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Zheng L, Li B, Yuan A, Bi S, Puscher H, Liu C, Qiao L, Qiao Y, Wang S, Zhang Y. TFEB activator tanshinone IIA and derivatives derived from Salvia miltiorrhiza Bge. Attenuate hepatic steatosis and insulin resistance. JOURNAL OF ETHNOPHARMACOLOGY 2024; 335:118662. [PMID: 39117022 DOI: 10.1016/j.jep.2024.118662] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/05/2024] [Revised: 07/03/2024] [Accepted: 08/01/2024] [Indexed: 08/10/2024]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Salvia miltiorrhiza Bge. (SMB) is an herbal medicine extensively used for improving metabolic disorders, including Nonalcoholic fatty liver disease (NAFLD). However, the potential material basis and working mechanism still remained to be elucidated. AIM OF THE STUDY To find potential ingredients for therapy of NAFLD by high content screening and further verify the efficacy on restoring hepatic steatosis and insulin resistance, and clarify the potential working mechanism. MATERIALS AND METHODS The mouse transcription factor EB (Tfeb) in preadipocytes was knocked out by CRISPR-Cas9 gene editing. High content screening of TFEB nuclear translocation was performed to identify TFEB activators. The effect of candidate compounds on reducing lipid accumulation was evaluated using Caenorhabditis elegans (C. elegans). Then the role of Salvia miltiorrhiza extract (SMB) containing Tanshinone IIA and the derivatives were further investigated on high-fat diet (HFD) fed mice. RNA-seq was performed to explore potential molecular mechanism of SMB. Finally, the gut microbiota diversity was evaluated using 16S rRNA sequencing to investigate the protective role of SMB on regulating gut microbiota homeostasis. RESULTS Knockout of Tfeb led to excessive lipid accumulation in adipocytes while expression of TFEB homolog HLH-30 in C. elegans (MAH240) attenuated lipid deposition. Screening of TFEB activators identified multiple candidates from Salvia miltiorrhiza, all of them markedly induced lysosome biogenesis in HepG2 cells. One of the candidate compounds Tanshinone IIA significantly decreased lipid droplet deposition in HFD fed C. elegans. Administration of SMB on C57BL/6J mice via gastric irrigation at the dose of 15 g/kg/d markedly alleviated hepatic steatosis, restored serum lipid profile, and glucose tolerance. RNA-seq showed that gene expression profile was altered and the genes related to lipid metabolism were restored. The disordered microbiome was remodeled by SMB, Firmicutes and Actinobacteriotawere notably reduced, Bacteroidota and Verrucomicrobiota were significantly increased. CONCLUSION Taken together, the observations presented here help address the question concerning what were the main active ingredients in SMB for alleviating NAFLD, and established that targeting TFEB was key molecular basis for the efficacy of SMB.
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Affiliation(s)
- Lulu Zheng
- Key Laboratory of TCM-information Engineer of State Administration of TCM, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beisanhuan East Road No. 11, Chaoyang District, Beijing, 100029, China
| | - Beiyan Li
- Key Laboratory of TCM-information Engineer of State Administration of TCM, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beisanhuan East Road No. 11, Chaoyang District, Beijing, 100029, China
| | - Anlei Yuan
- Key Laboratory of TCM-information Engineer of State Administration of TCM, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beisanhuan East Road No. 11, Chaoyang District, Beijing, 100029, China
| | - Shijie Bi
- Key Laboratory of TCM-information Engineer of State Administration of TCM, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beisanhuan East Road No. 11, Chaoyang District, Beijing, 100029, China
| | - Harrison Puscher
- Department of Molecular, Cellular and Developmental Biology, University of Colorado, Boulder, CO, 80309, USA
| | - Chaoqun Liu
- Key Laboratory of TCM-information Engineer of State Administration of TCM, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beisanhuan East Road No. 11, Chaoyang District, Beijing, 100029, China
| | - Liansheng Qiao
- Key Laboratory of TCM-information Engineer of State Administration of TCM, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beisanhuan East Road No. 11, Chaoyang District, Beijing, 100029, China
| | - Yanjiang Qiao
- Key Laboratory of TCM-information Engineer of State Administration of TCM, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beisanhuan East Road No. 11, Chaoyang District, Beijing, 100029, China
| | - Shifeng Wang
- Key Laboratory of TCM-information Engineer of State Administration of TCM, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beisanhuan East Road No. 11, Chaoyang District, Beijing, 100029, China.
| | - Yanling Zhang
- Key Laboratory of TCM-information Engineer of State Administration of TCM, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beisanhuan East Road No. 11, Chaoyang District, Beijing, 100029, China.
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Ding Z, Song H, Wang F. Role of lipins in cardiovascular diseases. Lipids Health Dis 2023; 22:196. [PMID: 37964368 PMCID: PMC10644651 DOI: 10.1186/s12944-023-01961-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2023] [Accepted: 11/01/2023] [Indexed: 11/16/2023] Open
Abstract
Lipin family members in mammals include lipins 1, 2, and 3. Lipin family proteins play a crucial role in lipid metabolism due to their bifunctionality as both transcriptional coregulators and phosphatidate phosphatase (PAP) enzymes. In this review, we discuss the structural features, expression patterns, and pathophysiologic functions of lipins, emphasizing their direct as well as indirect roles in cardiovascular diseases (CVDs). Elucidating the regulation of lipins facilitates a deeper understanding of the roles of lipins in the processes underlying CVDs. The activity of lipins is modulated at various levels, e.g., in the form of the transcription of genes, post-translational modifications, and subcellular protein localization. Because lipin characteristics are undergoing progressive clarification, further research is necessitated to then actuate the investigation of lipins as viable therapeutic targets in CVDs.
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Affiliation(s)
- Zerui Ding
- The Endocrinology Department of the Third Xiangya Hospital, Central South University, Changsha, 410013, China
- Xiangya School of Medicine, Central South University, Changsha, 410013, China
| | - Hongyu Song
- The Endocrinology Department of the Third Xiangya Hospital, Central South University, Changsha, 410013, China
- Xiangya School of Medicine, Central South University, Changsha, 410013, China
| | - Fang Wang
- The Endocrinology Department of the Third Xiangya Hospital, Central South University, Changsha, 410013, China.
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Singh SP, Anirvan P, Khandelwal R, Satapathy SK. Nonalcoholic Fatty Liver Disease (NAFLD) Name Change: Requiem or Reveille? J Clin Transl Hepatol 2021; 9:931-938. [PMID: 34966656 PMCID: PMC8666378 DOI: 10.14218/jcth.2021.00174] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2021] [Revised: 06/21/2021] [Accepted: 07/18/2021] [Indexed: 12/04/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) affects about a quarter of the world's population and poses a major health and economic burden globally. Recently, there have been hasty attempts to rename NAFLD to metabolic-associated fatty liver disease (MAFLD) despite the fact that there is no scientific rationale for this. Quest for a "positive criterion" to diagnose the disease and destigmatizing the disease have been the main reasons put forth for the name change. A close scrutiny of the pathogenesis of NAFLD would make it clear that NAFLD is a heterogeneous disorder, involving different pathogenic mechanisms of which metabolic dysfunction-driven hepatic steatosis is only one. Replacing NAFLD with MAFLD would neither enhance the legitimacy of clinical practice and clinical trials, nor improve clinical care or move NAFLD research forward. Rather than changing the nomenclature without a strong scientific backing to support such a change, efforts should be directed at understanding NAFLD pathogenesis across diverse populations and ethnicities which could potentially help develop newer therapeutic options.
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Affiliation(s)
- Shivaram P. Singh
- Department of Gastroenterology, Sriram Chandra Bhanj Medical College, Cuttack, Odisha, India
| | - Prajna Anirvan
- Department of Gastroenterology, Sriram Chandra Bhanj Medical College, Cuttack, Odisha, India
| | - Reshu Khandelwal
- Department of Gastroenterology, Sriram Chandra Bhanj Medical College, Cuttack, Odisha, India
| | - Sanjaya K. Satapathy
- Division of Hepatology, Sandra Atlas Bass Center for Liver Diseases and Transplantation, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell Health, Manhasset, NY, USA
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Villani R, Magnati GP, De Girolamo G, Sangineto M, Romano AD, Cassano T, Serviddio G. Genetic Polymorphisms and Clinical Features in Diabetic Patients With Fatty Liver: Results From a Single-Center Experience in Southern Italy. Front Med (Lausanne) 2021; 8:737759. [PMID: 34746177 PMCID: PMC8566437 DOI: 10.3389/fmed.2021.737759] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2021] [Accepted: 09/10/2021] [Indexed: 12/12/2022] Open
Abstract
Genetic background may be involved in the promotion and progression of non-alcoholic fatty liver disease (NAFLD). Previous studies have suggested that the single nucleotide polymorphisms (SNPs) may be associated with the specific clinical features in the patients with hepatic steatosis; however, data on the patients with diabetes from Southern Italy are lacking. We enrolled 454 patients and 260 of them had type 2 diabetes. We studied the PNPLA3 rs738409, LPIN1 rs13412852, KLF6 rs3750861, SOD2 rs4880, TM6SF2 rs58542926, and ZNF624 rs12603226 SNPs and their distribution in the study population. Lipid profile, liver stiffness, and kidney function were also studied to understand the potential role of the SNPs in the development of clinical phenotypes. No differences were observed in the distribution of polymorphisms between the diabetic and non-diabetic subjects. Carriers of risk allele G for PNPLA3 rs738409 SNP showed a lower mean value of serum triglycerides and a higher liver stiffness. Risk allele for KLF6 rs3750861 and SOD2 rs4880 polymorphism had a lower estimated glomerular filtration rate (eGFR) value, whereas no differences in the glucose and glycated hemoglobin level were observed in the subgroups by the different genotypes. Genetic polymorphisms are useful to identify the patients at higher risk of development of liver fibrosis and lower eGFR values in the patients with diabetes and NAFLD. Their use in clinical practice may help the clinicians to identify the patients who require a more strict follow-up program.
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Affiliation(s)
- Rosanna Villani
- C.U.R.E. (University Centre for Liver Disease Research and Treatment), Liver Unit, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
| | - Grazia Pia Magnati
- C.U.R.E. (University Centre for Liver Disease Research and Treatment), Liver Unit, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
| | - Giuseppe De Girolamo
- C.U.R.E. (University Centre for Liver Disease Research and Treatment), Liver Unit, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
| | - Moris Sangineto
- C.U.R.E. (University Centre for Liver Disease Research and Treatment), Liver Unit, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
| | - Antonino Davide Romano
- C.U.R.E. (University Centre for Liver Disease Research and Treatment), Liver Unit, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
| | - Tommaso Cassano
- Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
| | - Gaetano Serviddio
- C.U.R.E. (University Centre for Liver Disease Research and Treatment), Liver Unit, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
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Jonas W, Schürmann A. Genetic and epigenetic factors determining NAFLD risk. Mol Metab 2020; 50:101111. [PMID: 33160101 PMCID: PMC8324682 DOI: 10.1016/j.molmet.2020.101111] [Citation(s) in RCA: 102] [Impact Index Per Article: 20.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2020] [Revised: 10/27/2020] [Accepted: 11/03/2020] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Hepatic steatosis is a common chronic liver disease that can progress into more severe stages of NAFLD or promote the development of life-threatening secondary diseases for some of those affected. These include the liver itself (nonalcoholic steatohepatitis or NASH; fibrosis and cirrhosis, and hepatocellular carcinoma) or other organs such as the vessels and the heart (cardiovascular disease) or the islets of Langerhans (type 2 diabetes). In addition to elevated caloric intake and a sedentary lifestyle, genetic and epigenetic predisposition contribute to the development of NAFLD and the secondary diseases. SCOPE OF REVIEW We present data from genome-wide association studies (GWAS) and functional studies in rodents which describe polymorphisms identified in genes relevant for the disease as well as changes caused by altered DNA methylation and gene regulation via specific miRNAs. The review also provides information on the current status of the use of genetic and epigenetic factors as risk markers. MAJOR CONCLUSION With our overview we provide an insight into the genetic and epigenetic landscape of NAFLD and argue about the applicability of currently defined risk scores for risk stratification and conclude that further efforts are needed to make the scores more usable and meaningful.
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Affiliation(s)
- Wenke Jonas
- Department of Experimental Diabetology, German Institute of Human Nutrition Potsdam-Rehbruecke, Arthur-Scheunert-Allee 114-116, D-14558, Nuthetal, Germany; German Center for Diabetes Research (DZD), Ingolstädter Landstraße 1, D-85764, München-Neuherberg, Germany
| | - Annette Schürmann
- Department of Experimental Diabetology, German Institute of Human Nutrition Potsdam-Rehbruecke, Arthur-Scheunert-Allee 114-116, D-14558, Nuthetal, Germany; German Center for Diabetes Research (DZD), Ingolstädter Landstraße 1, D-85764, München-Neuherberg, Germany; University of Potsdam, Institute of Nutritional Sciences, Arthur-Scheunert-Allee 114-116, D-14558, Nuthetal, Germany; Faculty of Health Sciences, Joint Faculty of the Brandenburg University of Technology, Cottbus-Senftenberg, The Brandenburg Medical School Theodor Fontane and the University of Potsdam, Potsdam, Germany.
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Jung Y, Kwon S, Ham S, Lee D, Park HH, Yamaoka Y, Jeong D, Artan M, Altintas O, Park S, Hwang W, Lee Y, Son HG, An SWA, Kim EJE, Seo M, Lee SV. Caenorhabditis elegans Lipin 1 moderates the lifespan-shortening effects of dietary glucose by maintaining ω-6 polyunsaturated fatty acids. Aging Cell 2020; 19:e13150. [PMID: 32475074 PMCID: PMC7294780 DOI: 10.1111/acel.13150] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2019] [Revised: 02/19/2020] [Accepted: 03/16/2020] [Indexed: 12/15/2022] Open
Abstract
Excessive glucose causes various diseases and decreases lifespan by altering metabolic processes, but underlying mechanisms remain incompletely understood. Here, we show that Lipin 1/LPIN-1, a phosphatidic acid phosphatase and a putative transcriptional coregulator, prevents life-shortening effects of dietary glucose on Caenorhabditis elegans. We found that depletion of lpin-1 decreased overall lipid levels, despite increasing the expression of genes that promote fat synthesis and desaturation, and downregulation of lipolysis. We then showed that knockdown of lpin-1 altered the composition of various fatty acids in the opposite direction of dietary glucose. In particular, the levels of two ω-6 polyunsaturated fatty acids (PUFAs), linoleic acid and arachidonic acid, were increased by knockdown of lpin-1 but decreased by glucose feeding. Importantly, these ω-6 PUFAs attenuated the short lifespan of glucose-fed lpin-1-inhibited animals. Thus, the production of ω-6 PUFAs is crucial for protecting animals from living very short under glucose-rich conditions.
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Affiliation(s)
- Yoonji Jung
- Department of Biological Sciences Korea Advanced Institute of Science and Technology Daejeon South Korea
| | - Sujeong Kwon
- Department of Biological Sciences Korea Advanced Institute of Science and Technology Daejeon South Korea
| | - Seokjin Ham
- Department of Biological Sciences Korea Advanced Institute of Science and Technology Daejeon South Korea
| | - Dongyeop Lee
- Department of Life Sciences Pohang University of Science and Technology Pohang South Korea
| | - Hae‐Eun H. Park
- Department of Biological Sciences Korea Advanced Institute of Science and Technology Daejeon South Korea
| | - Yasuyo Yamaoka
- Department of Life Sciences Pohang University of Science and Technology Pohang South Korea
| | - Dae‐Eun Jeong
- Department of Life Sciences Pohang University of Science and Technology Pohang South Korea
| | - Murat Artan
- Department of Life Sciences Pohang University of Science and Technology Pohang South Korea
| | - Ozlem Altintas
- School of Interdisciplinary Bioscience and Bioengineering Pohang University of Science and Technology Pohang South Korea
| | - Sangsoon Park
- Department of Life Sciences Pohang University of Science and Technology Pohang South Korea
| | - Wooseon Hwang
- Department of Life Sciences Pohang University of Science and Technology Pohang South Korea
| | - Yujin Lee
- Department of Biological Sciences Korea Advanced Institute of Science and Technology Daejeon South Korea
| | - Heehwa G. Son
- Department of Biological Sciences Korea Advanced Institute of Science and Technology Daejeon South Korea
| | - Seon Woo A. An
- Department of Biological Sciences Korea Advanced Institute of Science and Technology Daejeon South Korea
| | - Eun Ji E. Kim
- Department of Biological Sciences Korea Advanced Institute of Science and Technology Daejeon South Korea
| | - Mihwa Seo
- Department of Life Sciences Pohang University of Science and Technology Pohang South Korea
| | - Seung‐Jae V. Lee
- Department of Biological Sciences Korea Advanced Institute of Science and Technology Daejeon South Korea
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Wang G, Zhou H, Gong H, He J, Luo Y, Hickford JGH, Hu J, Wang J, Liu X, Li S. Variation in the Lipin 1 Gene Is Associated with Birth Weight and Selected Carcass Traits in New Zealand Romney Sheep. Animals (Basel) 2020; 10:ani10020237. [PMID: 32028610 PMCID: PMC7071029 DOI: 10.3390/ani10020237] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2019] [Revised: 01/23/2020] [Accepted: 01/30/2020] [Indexed: 11/16/2022] Open
Abstract
Lipin 1 plays an important role in lipid metabolism. In this study; we searched for variation in the ovine lipin 1 gene (LPIN1) in three gene regions (a 5' non-coding region; a region containing an alternatively spliced exon in intron 4; and a region containing coding exon 6) using polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) analysis. The greatest amount of alleles was found in coding exon 6; with five sequences being detected. The effect of variation in this exon was investigated in 242 New Zealand Romney lambs derived from 12 sire-lines. The presence of variant E3 was associated with a decrease in birth weight (p = 0.005) and the proportion of leg yield (p = 0.045), but with an increase in hot carcass weight (p = 0.032) and the proportion of loin yield (p = 0.014). The presence of variant B3 was associated with an increased pre-weaning growth rate (p = 0.041), whereas the presence of variant C3 was associated with an increase in shoulder yield (p < 0.001). These results suggest that ovine LPIN1 variation may have value as a genetic marker for improving meat production and carcass traits.
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Affiliation(s)
- Guan Wang
- Gansu Key Laboratory of Herbivorous Animal Biotechnology, Faculty of Animal Science and Technology, Gansu Agricultural University, Lanzhou 730070, China
- International Wool Research Institute, Gansu Agricultural University, Lanzhou 730070, China
| | - Huitong Zhou
- Gansu Key Laboratory of Herbivorous Animal Biotechnology, Faculty of Animal Science and Technology, Gansu Agricultural University, Lanzhou 730070, China
- International Wool Research Institute, Gansu Agricultural University, Lanzhou 730070, China
- Gene-Marker Laboratory, Faculty of Agriculture and Life Sciences, Lincoln University, Lincoln 7647, New Zealand
| | - Hua Gong
- International Wool Research Institute, Gansu Agricultural University, Lanzhou 730070, China
- Gene-Marker Laboratory, Faculty of Agriculture and Life Sciences, Lincoln University, Lincoln 7647, New Zealand
| | - Jianning He
- College of Animal Science and Technology, Qingdao Agricultural University, Qingdao 266109, China
| | - Yuzhu Luo
- Gansu Key Laboratory of Herbivorous Animal Biotechnology, Faculty of Animal Science and Technology, Gansu Agricultural University, Lanzhou 730070, China
- International Wool Research Institute, Gansu Agricultural University, Lanzhou 730070, China
| | - Jon G H Hickford
- International Wool Research Institute, Gansu Agricultural University, Lanzhou 730070, China
- Gene-Marker Laboratory, Faculty of Agriculture and Life Sciences, Lincoln University, Lincoln 7647, New Zealand
| | - Jiang Hu
- Gansu Key Laboratory of Herbivorous Animal Biotechnology, Faculty of Animal Science and Technology, Gansu Agricultural University, Lanzhou 730070, China
- International Wool Research Institute, Gansu Agricultural University, Lanzhou 730070, China
| | - Jiqing Wang
- Gansu Key Laboratory of Herbivorous Animal Biotechnology, Faculty of Animal Science and Technology, Gansu Agricultural University, Lanzhou 730070, China
- International Wool Research Institute, Gansu Agricultural University, Lanzhou 730070, China
| | - Xiu Liu
- Gansu Key Laboratory of Herbivorous Animal Biotechnology, Faculty of Animal Science and Technology, Gansu Agricultural University, Lanzhou 730070, China
- International Wool Research Institute, Gansu Agricultural University, Lanzhou 730070, China
| | - Shaobin Li
- Gansu Key Laboratory of Herbivorous Animal Biotechnology, Faculty of Animal Science and Technology, Gansu Agricultural University, Lanzhou 730070, China
- International Wool Research Institute, Gansu Agricultural University, Lanzhou 730070, China
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Yim SW, Chan TYC, Belaramani KM, Man SS, Wong FCK, Chen SPL, Lee HHC, Mak CM, Ching CK. Case Report: The first probable Hong Kong Chinese case of LPIN1-related acute recurrent rhabdomyolysis in a boy with two novel variants. F1000Res 2019; 8:1566. [PMID: 31723421 PMCID: PMC6823901 DOI: 10.12688/f1000research.20343.1] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 08/22/2019] [Indexed: 01/18/2023] Open
Abstract
Recurrent rhabdomyolysis is frequently ascribed to fatty acid ß-oxidation defects, mitochondrial respiratory chain disorders and glycogen storage-related diseases. In recent years, autosomal recessive
LPIN1 mutations have been identified as a prevailing cause of severe rhabdomyolysis in children in Western countries. We report the first probable Hong Kong Chinese case of recurrent severe rhabdomyolysis in early childhood caused by
LPIN1 variants. Compound heterozygous novel variants NM_145693.2(LPIN1):c.[1949_1967dupGTGTCACCACGCAGTACCA]; [2410G>C] (p.[Gly657Cysfs*12];[Asp804His]) were detected. The former variant was classified as likely pathogenic while the latter variant was classified as a variant of uncertain significance (VUS) based on the guideline published by the American College of Medical Genetics and Genomics (ACMG) in 2015. Although the genetic findings were inconclusive, the patient’s presentation was compatible with LPIN1-related acute recurrent rhabdomyolysis, and the patient was treated as such. The early recognition, timely diagnosis and management of this condition are important to avoid fatal consequences. To our knowledge, there has been no previous report in the English-language literature of a child with Chinese ethnicity and
LPIN1-related acute recurrent rhabdomyolysis (MIM #268200). Functional characterization of the novel variants detected in this study are warranted in future studies.
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Affiliation(s)
- Sau Wing Yim
- Department of Paediatrics and Adolescent Medicine, Tuen Mun Hospital, Tuen Mun, Hong Kong.,Chemical Pathology Laboratory, Department of Pathology, Hong Kong Children's Hospital, Kowloon Bay, Hong Kong
| | - Tina Yee Ching Chan
- Kowloon West Cluster Laboratory Genetic Service, Chemical Pathology Laboratory, Department of Pathology, Princess Margaret Hospital, Hong Kong, Laichikok, Hong Kong
| | - Kiran M Belaramani
- Department of Paediatrics and Adolescent Medicine, Tuen Mun Hospital, Tuen Mun, Hong Kong.,Chemical Pathology Laboratory, Department of Pathology, Hong Kong Children's Hospital, Kowloon Bay, Hong Kong
| | - Sze Shun Man
- Department of Paediatrics and Adolescent Medicine, Tuen Mun Hospital, Tuen Mun, Hong Kong.,Chemical Pathology Laboratory, Department of Pathology, Hong Kong Children's Hospital, Kowloon Bay, Hong Kong
| | - Felix Chi Kin Wong
- Department of Chemical Pathology, Prince of Wales Hospital, Shatin, Hong Kong
| | - Sammy Pak Lam Chen
- Kowloon West Cluster Laboratory Genetic Service, Chemical Pathology Laboratory, Department of Pathology, Princess Margaret Hospital, Hong Kong, Laichikok, Hong Kong.,Chemical Pathology Laboratory, Department of Pathology, Queen Elizabeth Hospital, Kowloon, Hong Kong
| | - Hencher Han Chih Lee
- Kowloon West Cluster Laboratory Genetic Service, Chemical Pathology Laboratory, Department of Pathology, Princess Margaret Hospital, Hong Kong, Laichikok, Hong Kong
| | - Chloe Miu Mak
- Chemical Pathology Laboratory, Department of Pathology, Hong Kong Children's Hospital, Kowloon Bay, Hong Kong.,Kowloon West Cluster Laboratory Genetic Service, Chemical Pathology Laboratory, Department of Pathology, Princess Margaret Hospital, Hong Kong, Laichikok, Hong Kong
| | - Chor Kwan Ching
- Kowloon West Cluster Laboratory Genetic Service, Chemical Pathology Laboratory, Department of Pathology, Princess Margaret Hospital, Hong Kong, Laichikok, Hong Kong
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Han B, Yuan Y, Liang R, Li Y, Liu L, Sun D. Genetic Effects of LPIN1 Polymorphisms on Milk Production Traits in Dairy Cattle. Genes (Basel) 2019; 10:genes10040265. [PMID: 30986988 PMCID: PMC6523124 DOI: 10.3390/genes10040265] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2019] [Revised: 03/27/2019] [Accepted: 03/28/2019] [Indexed: 12/16/2022] Open
Abstract
Our initial RNA sequencing work identified that lipin 1 (LPIN1) was differentially expressed during dry period, early lactation, and peak of lactation in dairy cows, and it was enriched into the fat metabolic Gene Ontology (GO) terms and pathways, thus we considered LPIN1 as the candidate gene for milk production traits. In this study, we detected the polymorphisms of LPIN1 and verified their genetic effects on milk yield and composition in a Chinese Holstein cow population. We found seven SNPs by re-sequencing the entire coding region and partial flanking region of LPIN1, including one in 5′ flanking region, four in exons, and two in 3′ flanking region. Of these, four SNPs, c.637T > C, c.708A > G, c.1521C > T, and c.1555A > C, in the exons were predicted to result in the amino acid replacements. With the Haploview 4.2, we found that seven SNPs in LPIN1 formed two haplotype blocks (D′ = 0.98–1.00). Single-SNP association analyses showed that SNPs were significantly associated with milk yield, fat yield, fat percentage, or protein yield in the first or second lactation (p = < 0.0001–0.0457), and only g.86049389C > T was strongly associated with protein percentage in both lactations (p = 0.0144 and 0.0237). The haplotype-based association analyses showed that the two haplotype blocks were significantly associated with milk yield, fat yield, protein yield, or protein percentage (p = < 0.0001–0.0383). By quantitative real-time PCR (qRT-PCR), we found that LPIN1 had relatively high expression in mammary gland and liver tissues. Furthermore, we predicted three SNPs, c.637T > C, c.708A > G, and c.1521C > T, using SOPMA software, changing the LPIN1 protein structure that might be potential functional mutations. In summary, we demonstrated the significant genetic effects of LPIN1 on milk production traits, and the identified SNPs could serve as genetic markers for dairy breeding.
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Affiliation(s)
- Bo Han
- Department of Animal Genetics, Breeding and Reproduction, College of Animal Science and Technology, Key Laboratory of Animal Genetics, Breeding and Reproduction of Ministry of Agriculture and Rural Affairs, National Engineering Laboratory for Animal Breeding, China Agricultural University, Beijing 100193, China.
| | - Yuwei Yuan
- Department of Animal Genetics, Breeding and Reproduction, College of Animal Science and Technology, Key Laboratory of Animal Genetics, Breeding and Reproduction of Ministry of Agriculture and Rural Affairs, National Engineering Laboratory for Animal Breeding, China Agricultural University, Beijing 100193, China.
| | - Ruobing Liang
- Department of Animal Genetics, Breeding and Reproduction, College of Animal Science and Technology, Key Laboratory of Animal Genetics, Breeding and Reproduction of Ministry of Agriculture and Rural Affairs, National Engineering Laboratory for Animal Breeding, China Agricultural University, Beijing 100193, China.
| | - Yanhua Li
- Beijing Dairy Cattle Center, Qinghe'nanzhen Deshengmenwai Street, Chaoyang District, Beijing 100192, China.
| | - Lin Liu
- Beijing Dairy Cattle Center, Qinghe'nanzhen Deshengmenwai Street, Chaoyang District, Beijing 100192, China.
| | - Dongxiao Sun
- Department of Animal Genetics, Breeding and Reproduction, College of Animal Science and Technology, Key Laboratory of Animal Genetics, Breeding and Reproduction of Ministry of Agriculture and Rural Affairs, National Engineering Laboratory for Animal Breeding, China Agricultural University, Beijing 100193, China.
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10
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Xu S, Zhang X, Liu P. Lipid droplet proteins and metabolic diseases. Biochim Biophys Acta Mol Basis Dis 2018; 1864:1968-1983. [DOI: 10.1016/j.bbadis.2017.07.019] [Citation(s) in RCA: 68] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2017] [Revised: 07/14/2017] [Accepted: 07/19/2017] [Indexed: 12/13/2022]
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11
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May P, Bremond P, Sauzet C, Piccerelle P, Grimaldi F, Champion S, Villard PH. In Vitro Cocktail Effects of PCB-DL (PCB118) and Bulky PCB (PCB153) with BaP on Adipogenesis and on Expression of Genes Involved in the Establishment of a Pro-Inflammatory State. Int J Mol Sci 2018. [PMID: 29534036 PMCID: PMC5877702 DOI: 10.3390/ijms19030841] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Abstract
(1) Objective: Highlight the in vitro effects of 3T3-L1 cell exposure to polychlorinated biphenyls (PCB118 and 153) or benzo(a)pyrene (BaP) alone or as a cocktail on adipogenesis (ADG) by focusing on changes in lipid metabolism and inflammatory-related genes expression (INFG) and ADG-related genes expression (ADGG); (2) Results: Treatment from the early stage of cell differentiation by BaP alone or in combination with PCBs decreased the expression of some of the ADGG (PPARγGlut-4, FAS, Lipin-1a, Leptin, and Adiponectin). BaP enhanced the INFG, especially MCP-1 and TNFα. Co-exposure to BaP and PCB153 showed a synergistic effect on TNFα and IL6 expression. Treatment with BaP and PCBs during only the maturation period up-regulated the INFG (IL6, TNFα, CXCL-10 & MCP-1). PCB118 alone also enhanced TNFα, CXCL-10, and PAI-1 expression. The change in MCP-1 protein expression was in agreement with that of the gene. Finally, the BaP-induced up-regulation of the xenobiotic responsive element (XRE)-controlled luciferase activity was impaired by PCB153 but not by PCB118; (3) Conclusion: BaP and PCBs down-regulate a part of ADGG and enhance INFG. The direct regulatory effect of PCBs on both ADGG and INFG is usually rather lower than that of BaP and synergistic or antagonistic cocktail effects are clearly observed.
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Affiliation(s)
- Phealay May
- Aix Marseille Univ, Univ Avignon, CNRS, IRD, IMBE, Faculté de Pharmacie 27 Bd Jean Moulin, 13385 Marseille CEDEX 5, France.
| | - Patricia Bremond
- Aix Marseille Univ, Univ Avignon, CNRS, IRD, IMBE, Faculté de Pharmacie 27 Bd Jean Moulin, 13385 Marseille CEDEX 5, France.
| | - Christophe Sauzet
- Aix Marseille Univ, Univ Avignon, CNRS, IRD, IMBE, Faculté de Pharmacie 27 Bd Jean Moulin, 13385 Marseille CEDEX 5, France.
| | - Philippe Piccerelle
- Aix Marseille Univ, Univ Avignon, CNRS, IRD, IMBE, Faculté de Pharmacie 27 Bd Jean Moulin, 13385 Marseille CEDEX 5, France.
| | - Frédérique Grimaldi
- Aix Marseille Univ, Univ Avignon, CNRS, IRD, IMBE, Faculté de Pharmacie 27 Bd Jean Moulin, 13385 Marseille CEDEX 5, France.
| | - Serge Champion
- Aix Marseille Univ, Univ Avignon, CNRS, IRD, IMBE, Faculté de Pharmacie 27 Bd Jean Moulin, 13385 Marseille CEDEX 5, France.
| | - Pierre-Henri Villard
- Aix Marseille Univ, Univ Avignon, CNRS, IRD, IMBE, Faculté de Pharmacie 27 Bd Jean Moulin, 13385 Marseille CEDEX 5, France.
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12
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Metwally M, Eslam M, George J. Genetic and Epigenetic Associations of NAFLD: Focus on Clinical Decision Making. CURRENT HEPATOLOGY REPORTS 2017; 16:335-345. [DOI: 10.1007/s11901-017-0372-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/17/2025]
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13
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Gao G, Chen FJ, Zhou L, Su L, Xu D, Xu L, Li P. Control of lipid droplet fusion and growth by CIDE family proteins. Biochim Biophys Acta Mol Cell Biol Lipids 2017. [DOI: 10.1016/j.bbalip.2017.06.009] [Citation(s) in RCA: 55] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
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14
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Temprano A, Sembongi H, Han GS, Sebastián D, Capellades J, Moreno C, Guardiola J, Wabitsch M, Richart C, Yanes O, Zorzano A, Carman GM, Siniossoglou S, Miranda M. Redundant roles of the phosphatidate phosphatase family in triacylglycerol synthesis in human adipocytes. Diabetologia 2016; 59:1985-94. [PMID: 27344312 PMCID: PMC4969345 DOI: 10.1007/s00125-016-4018-0] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2016] [Accepted: 05/23/2016] [Indexed: 12/20/2022]
Abstract
AIMS/HYPOTHESIS In mammals, the evolutionary conserved family of Mg(2+)-dependent phosphatidate phosphatases (PAP1), involved in phospholipid and triacylglycerol synthesis, consists of lipin-1, lipin-2 and lipin-3. While mutations in the murine Lpin1 gene cause lipodystrophy and its knockdown in mouse 3T3-L1 cells impairs adipogenesis, deleterious mutations of human LPIN1 do not affect adipose tissue distribution. However, reduced LPIN1 and PAP1 activity has been described in participants with type 2 diabetes. We aimed to characterise the roles of all lipin family members in human adipose tissue and adipogenesis. METHODS The expression of the lipin family was analysed in adipose tissue in a cross-sectional study. Moreover, the effects of lipin small interfering RNA (siRNA)-mediated depletion on in vitro human adipogenesis were assessed. RESULTS Adipose tissue gene expression of the lipin family is altered in type 2 diabetes. Depletion of every lipin family member in a human Simpson-Golabi-Behmel syndrome (SGBS) pre-adipocyte cell line, alters expression levels of adipogenic transcription factors and lipid biosynthesis genes in early stages of differentiation. Lipin-1 knockdown alone causes a 95% depletion of PAP1 activity. Despite the reduced PAP1 activity and alterations in early adipogenesis, lipin-silenced cells differentiate and accumulate neutral lipids. Even combinatorial knockdown of lipins shows mild effects on triacylglycerol accumulation in mature adipocytes. CONCLUSIONS/INTERPRETATION Overall, our data support the hypothesis of alternative pathways for triacylglycerol synthesis in human adipocytes under conditions of repressed lipin expression. We propose that induction of alternative lipid phosphate phosphatases, along with the inhibition of lipid hydrolysis, contributes to the maintenance of triacylglycerol content to near normal levels.
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Affiliation(s)
- Ana Temprano
- Joan XXIII University Hospital, Pere Virgili Health Research Institut (IISPV), Modular Building, C/ Mallafre Guasch, Tarragona, 43005, Spain
- Department of Biochemistry and Molecular Biology, Rovira i Virgili University, Tarragona, Spain
| | - Hiroshi Sembongi
- Cambridge Institute for Medical Research, University of Cambridge, Wellcome Trust/Medical Research Council Building, Hills Road, Cambridge, CB2 0XY, UK
- , Chesterford Research Park, Little Chesterford, Saffron Walden, UK
| | - Gil-Soo Han
- Department of Food Science and the Rutgers Center for Lipid Research, New Jersey Institute for Food, Nutrition and Health, Rutgers University, New Brunswick, NJ, USA
| | - David Sebastián
- Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain
- Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Barcelona, Barcelona, Spain
- Biomedical Research Networking Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain
| | - Jordi Capellades
- Biomedical Research Networking Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain
- Centre for Omic Sciences, Rovira i Virgili University, Reus, Spain
| | - Cristóbal Moreno
- Joan XXIII University Hospital, Pere Virgili Health Research Institut (IISPV), Modular Building, C/ Mallafre Guasch, Tarragona, 43005, Spain
- Biomedical Research Networking Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain
| | - Juan Guardiola
- Department of Pulmonary, Critical Care and Sleep Medicine, University of Louisville, Louisville, KY, USA
| | - Martin Wabitsch
- Division of Paediatric Endocrinology and Diabetes, Interdisciplinary Obesity Clinic, University Clinic for Child and Adolescent Medicine, University of Ulm, Ulm, Germany
| | - Cristóbal Richart
- Joan XXIII University Hospital, Pere Virgili Health Research Institut (IISPV), Modular Building, C/ Mallafre Guasch, Tarragona, 43005, Spain
- GEMMAIR Research Group - Applied Medicine, Department of Medicine and Surgery, Rovira i Virgili University (URV), Tarragona, Spain
| | - Oscar Yanes
- Biomedical Research Networking Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain
- Centre for Omic Sciences, Rovira i Virgili University, Reus, Spain
- Department of Electronic Engineering, Rovira i Virgili University, Tarragona, Spain
| | - Antonio Zorzano
- Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain
- Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Barcelona, Barcelona, Spain
- Biomedical Research Networking Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain
| | - George M Carman
- Department of Food Science and the Rutgers Center for Lipid Research, New Jersey Institute for Food, Nutrition and Health, Rutgers University, New Brunswick, NJ, USA
| | - Symeon Siniossoglou
- Cambridge Institute for Medical Research, University of Cambridge, Wellcome Trust/Medical Research Council Building, Hills Road, Cambridge, CB2 0XY, UK.
| | - Merce Miranda
- Joan XXIII University Hospital, Pere Virgili Health Research Institut (IISPV), Modular Building, C/ Mallafre Guasch, Tarragona, 43005, Spain.
- Biomedical Research Networking Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain, .
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A Fomitopsis pinicola Jeseng Formulation Has an Antiobesity Effect and Protects against Hepatic Steatosis in Mice with High-Fat Diet-Induced Obesity. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2016; 2016:7312472. [PMID: 27200103 PMCID: PMC4855004 DOI: 10.1155/2016/7312472] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/01/2016] [Revised: 03/23/2016] [Accepted: 03/31/2016] [Indexed: 11/17/2022]
Abstract
This study investigated the antiobesity effect of an extract of the Fomitopsis pinicola Jeseng-containing formulation (FAVA), which is a combination of four natural components: Fomitopsis pinicola Jeseng; Acanthopanax senticosus; Viscum album coloratum; and Allium tuberosum. High-fat diet- (HFD-) fed male C57BL/6J mice were treated with FAVA (200 mg/kg/day) for 12 weeks to monitor the antiobesity effect and amelioration of nonalcoholic fatty liver diseases (NAFLD). Body and white adipose tissue (WAT) weights were reduced in FAVA-treated mice, and a histological examination showed an amelioration of fatty liver in FAVA-treated mice without decreasing food consumption. Additionally, FAVA reduced serum lipid profiles, leptin, and insulin levels compared with the HFD control group. The FAVA extract suppressed lipogenic mRNA expression levels from WAT concomitantly with the cholesterol biosynthesis level in the liver. These results demonstrate the inhibitory effects of FAVA on obesity and NAFLD in the diet-induced obese (DIO) mouse model. Therefore, FAVA may be an effective therapeutic candidate for treating obesity and fatty liver caused by a high-fat diet.
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Jaradat SA, Amayreh W, Al-Qa'qa' K, Krayyem J. Molecular analysis of LPIN1 in Jordanian patients with rhabdomyolysis. Meta Gene 2015; 7:90-4. [PMID: 26909335 PMCID: PMC4733219 DOI: 10.1016/j.mgene.2015.12.003] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2015] [Revised: 09/15/2015] [Accepted: 12/02/2015] [Indexed: 12/31/2022] Open
Abstract
Recessive mutations in LPIN1, which encodes a phosphatidate phosphatase enzyme, are a frequent cause of severe rhabdomyolysis in childhood. Hence, we sequenced the 19 coding exons of the gene in eight patients with recurrent hereditary myoglobinuria from four unrelated families in Jordan. The long-term goal is to facilitate molecular genetic diagnosis without the need for invasive procedures such as muscle biopsies. Three different mutations were detected, including the novel missense mutation c.2395G>C (Gly799Arg), which was found in two families. The two other mutations, c.2174G>A (Arg725His) and c.1162C>T (Arg388X), have been previously identified, and were found to cosegregate with the disease phenotype in the other two families. Intriguingly, patients homozygous for Arg725His were also homozygous for the c.1828C>T (Pro610Ser) polymorphism, and were exercise-intolerant between myoglobinuria episodes. Notably, patients homozygous for Arg388X were also homozygous for the c.2250G>C silent variant (Gly750Gly). Taken together, the data provide family-based evidence linking hereditary myoglobinuria to pathogenic variations in the C-terminal lipin domain of the enzyme. This finding highlights the functional significance of this domain in the absence of structural information. This is the first analysis of LPIN1 in myoglobinuria patients of Jordanian origin, and the fourth such analysis worldwide.
LPIN1 mutations were cataloged in families with hereditary myoglobinuria. A novel missense Gly799Arg mutation was identified. Arg725His, the only other known missense mutation, was confirmed to be pathogenic. Arg388X, a known nonsense mutation, was the most common among Arabic patients. Patients exercise-intolerant between myoglobinuria episodes have a second mutation.
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Affiliation(s)
- Saied A Jaradat
- Princess Haya Biotechnology Center, Jordan University of Science and Technology, Irbid 22110, Jordan
| | - Wajdi Amayreh
- Department of Pediatrics, Metabolic Genetics Clinic, Queen Rania Al-Abdullah Children's Hospital, King Hussein Medical Centre, Amman 11855, Jordan
| | - Kefah Al-Qa'qa'
- Department of Pediatrics, Metabolic Genetics Clinic, Queen Rania Al-Abdullah Children's Hospital, King Hussein Medical Centre, Amman 11855, Jordan
| | - Jan Krayyem
- Princess Haya Biotechnology Center, Jordan University of Science and Technology, Irbid 22110, Jordan
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Lonardo A, Bellentani S, Argo CK, Ballestri S, Byrne CD, Caldwell SH, Cortez-Pinto H, Grieco A, Machado MV, Miele L, Targher G. Epidemiological modifiers of non-alcoholic fatty liver disease: Focus on high-risk groups. Dig Liver Dis 2015; 47:997-1006. [PMID: 26454786 DOI: 10.1016/j.dld.2015.08.004] [Citation(s) in RCA: 334] [Impact Index Per Article: 33.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2015] [Revised: 07/27/2015] [Accepted: 08/06/2015] [Indexed: 02/07/2023]
Abstract
An improved understanding of non-alcoholic fatty liver disease epidemiology would lead to identification of individuals at high risk of developing chronic liver disease and extra-hepatic complications, thus contributing to more effective case finding of non-alcoholic fatty liver disease among selected groups. We aimed to illustrate the epidemiology of non-alcoholic fatty liver disease in high-risk groups, which were identified based on existing literature. To this end, PubMed was searched to retrieve original articles published until May 2015 using relevant and pertinent keywords "nonalcoholic fatty liver disease" and "diabetes", "obesity", "hyperlipidaemia", "familial heterozygous hypobetalipoproteinaemia", "hypertension", "metabolic syndrome", "ethnicity", "family history" or "genetic polymorphisms". We found that age, sex and ethnicity are major physiological modifiers of the risk of non-alcoholic fatty liver disease, along with belonging to "non-alcoholic fatty liver disease families" and carrying risk alleles for selected genetic polymorphisms. Metabolic syndrome, diabetes, obesity, mixed hyperlipidaemia and hypocholesterolaemia due to familial hypobetalipoproteinaemia are the major metabolic modifiers of non-alcoholic fatty liver disease risk. Compared with these metabolic conditions, however, arterial hypertension appears to carry a relatively more modest risk of non-alcoholic fatty liver disease. A better understanding of the epidemiology of non-alcoholic fatty liver disease may result in a more liberal policy of case finding among high-risk groups.
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Affiliation(s)
- Amedeo Lonardo
- Internal Medicine and Outpatient Liver Clinic, NOCSAE Baggiovara, Azienda USL di Modena, Modena, Italy.
| | - Stefano Bellentani
- Internal Medicine and Outpatient Liver Clinic, NOCSAE Baggiovara, Azienda USL di Modena, Modena, Italy; Department of Gastroenterology and Endoscopy, NOCSE Baggiovara, Azienda USL di Modena Modena, Italy
| | | | - Stefano Ballestri
- Internal Medicine Pavullo Hospital, Azienda USL di Modena, Modena, Italy
| | - Christopher D Byrne
- Nutrition and Metabolism, University of Southampton, Southampton National Institute for Health Research Biomedical Research Centre, Southampton, UK
| | | | - Helena Cortez-Pinto
- Department of Gastroenterology, University Hospital of Santa Maria, Faculty of Medicine, Lisbon, Portugal
| | - Antonio Grieco
- Institute of Internal Medicine, Catholic University of Rome, Rome, Italy
| | - Mariana V Machado
- Department of Gastroenterology, University Hospital of Santa Maria, Faculty of Medicine, Lisbon, Portugal
| | - Luca Miele
- Institute of Internal Medicine, Catholic University of Rome, Rome, Italy
| | - Giovanni Targher
- Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Verona and Azienda Ospedaliera Universitaria Integrata di Verona, Verona, Italy
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Macaluso FS, Maida M, Petta S. Genetic background in nonalcoholic fatty liver disease: A comprehensive review. World J Gastroenterol 2015; 21:11088-11111. [PMID: 26494964 PMCID: PMC4607907 DOI: 10.3748/wjg.v21.i39.11088] [Citation(s) in RCA: 59] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/23/2015] [Revised: 06/11/2015] [Accepted: 09/02/2015] [Indexed: 02/06/2023] Open
Abstract
In the Western world, nonalcoholic fatty liver disease (NAFLD) is considered as one of the most significant liver diseases of the twenty-first century. Its development is certainly driven by environmental factors, but it is also regulated by genetic background. The role of heritability has been widely demonstrated by several epidemiological, familial, and twin studies and case series, and likely reflects the wide inter-individual and inter-ethnic genetic variability in systemic metabolism and wound healing response processes. Consistent with this idea, genome-wide association studies have clearly identified Patatin-like phosholipase domain-containing 3 gene variant I148M as a major player in the development and progression of NAFLD. More recently, the transmembrane 6 superfamily member 2 E167K variant emerged as a relevant contributor in both NAFLD pathogenesis and cardiovascular outcomes. Furthermore, numerous case-control studies have been performed to elucidate the potential role of candidate genes in the pathogenesis and progression of fatty liver, although findings are sometimes contradictory. Accordingly, we performed a comprehensive literature search and review on the role of genetics in NAFLD. We emphasize the strengths and weaknesses of the available literature and outline the putative role of each genetic variant in influencing susceptibility and/or progression of the disease.
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Chen Y, Rui BB, Tang LY, Hu CM. Lipin Family Proteins - Key Regulators in Lipid Metabolism. ANNALS OF NUTRITION AND METABOLISM 2014; 66:10-8. [DOI: 10.1159/000368661] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/04/2014] [Accepted: 09/19/2014] [Indexed: 11/19/2022]
Abstract
Background: Proteins in the lipin family play a key role in lipid synthesis due to their phosphatidate phosphatase activity, and they also act as transcriptional coactivators to regulate the expression of genes involved in lipid metabolism. The lipin family includes three members, lipin1, lipin2, and lipin3, which exhibit tissue-specific expression, indicating that they may have distinct roles in mediating disease. To date, most studies have focused on lipin1, whereas the roles of lipin2 and lipin3 are less understood. Summary: This review introduces the structural characteristics, physiological functions, relationship to lipid metabolism, and patterns of expression of the lipin family proteins, highlighting their roles in lipid metabolic homeostasis. © 2014 S. Karger AG, Basel
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20
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Sam S, Mazzone T. Adipose tissue changes in obesity and the impact on metabolic function. Transl Res 2014; 164:284-92. [PMID: 24929206 DOI: 10.1016/j.trsl.2014.05.008] [Citation(s) in RCA: 67] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2014] [Revised: 05/13/2014] [Accepted: 05/14/2014] [Indexed: 12/18/2022]
Abstract
Obesity is associated with adverse alterations in adipose tissue that predispose to metabolic dysregulation. These adverse alterations include accumulation of inflammatory macrophages leading to the activation of inflammation pathways, reduction in lipid turnover, and deposition of fat in ectopic locations. These alterations are precursors to the development of insulin resistance and metabolic dysfunction.
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Affiliation(s)
- Susan Sam
- Department of Medicine, Section of Endocrinology, Pritzker School of Medicine, University of Chicago, Chicago, Ill.
| | - Theodore Mazzone
- Department of Medicine, NorthShore University Health System, Pritzker School of Medicine, University of Chicago, Chicago, Ill
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A 4-polymorphism risk score predicts steatohepatitis in children with nonalcoholic fatty liver disease. J Pediatr Gastroenterol Nutr 2014; 58:632-6. [PMID: 24345846 DOI: 10.1097/mpg.0000000000000279] [Citation(s) in RCA: 57] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
OBJECTIVE Nonalcoholic fatty liver disease (NAFLD) has become the most common cause of chronic liver disease in industrialized countries in adults and children, following the trail of the epidemic diffusion of obesity. Nonalcoholic steatohepatitis (NASH) is a potentially serious form of NAFLD linked with a significant increase in overall and liver-related morbidity and mortality. Because diagnosis still requires liver biopsy, there is urgent need of developing noninvasive early markers. The aim of the present study was to assess whether the simultaneous detection of genetic risk factors could predict NASH. METHOD We enrolled 152 untreated, consecutive obese children and adolescents with biopsy-proven NAFLD and increased liver enzymes. The PNPLA3 rs738409 C>G (I148 M), SOD2 rs4880 C>T, KLF6 rs3750861 G>A, and LPIN1 rs13412852 C>T polymorphisms were detected by Taqman assays. RESULTS A multivariate logistic model based on the genetic risk factors significantly predicted NASH (area under the receiver-operating characteristic curve [AUC] 0.75, 95% confidence interval [CI] 0.67-0.82, P < 0.0001), performing better than a clinical risk score identified at stepwise regression based on age, aspartate aminotransferase levels, and diastolic blood pressure (AUC 0.66, 95% CI 0.57-0.75). A single cutoff value of the genetic risk score had 90% sensitivity and 36% specificity for NASH. A risk score combining the clinical and genetic risk factors resulted in an AUC of 0.80 (95% CI 0.73-0.87). CONCLUSIONS A score based on genetic risk factors significantly predicts NASH in obese children with increased liver enzymes, representing a proof-of-principle that genetic scores may be useful to predict long-term outcomes of the disease and guide clinical management.
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Dongiovanni P, Anstee QM, Valenti L. Genetic predisposition in NAFLD and NASH: impact on severity of liver disease and response to treatment. Curr Pharm Des 2014; 19:5219-38. [PMID: 23394097 PMCID: PMC3850262 DOI: 10.2174/13816128113199990381] [Citation(s) in RCA: 162] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2012] [Accepted: 02/01/2013] [Indexed: 02/07/2023]
Abstract
Liver fat deposition related to systemic insulin resistance defines non-alcoholic fatty liver disease (NAFLD) which, when associated with oxidative hepatocellular damage, inflammation, and activation of fibrogenesis, i.e. non-alcoholic steatohepatitis (NASH), can progress towards cirrhosis and hepatocellular carcinoma. Due to the epidemic of obesity, NAFLD is now the most frequent liver disease and the leading cause of altered liver enzymes in Western countries. Epidemiological, familial, and twin studies provide evidence for an element of heritability of NAFLD. Genetic modifiers of disease severity and progression have been identified through genome-wide association studies. These include the Patatin-like phosholipase domain-containing 3 (PNPLA3) gene variant I148M as a major determinant of inter-individual and ethnicity-related differences in hepatic fat content independent of insulin resistance and serum lipid concentration. Association studies confirm that the I148M polymorphism is also a strong modifier of NASH and progressive hepatic injury. Furthermore, a few large multicentre case-control studies have demonstrated a role for genetic variants implicated in insulin signalling, oxidative stress, and fibrogenesis in the progression of NAFLD towards fibrosing NASH, and confirm that hepatocellular fat accumulation and insulin resistance are key operative mechanisms closely involved in the progression of liver damage. It is now important to explore the molecular mechanisms underlying these associations between gene variants and progressive liver disease, and to evaluate their impact on the response to available therapies. It is hoped that this knowledge will offer further insights into pathogenesis, suggest novel therapeutic targets, and could help guide physicians towards individualised therapy that improves clinical outcome.
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Affiliation(s)
- Paola Dongiovanni
- Department of Pathophysiology and Transplantation, section Internal Medicine, Università degli Studi Milano, UO Medicina Interna1B, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
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Lipins, lipinopathies, and the modulation of cellular lipid storage and signaling. Prog Lipid Res 2013; 52:305-16. [PMID: 23603613 DOI: 10.1016/j.plipres.2013.04.001] [Citation(s) in RCA: 100] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2013] [Revised: 03/29/2013] [Accepted: 04/04/2013] [Indexed: 01/13/2023]
Abstract
Members of the lipin protein family are phosphatidate phosphatase (PAP) enzymes, which catalyze the dephosphorylation of phosphatidic acid to diacylglycerol, the penultimate step in TAG synthesis. Lipins are unique among the glycerolipid biosynthetic enzymes in that they also promote fatty acid oxidation through their activity as co-regulators of gene expression by DNA-bound transcription factors. Lipin function has been evolutionarily conserved from a single ortholog in yeast to the mammalian family of three lipin proteins-lipin-1, lipin-2, and lipin-3. In mice and humans, the levels of lipin activity are a determinant of TAG storage in diverse cell types, and humans with deficiency in lipin-1 or lipin-2 have severe metabolic diseases. Recent work has highlighted the complex physiological interactions between members of the lipin protein family, which exhibit both overlapping and unique functions in specific tissues. The analysis of "lipinopathies" in mouse models and in humans has revealed an important role for lipin activity in the regulation of lipid intermediates (phosphatidate and diacylglycerol), which influence fundamental cellular processes including adipocyte and nerve cell differentiation, adipocyte lipolysis, and hepatic insulin signaling. The elucidation of lipin molecular and physiological functions could lead to novel approaches to modulate cellular lipid storage and metabolic disease.
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Influence of SNPs in nutrient-sensitive candidate genes and gene–diet interactions on blood lipids: the DiOGenes study. Br J Nutr 2013; 110:790-6. [DOI: 10.1017/s0007114512006058] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Blood lipid response to a given dietary intervention could be determined by the effect of diet, gene variants or gene–diet interactions. The objective of the present study was to investigate whether variants in presumed nutrient-sensitive genes involved in lipid metabolism modified lipid profile after weight loss and in response to a given diet, among overweight European adults participating in the Diet Obesity and Genes study. By multiple linear regressions, 240 SNPs in twenty-four candidate genes were investigated for SNP main and SNP–diet interaction effects on total cholesterol, LDL-cholesterol, HDL-cholesterol and TAG after an 8-week low-energy diet (only main effect), and a 6-monthad libitumweight maintenance diet, with different contents of dietary protein or glycaemic index. After adjusting for multiple testing, a SNP–dietary protein interaction effect on TAG was identified for lipin 1 (LPIN1) rs4315495, with a decrease in TAG of − 0·26 mmol/l per A-allele/protein unit (95 % CI − 0·38, − 0·14,P= 0·000043). In conclusion, we investigated SNP–diet interactions for blood lipid profiles for 240 SNPs in twenty-four candidate genes, selected for their involvement in lipid metabolism pathways, and identified one significant interaction betweenLPIN1rs4315495 and dietary protein for TAG concentration.
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Bociąga-Jasik M, Polus A, Góralska J, Czech U, Gruca A, Śliwa A, Garlicki A, Mach T, Dembińska-Kieć A. Metabolic effects of the HIV protease inhibitor--saquinavir in differentiating human preadipocytes. Pharmacol Rep 2013; 65:937-950. [PMID: 24145088 DOI: 10.1016/s1734-1140(13)71075-2] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2012] [Revised: 03/12/2013] [Indexed: 11/30/2022]
Abstract
BACKGROUND The iatrogenic, HIV-related lipodystrophy is associated with development of the significant metabolic and cardiovascular complications. The underlying mechanisms of antiretroviral (ARV) drugs are not completely explored. METHODS The aim of the study was to characterize effects of the protease inhibitor (PI)--saquinavir (SQV) on metabolic functions, and gene expression during differentiation in cells (Chub-S7) culture. RESULTS SQV in concentrations observed during antiretroviral therapy (ART) significantly decreased mitochondrial membrane potential (MMP), oxygen consumption and ATP generation. The effects were greater in already differentiated cells. This was accompanied by characteristic changes in the expression of the genes involved in endoplasmic reticulum (ER) stress, and differentiation (lipid droplet formation) process such as: WNT10a, C/EBPa, AFT4, CIDEC, ADIPOQ, LPIN1. CONCLUSIONS The results indicate that SQV affects not only metabolic (mitochondrial) activity of adipocytes, but affects the expression of genes related to differentiation and to a lesser extent to cell apoptosis.
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Affiliation(s)
- Monika Bociąga-Jasik
- Chair of Gastroenterology, Hepatology and Infectious Diseases, Department of Infectious Diseases, Jagiellonian University, Collegium Medicum, Sniadeckich 5, PL 31-501 Kraków, Poland.
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Tang SQ, Jiang QY, Yang CF, Zou XT, Dong XY. [Research and development of Lipin family.]. YI CHUAN = HEREDITAS 2012; 32:981-93. [PMID: 20943485 DOI: 10.3724/sp.j.1005.2010.00981] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
Lipin family including at least three members Lipin 1, Lipin 2, and Lipin 3 is a critical regulatory enzyme identified recently, which plays dual roles in lipid metabolisms. Lipin family has physiological effects not only on regulating lipid metabolism, but also on maintaining normal peripheral nervous functions, liver lipoprotein secretion, cell morphous, reproductive functions, and energy homeostasis. Since mutations in Lipin gene express may be associated with AIDS, insulin resistance, obesity, diabetes mellitus, and the other diseases of metabolic syndrome, Lipin may be a new useful target in treatment of above-mentioned clinical-related diseases. In this article, we focused on discovery, construction features, expression, regulatory mechanism, and biological functions of Lipin, as well as its correlation research with clinical-related diseases.
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Michot C, Hubert L, Romero NB, Gouda A, Mamoune A, Mathew S, Kirk E, Viollet L, Rahman S, Bekri S, Peters H, McGill J, Glamuzina E, Farrar M, von der Hagen M, Alexander IE, Kirmse B, Barth M, Laforet P, Benlian P, Munnich A, JeanPierre M, Elpeleg O, Pines O, Delahodde A, de Keyzer Y, de Lonlay P. Study of LPIN1, LPIN2 and LPIN3 in rhabdomyolysis and exercise-induced myalgia. J Inherit Metab Dis 2012; 35:1119-28. [PMID: 22481384 DOI: 10.1007/s10545-012-9461-6] [Citation(s) in RCA: 68] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2011] [Revised: 01/19/2012] [Accepted: 01/30/2012] [Indexed: 01/21/2023]
Abstract
BACKGROUND Recessive LPIN1 mutations were identified as a cause of severe rhabdomyolysis in pediatric patients. The human lipin family includes two other closely related members, lipin-2 and 3, which share strong homology and similar activity. The study aimed to determine the involvement of the LPIN family genes in a cohort of pediatric and adult patients (n = 171) presenting with muscular symptoms, ranging from severe (CK >10 000 UI/L) or moderate (CK <10 000 UI/L) rhabdomyolysis (n = 141) to exercise-induced myalgia (n = 30), and to report the clinical findings in patients harboring mutations. METHODS Coding regions of LPIN1, LPIN2 and LPIN3 genes were sequenced using genomic or complementary DNAs. RESULTS Eighteen patients harbored two LPIN1 mutations, including a frequent intragenic deletion. All presented with severe episodes of rhabdomyolysis, starting before age 6 years except two (8 and 42 years). Few patients also suffered from permanent muscle symptoms, including the eldest ones (≥ 40 years). Around 3/4 of muscle biopsies showed accumulation of lipid droplets. At least 40% of heterozygous relatives presented muscular myalgia. Nine heterozygous SNPs in LPIN family genes were identified in milder phenotypes (mild rhabdomyolysis or myalgia). These variants were non-functional in yeast complementation assay based on respiratory activity, except the LPIN3-P24L variant. CONCLUSION LPIN1-related myolysis constitutes a major cause of early-onset rhabdomyolysis and occasionally in adults. Heterozygous LPIN1 mutations may cause mild muscular symptoms. No major defects of LPIN2 or LPIN3 genes were associated with muscular manifestations.
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Affiliation(s)
- Caroline Michot
- Paris Descartes University, INSERM U781 and Reference Center of Metabolic Diseases, Necker Hospital, Paris, France
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Fox CS, White CC, Lohman K, Heard-Costa N, Cohen P, Zhang Y, Johnson AD, Emilsson V, Liu CT, Chen YDI, Taylor KD, Allison M, Budoff M, Rotter JI, Carr JJ, Hoffmann U, Ding J, Cupples LA, Liu Y. Genome-wide association of pericardial fat identifies a unique locus for ectopic fat. PLoS Genet 2012; 8:e1002705. [PMID: 22589742 PMCID: PMC3349742 DOI: 10.1371/journal.pgen.1002705] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2011] [Accepted: 03/27/2012] [Indexed: 12/18/2022] Open
Abstract
Pericardial fat is a localized fat depot associated with coronary artery calcium and myocardial infarction. We hypothesized that genetic loci would be associated with pericardial fat independent of other body fat depots. Pericardial fat was quantified in 5,487 individuals of European ancestry from the Framingham Heart Study (FHS) and the Multi-Ethnic Study of Atherosclerosis (MESA). Genotyping was performed using standard arrays and imputed to ∼2.5 million Hapmap SNPs. Each study performed a genome-wide association analysis of pericardial fat adjusted for age, sex, weight, and height. A weighted z-score meta-analysis was conducted, and validation was obtained in an additional 3,602 multi-ethnic individuals from the MESA study. We identified a genome-wide significant signal in our primary meta-analysis at rs10198628 near TRIB2 (MAF 0.49, p = 2.7×10-08). This SNP was not associated with visceral fat (p = 0.17) or body mass index (p = 0.38), although we observed direction-consistent, nominal significance with visceral fat adjusted for BMI (p = 0.01) in the Framingham Heart Study. Our findings were robust among African ancestry (n = 1,442, p = 0.001), Hispanic (n = 1,399, p = 0.004), and Chinese (n = 761, p = 0.007) participants from the MESA study, with a combined p-value of 5.4E-14. We observed TRIB2 gene expression in the pericardial fat of mice. rs10198628 near TRIB2 is associated with pericardial fat but not measures of generalized or visceral adiposity, reinforcing the concept that there are unique genetic underpinnings to ectopic fat distribution. Pericardial fat is a localized fat depot associated with coronary artery calcium and myocardial infarction. To test whether genetic loci are associated with pericardial fat independent of other body fat depots, we measured pericardial fat in 5,487 individuals of European ancestry. After performing an unbiased screen using genome-wide association, we identified a genome-wide significant signal in our primary meta-analysis at rs10198628 near TRIB2 (MAF 0.49, p = 2.7×10-08). This SNP was not associated with visceral fat (p = 0.17) or body mass index (p = 0.38). Our findings were robust among multi-ethnic participants from the MESA study, with a combined p-value of 5.4E-14. We observed TRIB2 gene expression in the pericardial fat of mice. rs10198628 near TRIB2 is associated with pericardial fat but not measures of generalized or visceral adiposity, reinforcing the concept that there are unique genetic underpinnings to ectopic fat distribution.
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Affiliation(s)
- Caroline S. Fox
- Framingham Heart Study, National Heart, Lung, and Blood Institute, Framingham, Massachusetts, United States of America
- Center for Population Studies, National Heart, Lung, and Blood Institute, Framingham, Massachusetts, United States of America
- Division of Endocrinology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America
- * E-mail: (CSF); (YL)
| | - Charles C. White
- Framingham Heart Study, National Heart, Lung, and Blood Institute, Framingham, Massachusetts, United States of America
- Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, United States of America
| | - Kurt Lohman
- Department of Epidemiology and Prevention, Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, North Carolina, United States of America
| | - Nancy Heard-Costa
- Department of Neurology, Boston University School of Medicine, Boston, Massachusetts, United States of America
| | - Paul Cohen
- Division of Cardiovascular Medicine and Department of Cancer Biology, Brigham and Women's Hospital and Dana Farber Cancer Institute, Boston, Massachusetts, United States of America
| | - Yingying Zhang
- Department of Cancer Biology, Dana Farber Cancer Institute, Boston, Massachusetts, United States of America
| | - Andrew D. Johnson
- Framingham Heart Study, National Heart, Lung, and Blood Institute, Framingham, Massachusetts, United States of America
- Center for Population Studies, National Heart, Lung, and Blood Institute, Framingham, Massachusetts, United States of America
| | | | - Ching-Ti Liu
- Framingham Heart Study, National Heart, Lung, and Blood Institute, Framingham, Massachusetts, United States of America
- Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, United States of America
| | - Y.-D. Ida Chen
- Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, California, United States of America
| | - Kent D. Taylor
- Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, California, United States of America
| | - Matthew Allison
- Department of Preventive Medicine, University of California San Diego, La Jolla, California, United States of America
| | - Matthew Budoff
- Los Angeles Biomedical Research Institute, Torrance, California, United States of America
| | | | - Jerome I. Rotter
- Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, California, United States of America
| | - J. Jeffrey Carr
- Departments of Radiologic Sciences, Internal Medicine-Cardiology, and Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, North Carolina, United States of America
| | - Udo Hoffmann
- Cardiac MR, PET, CT Program and the Department of Radiology, Massachusetts General Hospital, Boston, Massachusetts, United States of America
| | - Jingzhong Ding
- Department of Internal Medicine/Geriatrics, Wake Forest School of Medicine, Winston-Salem, North Carolina, United States of America
| | - L. Adrienne Cupples
- Framingham Heart Study, National Heart, Lung, and Blood Institute, Framingham, Massachusetts, United States of America
- Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, United States of America
| | - Yongmei Liu
- Department of Epidemiology and Prevention, Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, North Carolina, United States of America
- * E-mail: (CSF); (YL)
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Abstract
OBJECTIVES The aim of the present study was to evaluate whether the lipin1 rs13412852 C>T polymorphism is associated with nonalcoholic steatohepatitis and fibrosis in pediatric Italian patients with nonalcoholic fatty liver disease (NAFLD). METHODS A total of 142 untreated, consecutive children and 115 adults with biopsy-proven NAFLD and 337 healthy controls without steatosis were studied. Liver histology was assessed by the NAFLD activity score and the rs13412852 polymorphism by a 5' nuclease Taqman assay. RESULTS Homozygosity for the rs13412852 T allele was underrepresented in pediatric, but not adult, patients with NAFLD compared with healthy controls (7% vs 14%; odds ratio [OR] 0.58, 95% confidence interval [CI] 0.35-0.91), and it was associated with lower triglycerides both in pediatric patients and healthy controls (P ≤ 0.01). Affected children carrying the rs13412852 TT genotype had a trend for a lower prevalence of nonalcoholic steatohepatitis, and significantly less severe liver damage, as indicated by NAFLD activity score severity (P = 0.026) and a lower prevalence of liver fibrosis (P = 0.012). The negative association between rs13412852 TT genotype and fibrosis was independent of Patatin-like phospholipase domain-containing-3 genotype and other clinical risk factors, including age, waist circumference, the presence of hyperglycemia, and alanine transaminase levels (OR 0.29; 95% CI 0.11-0.66), and it was confirmed at multivariate analysis in adults (OR 0.15; 95% CI 0.02-0.67). CONCLUSIONS Lipin1 rs13412852 single nucleotide polymorphism is associated with the severity of liver damage and fibrosis progression in pediatric patients with histological NAFLD.
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Dahlman I, Arner P. Genetics of adipose tissue biology. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2011; 94:39-74. [PMID: 21036322 DOI: 10.1016/b978-0-12-375003-7.00003-0] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Adipose tissue morphology and release of free fatty acids, as well as peptide hormones, are believed to contribute to obesity and related metabolic disorders. These adipose tissue phenotypes are influenced by adiposity, but there is also a strong hereditary impact. Polymorphisms in numerous adipose-expressed genes have been evaluated for association with adipocyte and clinical phenotypes. In our opinion, some results are convincing. Thus ADRB2 and GPR74 genes are associated with adipocyte lipolysis, GPR74 also with BMI; PPARG and SREBP1, which promote adipogenesis and lipid storage, are associated with T2D and possible adiposity; ADIPOQ and ARL15 are associated with circulating levels of adiponectin, ARL15 also with coronary heart disease. We anticipate that the use of complementary approaches such as expression profiling and RNAi screening, and studies of additional levels of gene regulation, that is, miRNA and epigenetics, will be important to unravel the genetics of adipose tissue function.
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Abstract
The lipin proteins are evolutionarily conserved proteins with roles in lipid metabolism and disease. There are three lipin protein family members in mammals and one or two orthologs in plants, invertebrates, and single-celled eukaryotes. Studies in yeast and mouse led to the identification of two distinct molecular functions of lipin proteins. Lipin proteins have phosphatidate phosphatase activity and catalyze the formation of diacylglycerol in the glycerol-3-phosphate pathway, implicating them in the regulation of triglyceride and phospholipid biosynthesis. Mammalian lipin proteins also possess transcriptional coactivator activity and have been implicated in the regulation of metabolic gene expression. Here we review key findings in the field that demonstrate roles for lipin family members in metabolic homeostasis and in rare human diseases, and we examine evidence implicating genetic variations in lipin genes in common metabolic dysregulation such as obesity, hyperinsulinemia, hypertension, and type 2 diabetes.
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Affiliation(s)
- Lauren S Csaki
- Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, California 90095, USA
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Kammerer CM, Rainwater DL, Gouin N, Jasti M, Douglas KC, Dressen AS, Ganta P, Vandeberg JL, Samollow PB. Localization of genes for V+LDL plasma cholesterol levels on two diets in the opossum Monodelphis domestica. J Lipid Res 2010; 51:2929-39. [PMID: 20650928 DOI: 10.1194/jlr.m005686] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Plasma cholesterol levels among individuals vary considerably in response to diet. However, the genes that influence this response are largely unknown. Non-HDL (V+LDL) cholesterol levels vary dramatically among gray, short-tailed opossums fed an atherogenic diet, and we previously reported that two quantitative trait loci (QTLs) influenced V+LDL cholesterol on two diets. We used hypothesis-free, genome-wide linkage analyses on data from 325 pedigreed opossums and located one QTL for V+LDL cholesterol on the basal diet on opossum chromosome 1q [logarithm of the odds (LOD) = 3.11, genomic P = 0.019] and another QTL for V+LDL on the atherogenic diet (i.e., high levels of cholesterol and fat) on chromosome 8 (LOD = 9.88, genomic P = 5 x 10(-9)). We then employed a novel strategy involving combined analyses of genomic resources, expression analysis, sequencing, and genotyping to identify candidate genes for the chromosome 8 QTL. A polymorphism in ABCB4 was strongly associated (P = 9 x 10(-14)) with the plasma V+LDL cholesterol concentrations on the high-cholesterol, high-fat diet. The results of this study indicate that genetic variation in ABCB4, or closely linked genes, is responsible for the dramatic differences among opossums in their V+LDL cholesterol response to an atherogenic diet.
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Affiliation(s)
- Candace M Kammerer
- Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.
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Burgdorf KS, Sandholt CH, Sparsø T, Andersen G, Witte DR, Jørgensen T, Sandbaek A, Lauritzen T, Sørensen TIA, Madsbad S, Hansen T, Pedersen O. Studies of association between LPIN1 variants and common metabolic phenotypes among 17,538 Danes. Eur J Endocrinol 2010; 163:81-7. [PMID: 20356931 DOI: 10.1530/eje-10-0068] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
OBJECTIVE Lipin-1, encoded by LPIN1, is expressed in the major metabolically active tissues. Decreased expression of lipin-1 in adipose tissue correlates with increased insulin resistance, and tagging of the LPIN1 locus has shown that rs33997857, rs6744682, and rs6708316 associate with metabolic phenotypes, specifically body mass index (BMI) and fasting serum lipid levels, both on the individual single-nucleotide polymorphism level and with a three-marker haplotype. Our aim was to validate the reported findings in the Danish population. DESIGN In the present study, variants were analyzed in LPIN1 using case-control studies, haplotype analyses, and quantitative trait analyses in a population of 17,538 Danes. METHODS The three LPIN1 variants were genotyped in 17,538 Danes from four study populations of middle-aged people. This provided us with a statistical power >99% to replicate previous findings. Variants were analyzed individually and in haplotype combinations in studies of quantitative metabolic traits and in case-control studies. RESULTS None of the three variants were associated with the examined quantitative traits including BMI, waist circumference, blood pressure, fasting serum lipid concentrations, or plasma glucose or serum insulin concentrations in the fasting state and following an oral glucose tolerance test. Haplotypes were tested for association with quantitative traits; however, only nominal association with blood pressure (P=0.04) and waist circumference (P=0.04) was observed. In case-control studies, no association was found for individual variants or the three-marker haplotype. CONCLUSION LPIN1 rs33997857, rs6744682, and rs6708316 did not associate with type 2 diabetes, obesity, or related quantitative metabolic phenotypes in the Danish population examined.
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Chan JL, Oral EA. Clinical classification and treatment of congenital and acquired lipodystrophy. Endocr Pract 2010; 16:310-23. [PMID: 20061300 DOI: 10.4158/ep09154.ra] [Citation(s) in RCA: 57] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
OBJECTIVE To review the initial clinical manifestations of congenital and acquired lipodystrophy syndromes, discuss novel classifications associated with genetic mutations, and assess currently available therapeutic options for patients with lipodystrophy. METHODS This review is the result of the authors' collective clinical experience and a comprehensive MEDLINE literature search on the English-language literature published between January 1966 and October 2009 on "lipodystrophy." This review focuses primarily on severe dystrophy not related to human immunodeficiency virus (HIV) infection, in light of the additional scope required to cover HIV-related lipodystrophy. RESULTS Congenital lipodystrophy syndromes are characterized by a paucity of adipose tissue and classified on the basis of the extent of fat loss and heritability Paradoxically, they are associated with metabolic abnormalities often found in obese patients, including insulin resistance, diabetes, and severe hypertriglyceridemia. Patients with severe forms of lipodystrophy are also deficient in adipokines such as leptin, which may contribute to metabolic abnormalities. The search for molecular defects has revealed a role for genes that affect adipocyte differentiation (for example, peroxisome proliferator-activated receptor gamma), lipid droplet morphology (seipin, caveolin-1), or lipid metabolism (AGPAT2). Others (lamin A/C) are known to be associated with completely different diseases. There are also acquired forms of lipodystrophy that are thought to occur primarily attributable to autoimmune mechanisms. Recently, recombinant leptin has emerged as a useful therapy. CONCLUSION Lipodystrophy syndromes have advanced our understanding of the physiologic role of adipose tissue and allowed identification of key molecular mechanisms involved in adipocyte differentiation. Novel therapeutic strategies are being developed on the basis of the pathophysiologic aspects of these syndromes.
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Affiliation(s)
- Jean L Chan
- Amylin Pharmaceuticals, Inc., San Diego, California, USA
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Chang YC, Chang LY, Chang TJ, Jiang YD, Lee KC, Kuo SS, Lee WJ, Chuang LM. The associations of LPIN1 gene expression in adipose tissue with metabolic phenotypes in the Chinese population. Obesity (Silver Spring) 2010; 18:7-12. [PMID: 19543209 DOI: 10.1038/oby.2009.198] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
The LPIN1 gene, encoding lipin-1 protein, plays critical roles in adipocyte differentiation and lipid metabolism. This study aimed to analyze the association of LPIN1 mRNA levels in human adipose tissue with metabolic phenotypes. We also examined the association of LPIN1 genetic variation with type 2 diabetes and related metabolic phenotypes in the Chinese population. The relative LPIN1 mRNA levels were measured in abdominal visceral (VAT) and subcutaneous adipose tissue (SAT) obtained from 102 nondiabetic Chinese females. Seven single-nucleotide polymorphisms (SNPs) spanning from the 5'-upstream region to the 3'-end of the LPIN1 gene were genotyped in 1,520 Chinese (760 type 2 diabetic cases and 760 controls). LPIN1 mRNA levels in VAT were negatively correlated with BMI (r = -0.21, P = 0.03), body fat percentage (r = -0.22, P = 0.02), plasma triglycerides levels (r = -0.21, P = 0.03), and plasma leptin levels (r = -0.63, P = 0.0002). LPIN1 mRNA levels were positively correlated with PPARG and ADIPOQ mRNA levels in both VAT and SAT. No single SNP of the LPIN1 gene was associated with type 2 diabetes in our population. One rare haplotype showed a significant association with type 2 diabetes (odds ratio (OR), 4.35; 95% confidence interval, 1.86-11.75; P = 4 x 10(-4)). No SNP or haplotype of the LPIN1 gene was associated with quantitative metabolic traits in the nondiabetic subjects. The results confirmed the association of LPIN1 gene expression in adipose tissue with lower adiposity and favorable metabolic profiles in the Chinese population. However, the LPIN1 gene seemed not to be a major susceptibility gene for type 2 diabetes or related metabolic phenotypes in the Chinese population.
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Affiliation(s)
- Yi-Cheng Chang
- Department of Internal Medicine, National Taiwan University Hospital, Yun-Lin Branch, Yun-Lin, Taiwan
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Takeuchi K, Reue K. Biochemistry, physiology, and genetics of GPAT, AGPAT, and lipin enzymes in triglyceride synthesis. Am J Physiol Endocrinol Metab 2009; 296:E1195-209. [PMID: 19336658 PMCID: PMC2692402 DOI: 10.1152/ajpendo.90958.2008] [Citation(s) in RCA: 318] [Impact Index Per Article: 19.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/29/2008] [Accepted: 03/30/2009] [Indexed: 01/19/2023]
Abstract
Triacylglycerol (TAG) synthesis and storage in tissues such as adipose tissue and liver have important roles in metabolic homeostasis. The molecular identification of genes encoding enzymes that catalyze steps in TAG biosynthesis from glycerol 3-phosphate has revealed an unexpected number of protein isoforms of the glycerol phosphate acyltransferase (GPAT), acylglycerolphosphate acyltransferase (AGPAT), and lipin (phosphatidate phosphatase) families that appear to catalyze similar biochemical reactions. However, on the basis of available data for a few members in which genetic deficiencies in mouse and/or human have been studied, we postulate that each GPAT, AGPAT, and lipin family member likely has a specialized role that may be uncovered through careful biochemical and physiological analyses.
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Affiliation(s)
- Kazuharu Takeuchi
- Dept. of Human Genetics, Gonda 6506A, David Geffen School of Medicine at UCLA, 695 Charles E. Young Drive South, Los Angeles, CA 90095, USA
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Abstract
PURPOSE OF REVIEW The family of three lipin proteins act as phosphatidate phosphatase (PAP) enzymes required for glycerolipid biosynthesis, and also as transcriptional coactivators that regulate expression of lipid metabolism genes. The genes for lipin-1, lipin-2 and lipin-3 are expressed in key metabolic tissues, including adipose tissue, skeletal muscle and liver, but the physiological functions of each member of the family have not been fully elucidated. Here we examine the most recent studies that provide information about the roles of lipin proteins in metabolism and human disease. RECENT FINDINGS Recent studies have identified mutations that cause lipin-1 or lipin-2 deficiency in humans, leading to acute myoglobinuria in childhood or the inflammatory disorder Majeed syndrome, respectively. The effects of lipin-1 deficiency appear to include both the loss of glycerolipid building blocks and the accumulation of lipid intermediates that disrupt cellular function. Several studies have demonstrated that polymorphisms in the LPIN1 and LPIN2 genes are associated with metabolic disease traits, including insulin sensitivity, diabetes, blood pressure and response to thiazolidinedione drugs. Furthermore, lipin-1 expression levels in adipose tissue and/or liver are positively correlated with insulin sensitivity. Studies of lipin-1 in adipocytes have shed some light on its relationship with insulin sensitivity. SUMMARY Lipin-1 and lipin-2 are required for normal lipid homeostasis and have unique physiological roles. Future studies, for example using engineered mouse models, will be required to fully elucidate their specific roles in normal physiology and disease.
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Affiliation(s)
- Karen Reue
- Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, California, USA.
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Current literature in diabetes. Diabetes Metab Res Rev 2009; 25:i-x. [PMID: 19219862 DOI: 10.1002/dmrr.918] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
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Abstract
The lipin protein family, consisting of three members, was first identified early this century. In the last few years, the lipin proteins have been shown to have important roles in glycerolipid biosynthesis and gene regulation, and mutations in the corresponding genes cause lipodystrophy, myoglobinuria, and inflammatory disorders. Here, we review some of the progress toward elucidating the molecular and physiological functions of the lipin proteins.
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Affiliation(s)
- Karen Reue
- Department of Human Genetics, University of California, Los Angeles, CA 90095, USA.
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Reue K, Brindley DN. Thematic Review Series: Glycerolipids. Multiple roles for lipins/phosphatidate phosphatase enzymes in lipid metabolism. J Lipid Res 2008; 49:2493-503. [PMID: 18791037 DOI: 10.1194/jlr.r800019-jlr200] [Citation(s) in RCA: 141] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
Abstract
Phosphatidate phosphatase-1 (PAP1) enzymes have a key role in glycerolipid synthesis through the conversion of phosphatidate to diacylglycerol, the immediate precursor of triacylglycerol, phosphatidylcholine, and phosphatidylethanolamine. PAP1 activity in mammals is determined by the lipin family of proteins, lipin-1, lipin-2, and lipin-3, which each have distinct tissue expression patterns and appear to have unique physiological functions. In addition to its role in glycerolipid synthesis, lipin-1 also operates as a transcriptional coactivator, working in collaboration with known nuclear receptors and coactivators to modulate lipid metabolism gene expression. The requirement for different lipin activities in vivo is highlighted by the occurrence of lipodystrophy, insulin resistance, and neuropathy in a lipin-1-deficient mutant mouse strain. In humans, variations in lipin-1 expression levels and gene polymorphisms are associated with insulin sensitivity, metabolic rate, hypertension, and risk for the metabolic syndrome. Furthermore, critical mutations in lipin-2 result in the development of an inflammatory disorder in human patients. A key goal of future studies will be to further elucidate the specific roles and modes of regulation of each of the three lipin proteins in key metabolic processes, including triglyceride and phospholipid synthesis, fatty acid metabolism, and insulin sensitivity.
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Affiliation(s)
- Karen Reue
- Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
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