TSBMI), The University of Tokyo, Tokyo, 113-8655, Japan.,Department of Clinical Nutrition Therapy, The University of Tokyo Hospital, The University of Tokyo, Tokyo, 113-865, Japan
| | - Shinsuke Itoh
- Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-8655, Japan.,Kowa Company Limited, Nagoya, 460-0003, Japan
| | - Yukiko Okazaki
- Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-8655, Japan.,Department of Molecular Diabetic Medicine, Diabetes Research Center, National Center for Global Health and Medicine, Tokyo, 162-8655, Japan
| | - Ai Terai
- Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-8655, Japan.,Department of Molecular Diabetic Medicine, Diabetes Research Center, National Center for Global Health and Medicine, Tokyo, 162-8655, Japan
| | - Tetsuya Kubota
- Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-8655, Japan.,Clinical Nutrition Program, National Institute of Health and Nutrition, Tokyo, 162-8636, Japan.,Division of Cardiovascular Medicine, Toho University Ohashi Medical Center, Tokyo, 143-8541, Japan
| | - Satoshi Yamashita
- Department of Systems BioMedicine, Tokyo Medical and Dental University, Tokyo, 113-8510, Japan
| | - Kunio Nakatsukasa
- Division of Biological Sciences, Graduate School of Science, Nagoya University, Nagoya, 464-8601, Japan.,Graduate School of Natural Sciences, Nagoya City University, Nagoya, 464-8601, Japan
| | - Takumi Kamura
- Division of Biological Sciences, Graduate School of Science, Nagoya University, Nagoya, 464-8601, Japan
| | - Kaito Iwayama
- Graduate School of Comprehensive Human Science, University of Tsukuba, Tsukuba, 305-8577, Japan
| | - Kumpei Tokuyama
- Graduate School of Comprehensive Human Science, University of Tsukuba, Tsukuba, 305-8577, Japan
| | - Hiroshi Kiyonari
- Animal Resource Development Unit, RIKEN Center for Life Science Technologies, Kobe, 650-0047, Japan.,Genetic Engineering Team, RIKEN Center for Life Science Technologies, Kobe, 650-0047, Japan
| | - Yasuhide Furuta
- Animal Resource Development Unit, RIKEN Center for Life Science Technologies, Kobe, 650-0047, Japan.,Genetic Engineering Team, RIKEN Center for Life Science Technologies, Kobe, 650-0047, Japan
| | - Junji Shibahara
- Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-8655, Japan
| | - Masashi Fukayama
- Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-8655, Japan
| | - Kenichiro Enooku
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-8655, Japan
| | - Kazuya Okushin
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-8655, Japan
| | - Takeya Tsutsumi
- Department of Infectious Disease, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-8655, Japan
| | - Ryosuke Tateishi
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-8655, Japan
| | - Kazuyuki Tobe
- The First Department of Internal Medicine, Graduate School of Medicine and Pharmaceutical Sciences of Research, The University of Toyama, Toyama, 930-8555, Japan
| | - Hiroshi Asahara
- Department of Systems BioMedicine, Tokyo Medical and Dental University, Tokyo, 113-8510, Japan
| | - Kazuhiko Koike
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-8655, Japan
| | - Takashi Kadowaki
- Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-8655, Japan. .,Translational Systems Biology and Medicine Initiative (TSBMI), The University of Tokyo, Tokyo, 113-8655, Japan. .,Department of Prevention of Diabetes and Lifestyle-Related Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-8655, Japan. .,Department of Metabolism and Nutrition, Mizonokuchi Hospital, Faculty of Medicine, Teikyo University, Tokyo, 213-8507, Japan.
| | - Kohjiro Ueki
- Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-8655, Japan. .,Translational Systems Biology and Medicine Initiative (TSBMI), The University of Tokyo, Tokyo, 113-8655, Japan. .,Department of Molecular Diabetic Medicine, Diabetes Research Center, National Center for Global Health and Medicine, Tokyo, 162-8655, Japan.
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33
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Kim JY, Garcia-Carbonell R, Yamachika S, Zhao P, Dhar D, Loomba R, Kaufman RJ, Saltiel AR, Karin M. ER Stress Drives Lipogenesis and Steatohepatitis via Caspase-2 Activation of S1P. Cell 2018; 175:133-145.e15. [PMID: 30220454 DOI: 10.1016/j.cell.2018.08.020] [Citation(s) in RCA: 228] [Impact Index Per Article: 32.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2017] [Revised: 05/11/2018] [Accepted: 08/10/2018] [Indexed: 02/06/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) progresses to nonalcoholic steatohepatitis (NASH) in response to elevated endoplasmic reticulum (ER) stress. Whereas the onset of simple steatosis requires elevated de novo lipogenesis, progression to NASH is triggered by accumulation of hepatocyte-free cholesterol. We now show that caspase-2, whose expression is ER-stress inducible and elevated in human and mouse NASH, controls the buildup of hepatic-free cholesterol and triglycerides by activating sterol regulatory element-binding proteins (SREBP) in a manner refractory to feedback inhibition. Caspase-2 colocalizes with site 1 protease (S1P) and cleaves it to generate a soluble active fragment that initiates SCAP-independent SREBP1/2 activation in the ER. Caspase-2 ablation or pharmacological inhibition prevents diet-induced steatosis and NASH progression in ER-stress-prone mice. Caspase-2 inhibition offers a specific and effective strategy for preventing or treating stress-driven fatty liver diseases, whereas caspase-2-generated S1P proteolytic fragments, which enter the secretory pathway, are potential NASH biomarkers.
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Affiliation(s)
- Ju Youn Kim
- Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, University of California San Diego, School of Medicine, La Jolla, CA 92093, USA
| | - Ricard Garcia-Carbonell
- Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, University of California San Diego, School of Medicine, La Jolla, CA 92093, USA
| | - Shinichiro Yamachika
- Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, University of California San Diego, School of Medicine, La Jolla, CA 92093, USA
| | - Peng Zhao
- Division of Endocrinology and Metabolism, Department of Medicine, University of California San Diego, School of Medicine, La Jolla, CA 92093, USA
| | - Debanjan Dhar
- Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, University of California San Diego, School of Medicine, La Jolla, CA 92093, USA
| | - Rohit Loomba
- NAFLD Research Center, Division of Gastroenterology, University of California San Diego, School of Medicine, La Jolla, CA 92093, USA
| | - Randal J Kaufman
- Sanford-Burnham-Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA
| | - Alan R Saltiel
- Division of Endocrinology and Metabolism, Department of Medicine, University of California San Diego, School of Medicine, La Jolla, CA 92093, USA
| | - Michael Karin
- Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, University of California San Diego, School of Medicine, La Jolla, CA 92093, USA.
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34
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Jeung WH, Shim JJ, Woo SW, Sim JH, Lee JL. Lactobacillus curvatus HY7601 and Lactobacillus plantarum KY1032 Cell Extracts Inhibit Adipogenesis in 3T3-L1 and HepG2 Cells. J Med Food 2018; 21:876-886. [PMID: 30148699 DOI: 10.1089/jmf.2017.4157] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023] Open
Abstract
Some lactic acid bacteria (LAB) and their cellular components have antiobesity effects. In this study, we evaluated the antiadipogenic effects of a mixture of two LAB-Lactobacillus curvatus HY7601 and Lactobacillus plantarum KY1032-using 3T3-L1 preadipocytes and HepG2 hepatocarcinoma cells. 3T3-L1 cells treated with a 1:1 ratio of HY7601 and KY1032 during differentiation showed reduced lipid accumulation by Oil Red O staining, as well as decreased leptin secretion and mRNA expression of peroxisome proliferator-activated receptor-γ and CCAAT/enhancer binding protein-α. HY7601 and KY1032 treatment also suppressed mitochondrial biogenesis and inhibited the expression of genes encoding mitochondrial transcription factors, as well as those related to fatty acid synthesis in HepG2 cells. The antiadipogenic effects of LAB were associated with the cell membrane fraction. These results demonstrate that a mixture of two LAB (HY7601 and KY1032) inhibits adipogenesis in preadipocytes and liver cells and is a potential therapeutic strategy for the treatment of obesity.
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Affiliation(s)
| | - Jae-Jung Shim
- 1 R&BD Center , Korea Yakult Co. Ltd., Yongin, Korea.,2 College of Agriculture and Life Sciences, Seoul National University , Seoul, Korea
| | - Seon-Wook Woo
- 1 R&BD Center , Korea Yakult Co. Ltd., Yongin, Korea
| | - Jae-Hun Sim
- 1 R&BD Center , Korea Yakult Co. Ltd., Yongin, Korea
| | - Jung-Lyoul Lee
- 1 R&BD Center , Korea Yakult Co. Ltd., Yongin, Korea.,3 College of Veterinary Medicine, Konkuk University , Seoul, Korea
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35
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Chan JP, Wong BH, Chin CF, Galam DLA, Foo JC, Wong LC, Ghosh S, Wenk MR, Cazenave-Gassiot A, Silver DL. The lysolipid transporter Mfsd2a regulates lipogenesis in the developing brain. PLoS Biol 2018; 16:e2006443. [PMID: 30074985 PMCID: PMC6093704 DOI: 10.1371/journal.pbio.2006443] [Citation(s) in RCA: 69] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2018] [Revised: 08/15/2018] [Accepted: 07/11/2018] [Indexed: 01/12/2023] Open
Abstract
Brain development requires a massive increase in brain lipogenesis and accretion of the essential omega-3 fatty acid docosahexaenoic acid (DHA). Brain acquisition of DHA is primarily mediated by the transporter Major Facilitator Superfamily Domain containing 2a (Mfsd2a) expressed in the endothelium of the blood-brain barrier (BBB) and other abundant cell types within the brain. Mfsd2a transports DHA and other polyunsaturated fatty acids (PUFAs) esterified to lysophosphatidylcholine (LPC-DHA). However, the function of Mfsd2a and DHA in brain development is incompletely understood. Here, we demonstrate, using vascular endothelial-specific and inducible vascular endothelial-specific deletion of Mfsd2a in mice, that Mfsd2a is uniquely required postnatally at the BBB for normal brain growth and DHA accretion, with DHA deficiency preceding the onset of microcephaly. In Mfsd2a-deficient mouse models, a lipidomic signature was identified that is indicative of increased de novo lipogenesis of PUFAs. Gene expression profiling analysis of these DHA-deficient brains indicated that sterol regulatory-element binding protein (Srebp)-1 and Srebp-2 pathways were highly elevated. Mechanistically, LPC-DHA treatment of primary neural stem cells down-regulated Srebp processing and activation in a Mfsd2a-dependent fashion, resulting in profound effects on phospholipid membrane saturation. In addition, Srebp regulated the expression of Mfsd2a. These data identify LPC-DHA transported by Mfsd2a as a physiological regulator of membrane phospholipid saturation acting in a feedback loop on Srebp activity during brain development. The brain is the most lipid-rich organ in the body. Brain development involves a tremendous increase in the synthesis and accretion of fatty acids. De novo synthesis of fatty acids is mediated by Srebp transcription factors, whereas acquisition of essential fatty acids via uptake of plasma-derived lysophosphatidylcholine containing the essential omega-3 fatty acid docosahexaenoic acid (LPC-DHA) is mediated by the transporter Mfsd2a in the cells that line the blood vessels in the brain. The function of Mfsd2a and DHA in brain development is incompletely understood. Our study determined that Mfsd2a is required at the blood-brain barrier for brain development and accretion of DHA after birth in mice. Moreover, we determined that a major function of DHA in the brain is to negatively regulate Srebp activation, resulting in profound effects on membrane phospholipid composition. These findings reveal that LPC-DHA transported by Mfsd2a plays a physiological role in both brain growth and in maintaining plasma membrane phospholipid composition during brain development.
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Affiliation(s)
- Jia Pei Chan
- Signature Research Program in Cardiovascular and Metabolic Disorders, Duke-NUS Medical School, Singapore, Singapore
| | - Bernice H. Wong
- Signature Research Program in Cardiovascular and Metabolic Disorders, Duke-NUS Medical School, Singapore, Singapore
| | - Cheen Fei Chin
- Signature Research Program in Cardiovascular and Metabolic Disorders, Duke-NUS Medical School, Singapore, Singapore
| | - Dwight L. A. Galam
- Signature Research Program in Cardiovascular and Metabolic Disorders, Duke-NUS Medical School, Singapore, Singapore
| | - Juat Chin Foo
- Department of Biochemistry, National University of Singapore, Singapore, Singapore
| | - Loo Chin Wong
- Signature Research Program in Cardiovascular and Metabolic Disorders, Duke-NUS Medical School, Singapore, Singapore
| | - Sujoy Ghosh
- Centre for Computational Biology, Duke-NUS Medical School, Singapore, Singapore
| | - Markus R. Wenk
- Department of Biochemistry, National University of Singapore, Singapore, Singapore
| | | | - David L. Silver
- Signature Research Program in Cardiovascular and Metabolic Disorders, Duke-NUS Medical School, Singapore, Singapore
- * E-mail:
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36
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Kondo Y, Fu J, Wang H, Hoover C, McDaniel JM, Steet R, Patra D, Song J, Pollard L, Cathey S, Yago T, Wiley G, Macwana S, Guthridge J, McGee S, Li S, Griffin C, Furukawa K, James JA, Ruan C, McEver RP, Wierenga KJ, Gaffney PM, Xia L. Site-1 protease deficiency causes human skeletal dysplasia due to defective inter-organelle protein trafficking. JCI Insight 2018; 3:121596. [PMID: 30046013 PMCID: PMC6124414 DOI: 10.1172/jci.insight.121596] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2018] [Accepted: 06/08/2018] [Indexed: 01/18/2023] Open
Abstract
Site-1 protease (S1P), encoded by MBTPS1, is a serine protease in the Golgi. S1P regulates lipogenesis, endoplasmic reticulum (ER) function, and lysosome biogenesis in mice and in cultured cells. However, how S1P differentially regulates these diverse functions in humans has been unclear. In addition, no human disease with S1P deficiency has been identified. Here, we report a pediatric patient with an amorphic and a severely hypomorphic mutation in MBTPS1. The unique combination of these mutations results in a frequency of functional MBTPS1 transcripts of approximately 1%, a finding that is associated with skeletal dysplasia and elevated blood lysosomal enzymes. We found that the residually expressed S1P is sufficient for lipid homeostasis but not for ER and lysosomal functions, especially in chondrocytes. The defective S1P function specifically impairs activation of the ER stress transducer BBF2H7, leading to ER retention of collagen in chondrocytes. S1P deficiency also causes abnormal secretion of lysosomal enzymes due to partial impairment of mannose-6-phosphate-dependent delivery to lysosomes. Collectively, these abnormalities lead to apoptosis of chondrocytes and lysosomal enzyme-mediated degradation of the bone matrix. Correction of an MBTPS1 variant or reduction of ER stress mitigated collagen-trafficking defects. These results define a new congenital human skeletal disorder and, more importantly, reveal that S1P is particularly required for skeletal development in humans. Our findings may also lead to new therapies for other genetic skeletal diseases, as ER dysfunction is common in these disorders.
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Affiliation(s)
- Yuji Kondo
- Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA
| | - Jianxin Fu
- Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA.,Jiangsu Institute of Hematology, MOH Key Laboratory of Thrombosis and Hemostasis, Collaborative Innovation Center of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | | | - Christopher Hoover
- Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA.,Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA
| | - J Michael McDaniel
- Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA
| | - Richard Steet
- Complex Carbohydrate Research Center, University of Georgia, Georgia, Athens, USA
| | - Debabrata Patra
- Department of Orthopaedic Surgery, Washington University School of Medicine, St. Louis, Missouri, USA
| | - Jianhua Song
- Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA
| | - Laura Pollard
- Greenwood Genetic Center, Greenwood, South Carolina, USA
| | - Sara Cathey
- Greenwood Genetic Center, Greenwood, South Carolina, USA
| | - Tadayuki Yago
- Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA
| | - Graham Wiley
- Division of Genomics and Data Sciences, Arthritis and Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA
| | - Susan Macwana
- Division of Genomics and Data Sciences, Arthritis and Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA
| | - Joel Guthridge
- Division of Genomics and Data Sciences, Arthritis and Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA
| | - Samuel McGee
- Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA
| | | | - Courtney Griffin
- Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA
| | - Koichi Furukawa
- Department of Biochemistry II, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Judith A James
- Division of Genomics and Data Sciences, Arthritis and Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA
| | - Changgeng Ruan
- Jiangsu Institute of Hematology, MOH Key Laboratory of Thrombosis and Hemostasis, Collaborative Innovation Center of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Rodger P McEver
- Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA.,Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA
| | | | - Patrick M Gaffney
- Division of Genomics and Data Sciences, Arthritis and Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA
| | - Lijun Xia
- Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA.,Jiangsu Institute of Hematology, MOH Key Laboratory of Thrombosis and Hemostasis, Collaborative Innovation Center of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China.,Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA
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37
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Chen JW, Kong ZL, Tsai ML, Lo CY, Ho CT, Lai CS. Tetrahydrocurcumin ameliorates free fatty acid-induced hepatic steatosis and improves insulin resistance in HepG2 cells. J Food Drug Anal 2018; 26:1075-1085. [PMID: 29976400 PMCID: PMC9303024 DOI: 10.1016/j.jfda.2018.01.005] [Citation(s) in RCA: 45] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2017] [Revised: 01/05/2018] [Accepted: 01/10/2018] [Indexed: 01/07/2023] Open
Abstract
Elevated levels of free fatty acids (FFAs) in the liver, resulting from either increased lipolysis or imbalanced FFAs flux, is a key pathogenic factor of hepatic steatosis. This study was conducted to examine the therapeutic effect of tetrahydrocurcumin (THC), a naturally occurring curcuminoid and a metabolite of curcumin, on oleic acid (OA)-induced steatosis in human hepatocellular carcinoma cells and to elucidate the underlying mechanism. HepG2 cells were incubated with OA to induce steatosis, and then treated with various concentrations of THC. The results showed that THC treatment significantly decreased lipid accumulation in OA-treated HepG2 cells, possibly, by inhibiting the expression of the lipogenic proteins, sterol regulatory element-binding protein 1 (SREBP-1c), peroxisome proliferator-activated receptor gamma (PPARγ), fatty acid synthase (FAS), and fatty acid-binding protein 4 (FABP4). Moreover, THC attenuated OA-induced hepatic lipogenesis in an adenosine monophosphate–activated protein kinase (AMPK)-dependent manner, which was reversed by pretreatment with an AMPK inhibitor. THC promoted lipolysis and upregulated the expression of genes involved in β-oxidation. Glucose uptake and insulin signaling impaired in HepG2 cells incubated with OA were abated by THC treatment, including phosphorylation of the insulin receptor substrate 1 (IRS-1)/phosphoinositide 3-kinase (PI3K)/Akt and downstream signaling pathways, forkhead box protein O1 (FOXO1) and glycogen synthase kinase 3 β (GSK3β), which are involved in gluconeogenesis and glycogen synthesis, respectively. Altogether, these results demonstrated the novel therapeutic benefit of THC against hepatic steatosis and, consequently, a potential treatment for non-alcoholic fatty liver disease (NAFLD).
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38
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Böttcher-Friebertshäuser E, Garten W, Klenk HD. Characterization of Proprotein Convertases and Their Involvement in Virus Propagation. ACTIVATION OF VIRUSES BY HOST PROTEASES 2018. [PMCID: PMC7122180 DOI: 10.1007/978-3-319-75474-1_9] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Affiliation(s)
| | - Wolfgang Garten
- Institut für Virologie, Philipps Universität, Marburg, Germany
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39
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DeBose-Boyd RA, Ye J. SREBPs in Lipid Metabolism, Insulin Signaling, and Beyond. Trends Biochem Sci 2018; 43:358-368. [PMID: 29500098 DOI: 10.1016/j.tibs.2018.01.005] [Citation(s) in RCA: 211] [Impact Index Per Article: 30.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2017] [Revised: 01/08/2018] [Accepted: 01/10/2018] [Indexed: 12/22/2022]
Abstract
Sterol regulatory element-binding proteins (SREBPs) are a family of membrane-bound transcription factors that activate genes encoding enzymes required for synthesis of cholesterol and unsaturated fatty acids. SREBPs are controlled by multiple mechanisms at the level of mRNA synthesis, proteolytic activation, and transcriptional activity. In this review, we summarize the recent findings that contribute to the current understanding of the regulation of SREBPs and their physiologic roles in maintenance of lipid homeostasis, insulin signaling, innate immunity, and cancer development.
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Affiliation(s)
- Russell A DeBose-Boyd
- Department of Molecular Genetics, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9046, USA.
| | - Jin Ye
- Department of Molecular Genetics, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9046, USA.
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40
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Patra D, DeLassus E, Mueller J, Abou-Ezzi G, Sandell LJ. Site-1 protease regulates skeletal stem cell population and osteogenic differentiation in mice. Biol Open 2018; 7:bio.032094. [PMID: 29437042 PMCID: PMC5861364 DOI: 10.1242/bio.032094] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Site-1 protease (S1P) is a proprotein convertase with essential functions in the conversion of precursor proteins to their active form. In earlier studies, we demonstrated that S1P ablation in the chondrocyte lineage results in a drastic reduction in endochondral bone formation. To investigate the mechanistic contribution of S1P to bone development we ablated S1P in the osterix lineage in mice. S1P ablation in this lineage results in osteochondrodysplasia and variable degrees of early postnatal scoliosis. Embryonically, even though Runx2 and osterix expression are normal, S1P ablation results in a delay in vascular invasion and endochondral bone development. Mice appear normal when born, but by day 7 display pronounced dwarfism with fragile bones that exhibit significantly reduced mineral density, mineral apposition rate, bone formation rate and reduced osteoblasts indicating severe osteopenia. Mice suffer from a drastic reduction in bone marrow mesenchymal progenitors as analyzed by colony-forming unit-fibroblast assay. Fluorescence-activated cell sorting analysis of the skeletal mesenchyme harvested from bone marrow and collagenase-digested bone show a drastic reduction in hematopoietic lineage-negative, endothelial-negative, CD105+ skeletal stem cells. Bone marrow mesenchymal progenitors are unable to differentiate into osteoblasts in vitro, with no effect on adipogenic differentiation. Postnatal mice have smaller growth plates with reduced hypertrophic zone. Thus, S1P controls bone development directly by regulating the skeletal progenitor population and their differentiation into osteoblasts. This article has an associated First Person interview with the first author of the paper. Summary: S1P governs a fundamental aspect of skeletal development and homeostasis, mainly the maintenance and osteogenic differentiation of skeletogenic stem cells that are a source of osteoblast and chondrocyte lineages.
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Affiliation(s)
- Debabrata Patra
- Department of Orthopaedic Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Elizabeth DeLassus
- Department of Biochemistry, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Jennifer Mueller
- Department of Orthopaedic Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Grazia Abou-Ezzi
- Department of Medicine, Oncology Division, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Linda J Sandell
- Department of Orthopaedic Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA.,Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO 63110, USA
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41
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Fang H, Xu C, Lu A, Zou CJ, Xie S, Chen Y, Zhou L, Liu M, Wang L, Wang W, Yang T. (Pro)renin receptor mediates albumin-induced cellular responses: role of site-1 protease-derived soluble (pro)renin receptor in renal epithelial cells. Am J Physiol Cell Physiol 2017; 313:C632-C643. [PMID: 28903918 DOI: 10.1152/ajpcell.00006.2017] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
Proteinuria is a characteristic of chronic kidney disease and also a causative factor that promotes the disease progression, in part, via activation of the intrarenal renin-angiotensin system (RAS). (Pro)renin receptor (PRR), a newly discovered component of the RAS, binds renin and (pro)renin to promote angiotensin I generation. The present study was performed to test the role of soluble PRR (sPRR) in albumin overload-induced responses in cultured human renal proximal tubular cell line human kidney 2 (HK-2) cells. Bovine serum albmuin (BSA) treatment for 24 h at 20 mg/ml induced renin activity and inflammation, both of which were attenuated by a PRR decoy inhibitor PRO20. BSA treatment induced a more than fivefold increase in medium sPRR due to enhanced cleavage of PRR. Surprisingly, this cleavage event was unaffected by inhibition of furin or a disintegrin and metalloproteinase 19. Screening for a novel cleavage enzyme led to the identification of site-1 protease (S1P). Inhibition of S1P with PF-429242 or siRNA remarkably suppressed BSA-induced sPRR production, renin activity, and inflammatory response. Administration of a recombinant sPRR, termed sPRR-His, reversed the effects of S1P inhibition. In HK-2 cells overexpressing PRR, mutagenesis of the S1P, but not furin cleavage site, reduced sPRR levels. Together, these results suggest that PRR mediates albumin-induced cellular responses through S1P-derived sPRR.
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Affiliation(s)
- Hui Fang
- Institute of Hypertension, Sun Yat-sen University School of Medicine , Guangzhou , China
| | - Chuanming Xu
- Institute of Hypertension, Sun Yat-sen University School of Medicine , Guangzhou , China.,Department of Internal Medicine, University of Utah School of Medicine and Veterans Affairs Medical Center , Salt Lake City, Utah
| | - Aihua Lu
- Institute of Hypertension, Sun Yat-sen University School of Medicine , Guangzhou , China
| | - Chang-Jiang Zou
- Department of Internal Medicine, University of Utah School of Medicine and Veterans Affairs Medical Center , Salt Lake City, Utah
| | - Shiying Xie
- Institute of Hypertension, Sun Yat-sen University School of Medicine , Guangzhou , China
| | - Yanting Chen
- Institute of Hypertension, Sun Yat-sen University School of Medicine , Guangzhou , China
| | - Li Zhou
- Institute of Hypertension, Sun Yat-sen University School of Medicine , Guangzhou , China
| | - Mi Liu
- Institute of Hypertension, Sun Yat-sen University School of Medicine , Guangzhou , China
| | - Lei Wang
- Institute of Hypertension, Sun Yat-sen University School of Medicine , Guangzhou , China
| | - Weidong Wang
- Institute of Hypertension, Sun Yat-sen University School of Medicine , Guangzhou , China
| | - Tianxin Yang
- Institute of Hypertension, Sun Yat-sen University School of Medicine , Guangzhou , China.,Department of Internal Medicine, University of Utah School of Medicine and Veterans Affairs Medical Center , Salt Lake City, Utah
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42
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Engelking LJ, Cantoria MJ, Xu Y, Liang G. Developmental and extrahepatic physiological functions of SREBP pathway genes in mice. Semin Cell Dev Biol 2017; 81:98-109. [PMID: 28736205 DOI: 10.1016/j.semcdb.2017.07.011] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2017] [Accepted: 07/07/2017] [Indexed: 12/17/2022]
Abstract
Sterol regulatory element-binding proteins (SREBPs), master transcriptional regulators of cholesterol and fatty acid synthesis, have been found to contribute to a diverse array of cellular processes. In this review, we focus on genetically engineered mice in which the activities of six components of the SREBP gene pathway, namely SREBP-1, SREBP-2, Scap, Insig-1, Insig-2, or Site-1 protease have been altered through gene knockout or transgenic approaches. In addition to the expected impacts on lipid metabolism, manipulation of these genes in mice is found to affect a wide array of developmental and physiologic processes ranging from interferon signaling in macrophages to synaptic transmission in the brain. The findings reviewed herein provide a blueprint to guide future studies defining the complex interactions between lipid biology and the physiologic processes of many distinct organ systems.
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Affiliation(s)
- Luke J Engelking
- Departments of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX, USA; Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA.
| | - Mary Jo Cantoria
- Departments of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Yanchao Xu
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Guosheng Liang
- Departments of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX, USA.
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43
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Rong S, McDonald JG, Engelking LJ. Cholesterol auxotrophy and intolerance to ezetimibe in mice with SREBP-2 deficiency in the intestine. J Lipid Res 2017. [PMID: 28630260 DOI: 10.1194/jlr.m077610] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023] Open
Abstract
SREBP-2 activates transcription of all genes needed for cholesterol biosynthesis. To study SREBP-2 function in the intestine, we generated a mouse model (Vil-BP2-/- ) in which Cre recombinase ablates SREBP-2 in intestinal epithelia. Intestines of Vil-BP2-/- mice had reduced expression of genes required for sterol synthesis, in vivo sterol synthesis rates, and epithelial cholesterol contents. On a cholesterol-free diet, the mice displayed chronic enteropathy with histological abnormalities of both villi and crypts, growth restriction, and reduced survival that was prevented by supplementation of cholesterol in the diet. Likewise, SREBP-2-deficient enteroids required exogenous cholesterol for growth. Blockade of luminal cholesterol uptake into enterocytes with ezetimibe precipitated acutely lethal intestinal damage in Vil-BP2-/- mice, highlighting the critical interplay in the small intestine of sterol absorption via NPC1L1 and sterol synthesis via SREBP-2 in sustaining the intestinal mucosa. These data show that the small intestine requires SREBP-2 to drive cholesterol synthesis that sustains the intestinal epithelia when uptake of cholesterol from the gut lumen is not available, and provide a unique example of cholesterol auxotrophy expressed in an intact, adult mammal.
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Affiliation(s)
- Shunxing Rong
- Departments of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390-9046
| | - Jeffrey G McDonald
- Departments of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390-9046.,Center for Human Nutrition, University of Texas Southwestern Medical Center, Dallas, TX 75390-9046
| | - Luke J Engelking
- Departments of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390-9046 .,Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390-9046
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44
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Schmitt M, Dehay B, Bezard E, Garcia-Ladona FJ. U18666A, an activator of sterol regulatory element binding protein pathway, modulates presynaptic dopaminergic phenotype of SH-SY5Y neuroblastoma cells. Synapse 2017; 71. [DOI: 10.1002/syn.21980] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2016] [Revised: 03/22/2017] [Accepted: 04/10/2017] [Indexed: 11/06/2022]
Affiliation(s)
- Mathieu Schmitt
- Neuroscience Therapeutic Area, New Medicines, UCB Biopharma SPRL; 1420 Braine l'Alleud Belgium
- Univ. de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293; Bordeaux 33000 France
- CNRS, Institut des Maladies Neurodégénératives, UMR 5293; Bordeaux 33000 France
| | - Benjamin Dehay
- Univ. de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293; Bordeaux 33000 France
- CNRS, Institut des Maladies Neurodégénératives, UMR 5293; Bordeaux 33000 France
| | - Erwan Bezard
- Univ. de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293; Bordeaux 33000 France
- CNRS, Institut des Maladies Neurodégénératives, UMR 5293; Bordeaux 33000 France
| | - F. Javier Garcia-Ladona
- Neuroscience Therapeutic Area, New Medicines, UCB Biopharma SPRL; 1420 Braine l'Alleud Belgium
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45
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Nakagawa T, Suzuki-Nakagawa C, Watanabe A, Asami E, Matsumoto M, Nakano M, Ebihara A, Uddin MN, Suzuki F. Site-1 protease is required for the generation of soluble (pro)renin receptor. J Biochem 2017; 161:369-379. [PMID: 28013223 DOI: 10.1093/jb/mvw080] [Citation(s) in RCA: 74] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2016] [Accepted: 11/03/2016] [Indexed: 11/13/2022] Open
Abstract
The extracellular domain of the (pro)renin receptor [(P)RR] is cleaved to generate the soluble form of (P)RR [s(P)RR]. Multiple clinical studies have revealed the association between serum/plasma s(P)RR levels and certain diseases, thereby suggesting a potential role for s(P)RR as a disease biomarker. Here, we investigated whether site-1 protease (S1P) is responsible for cleaving (P)RR to generate s(P)RR. Reduction of endogenous S1P with siRNA attenuated s(P)RR generation in Chinese hamster ovary (CHO) cells exogenously expressing human (P)RR with a C-terminal decahistidine tag [CHO/h(P)RR-10His cells]; conversely, overexpression of S1P by transient transfection increased s(P)RR generation. The S1P inhibitor PF429242 suppressed s(P)RR generation in CHO/h(P)RR-10His and human cervical carcinoma HeLa cells; however, the ADAM inhibitor GM6001 had no effect. The furin inhibitor Dec-RVKR-CMK had no effect on the amount of s(P)RR, but caused a slight increase in the size of the s(P)RR. Moreover, the reversible vesicle-trafficking inhibitor brefeldin A (BFA) enhanced the generation of large-sized s(P)RR; PF429242, but not Dec-RVKR-CMK, suppressed this BFA-induced s(P)RR formation. The size of s(P)RR generated during BFA treatment was reduced after removal of BFA; Dec-RVKR-CMK, but not PF429242, suppressed this conversion. Together, these results suggest that s(P)RR is generated by sequential processing by S1P and furin.
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Affiliation(s)
- Tsutomu Nakagawa
- Department of Applied Life Science, Faculty of Applied Biological Sciences, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan
| | - Chiharu Suzuki-Nakagawa
- Department of Applied Life Science, Faculty of Applied Biological Sciences, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan
| | - Akiko Watanabe
- Department of Applied Life Science, Graduate School of Applied Biological Sciences, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan
| | - Eriko Asami
- Department of Applied Life Science, Graduate School of Applied Biological Sciences, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan
| | - Mizuki Matsumoto
- Department of Applied Life Science, Faculty of Applied Biological Sciences, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan
| | - Mami Nakano
- Department of Applied Life Science, Faculty of Applied Biological Sciences, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan
| | - Akio Ebihara
- Department of Applied Life Science, Faculty of Applied Biological Sciences, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan
| | - Mohammad Nasir Uddin
- Department of Obstetrics & Gynecology, Scott & White Healthcare and Texas A&M Health Science Center College of Medicine, Temple, TX 76508, USA
| | - Fumiaki Suzuki
- Department of Applied Life Science, Faculty of Applied Biological Sciences, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan
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Human Subtilisin Kexin Isozyme-1 (SKI-1)/Site-1 Protease (S1P) regulates cytoplasmic lipid droplet abundance: A potential target for indirect-acting anti-dengue virus agents. PLoS One 2017; 12:e0174483. [PMID: 28339489 PMCID: PMC5365115 DOI: 10.1371/journal.pone.0174483] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2016] [Accepted: 03/09/2017] [Indexed: 01/12/2023] Open
Abstract
Viral hijacking and manipulation of host-cell biosynthetic pathways by human enveloped viruses are shared molecular events essential for the viral lifecycle. For Flaviviridae members such as hepatitis C virus and dengue virus (DENV), one of the key subsets of cellular pathways that undergo manipulation is the lipid metabolic pathways, underlining the importance of cellular lipids and, in particular, lipid droplets (LDs) in viral infection. Here, we hypothesize that targeting cellular enzymes that act as key regulators of lipid homeostasis and LD formation could represent a powerful approach to developing a novel class of broad-spectrum antivirals against infection associated with all DENV serotypes (1–4) circulating around the world. Using PF-429242, an active-site-directed inhibitor of SKI-1/S1P, we demonstrate that inhibition of SKI-1/S1P enzymatic activity in human hepatoma Huh-7.5.1 cells results in a robust reduction of the LD numbers and LD-positive areas and provides a means of effectively inhibiting infection by DENV (1–4). Pre-treatment of Huh-7.5.1 cells with PF-429242 results in a dose-dependent inhibition of DENV infection [median inhibitory dose (EC50) = 1.2 microM; median cytotoxic dose (CC50) = 81 microM; selectivity index (SI) = 68)] and a ~3-log decrease in DENV-2 titer with 20 microM of PF-429242. Post-treatment of DENV-2 infected Huh-7.5.1 cells with PF-429242 does not affect viral RNA abundance, but it does compromise the assembly and/or release of infectious virus particles. PF-429242 antiviral activity is reversed by exogenous oleic acid, which acts as an inducer of LD formation in PF-429242-treated and non-treated control cells. Collectively, our results demonstrate that human SKI-1/S1P is a potential target for indirect-acting pan-serotypic anti-DENV agents and reveal new therapeutic opportunities associated with the use of lipid-modulating drugs for controlling DENV infection.
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47
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Somatic genome editing with CRISPR/Cas9 generates and corrects a metabolic disease. Sci Rep 2017; 7:44624. [PMID: 28300165 PMCID: PMC5353616 DOI: 10.1038/srep44624] [Citation(s) in RCA: 75] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2016] [Accepted: 02/09/2017] [Indexed: 12/14/2022] Open
Abstract
Germline manipulation using CRISPR/Cas9 genome editing has dramatically accelerated the generation of new mouse models. Nonetheless, many metabolic disease models still depend upon laborious germline targeting, and are further complicated by the need to avoid developmental phenotypes. We sought to address these experimental limitations by generating somatic mutations in the adult liver using CRISPR/Cas9, as a new strategy to model metabolic disorders. As proof-of-principle, we targeted the low-density lipoprotein receptor (Ldlr), which when deleted, leads to severe hypercholesterolemia and atherosclerosis. Here we show that hepatic disruption of Ldlr with AAV-CRISPR results in severe hypercholesterolemia and atherosclerosis. We further demonstrate that co-disruption of Apob, whose germline loss is embryonically lethal, completely prevented disease through compensatory inhibition of hepatic LDL production. This new concept of metabolic disease modeling by somatic genome editing could be applied to many other systemic as well as liver-restricted disorders which are difficult to study by germline manipulation.
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Rong S, Cortés VA, Rashid S, Anderson NN, McDonald JG, Liang G, Moon YA, Hammer RE, Horton JD. Expression of SREBP-1c Requires SREBP-2-mediated Generation of a Sterol Ligand for LXR in Livers of Mice. eLife 2017; 6. [PMID: 28244871 PMCID: PMC5348127 DOI: 10.7554/elife.25015] [Citation(s) in RCA: 85] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2017] [Accepted: 02/26/2017] [Indexed: 01/04/2023] Open
Abstract
The synthesis of cholesterol and fatty acids (FA) in the liver is independently regulated by SREBP-2 and SREBP-1c, respectively. Here, we genetically deleted Srebf-2 from hepatocytes and confirmed that SREBP-2 regulates all genes involved in cholesterol biosynthesis, the LDL receptor, and PCSK9; a secreted protein that degrades LDL receptors in the liver. Surprisingly, we found that elimination of Srebf-2 in hepatocytes of mice also markedly reduced SREBP-1c and the expression of all genes involved in FA and triglyceride synthesis that are normally regulated by SREBP-1c. The nuclear receptor LXR is necessary for Srebf-1c transcription. The deletion of Srebf-2 and subsequent lower sterol synthesis in hepatocytes eliminated the production of an endogenous sterol ligand required for LXR activity and SREBP-1c expression. These studies demonstrate that cholesterol and FA synthesis in hepatocytes are coupled and that flux through the cholesterol biosynthetic pathway is required for the maximal SREBP-1c expression and high rates of FA synthesis.
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Affiliation(s)
- Shunxing Rong
- Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, United States
| | - Víctor A Cortés
- Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, United States
| | - Shirya Rashid
- Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, United States
| | - Norma N Anderson
- Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, United States
| | - Jeffrey G McDonald
- Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, United States
| | - Guosheng Liang
- Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, United States
| | - Young-Ah Moon
- Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, United States
| | - Robert E Hammer
- Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, United States
| | - Jay D Horton
- Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, United States.,Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, United States
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Seidah NG, Abifadel M, Prost S, Boileau C, Prat A. The Proprotein Convertases in Hypercholesterolemia and Cardiovascular Diseases: Emphasis on Proprotein Convertase Subtilisin/Kexin 9. Pharmacol Rev 2016; 69:33-52. [DOI: 10.1124/pr.116.012989] [Citation(s) in RCA: 74] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
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Randy A, Kim M, Nho CW. Ligularia fischeri and its constituent 3,4-dicaffeoylquinic acid improve obesity-induced nonalcoholic fatty liver disease by regulating lipid metabolism and activating AMPK. J Funct Foods 2016. [DOI: 10.1016/j.jff.2016.08.050] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
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