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1
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Habib S. Team players in the pathogenesis of metabolic dysfunctions-associated steatotic liver disease: The basis of development of pharmacotherapy. World J Gastrointest Pathophysiol 2024; 15:93606. [PMID: 39220834 PMCID: PMC11362842 DOI: 10.4291/wjgp.v15.i4.93606] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2024] [Revised: 05/14/2024] [Accepted: 07/23/2024] [Indexed: 08/22/2024] Open
Abstract
Nutrient metabolism is regulated by several factors. Social determinants of health with or without genetics are the primary regulator of metabolism, and an unhealthy lifestyle affects all modulators and mediators, leading to the adaptation and finally to the exhaustion of cellular functions. Hepatic steatosis is defined by presence of fat in more than 5% of hepatocytes. In hepatocytes, fat is stored as triglycerides in lipid droplet. Hepatic steatosis results from a combination of multiple intracellular processes. In a healthy individual nutrient metabolism is regulated at several steps. It ranges from the selection of nutrients in a grocery store to the last step of consumption of ATP as an energy or as a building block of a cell as structural component. Several hormones, peptides, and genes have been described that participate in nutrient metabolism. Several enzymes participate in each nutrient metabolism as described above from ingestion to generation of ATP. As of now several publications have revealed very intricate regulation of nutrient metabolism, where most of the regulatory factors are tied to each other bidirectionally, making it difficult to comprehend chronological sequence of events. Insulin hormone is the primary regulator of all nutrients' metabolism both in prandial and fasting states. Insulin exerts its effects directly and indirectly on enzymes involved in the three main cellular function processes; metabolic, inflammation and repair, and cell growth and regeneration. Final regulators that control the enzymatic functions through stimulation or suppression of a cell are nuclear receptors in especially farnesoid X receptor and peroxisome proliferator-activated receptor/RXR ligands, adiponectin, leptin, and adiponutrin. Insulin hormone has direct effect on these final modulators. Whereas blood glucose level, serum lipids, incretin hormones, bile acids in conjunction with microbiota are intermediary modulators which are controlled by lifestyle. The purpose of this review is to overview the key players in the pathogenesis of metabolic dysfunction-associated steatotic liver disease (MASLD) that help us understand the disease natural course, risk stratification, role of lifestyle and pharmacotherapy in each individual patient with MASLD to achieve personalized care and target the practice of precision medicine. PubMed and Google Scholar databases were used to identify publication related to metabolism of carbohydrate and fat in states of health and disease states; MASLD, cardiovascular disease and cancer. More than 1000 publications including original research and review papers were reviewed.
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Affiliation(s)
- Shahid Habib
- Department of Hepatology, Liver Institute PLLC, Tucson, AZ 85712, United States
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2
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Josloff K, Beiriger J, Khan A, Gawel RJ, Kirby RS, Kendrick AD, Rao AK, Wang RX, Schafer MM, Pearce ME, Chauhan K, Shah YB, Marhefka GD, Halegoua-DeMarzio D. Comprehensive Review of Cardiovascular Disease Risk in Nonalcoholic Fatty Liver Disease. J Cardiovasc Dev Dis 2022; 9:419. [PMID: 36547416 PMCID: PMC9786069 DOI: 10.3390/jcdd9120419] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2022] [Revised: 11/16/2022] [Accepted: 11/23/2022] [Indexed: 11/29/2022] Open
Abstract
Nonalcoholic Fatty Liver Disease (NAFLD) is a growing global phenomenon, and its damaging effects in terms of cardiovascular disease (CVD) risk are becoming more apparent. NAFLD is estimated to affect around one quarter of the world population and is often comorbid with other metabolic disorders including diabetes mellitus, hypertension, coronary artery disease, and metabolic syndrome. In this review, we examine the current evidence describing the many ways that NAFLD itself increases CVD risk. We also discuss the emerging and complex biochemical relationship between NAFLD and its common comorbid conditions, and how they coalesce to increase CVD risk. With NAFLD's rising prevalence and deleterious effects on the cardiovascular system, a complete understanding of the disease must be undertaken, as well as effective strategies to prevent and treat its common comorbid conditions.
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Affiliation(s)
- Kevan Josloff
- Sidney Kimmel Medical College, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
| | - Jacob Beiriger
- Sidney Kimmel Medical College, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
| | - Adnan Khan
- Department of Internal Medicine, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
| | - Richard J. Gawel
- Sidney Kimmel Medical College, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
| | - Richard S. Kirby
- Sidney Kimmel Medical College, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
| | - Aaron D. Kendrick
- Sidney Kimmel Medical College, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
| | - Abhinav K. Rao
- Sidney Kimmel Medical College, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
| | - Roy X. Wang
- Sidney Kimmel Medical College, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
| | - Michelle M. Schafer
- Sidney Kimmel Medical College, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
| | - Margaret E. Pearce
- Sidney Kimmel Medical College, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
| | - Kashyap Chauhan
- Department of Internal Medicine, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
| | - Yash B. Shah
- Sidney Kimmel Medical College, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
| | - Gregary D. Marhefka
- Department of Internal Medicine, Division of Cardiology, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
| | - Dina Halegoua-DeMarzio
- Department of Internal Medicine, Division of Gastroenterology & Hepatology, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
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3
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Pansa CC, Molica LR, Moraes KCM. Non-alcoholic fatty liver disease establishment and progression: genetics and epigenetics as relevant modulators of the pathology. Scand J Gastroenterol 2022; 58:521-533. [PMID: 36426638 DOI: 10.1080/00365521.2022.2148835] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
BACKGROUND Non-alcoholic fatty liver disease (NAFLD) results from metabolic dysfunctions that affect more than one-third of the world population. Over the last decades, scientific investigations have clarified many details on the pathology establishment and development; however, effective therapeutics approaches are still evasive. In addition, studies demonstrated that NAFLD establishment and progression are related to several etiologies. Recently, genetics and epigenetics backgrounds have emerged as relevant elements to the pathology onset, and, hence, deserve deep investigation to clarify molecular details on NAFLD signaling, which may be correlated with population behavior. Thus, to minimize the global problem, public health and public policies should take advantage of studies on NAFLD over the next following decades. METHODS In this context, we have performed a selective literature review focusing on biochemistry of lipid metabolism, genetics, epigenetics, and the ethnicity as strong elements that drive NAFLD establishment. RESULTS Considering the etiological agents that acts on NAFLD development and progression, the genetics and the epigenetics emerged as relevant factors. Genetics acts as a powerful element in the establishment and progression of the NAFLD. Over the last decades, details concerning genes and their polymorphisms, as well as epigenetics, have been considered relevant elements in the systems biology of diseases, and their effects on NAFLD should be considered in-depth, as well as the ethnicity, clarifying whether people are susceptible to liver diseases. Moreover, the endemicity and social problems of hepatic disfunction are far to be solved, which require a combined effort of various sectors of society. CONCLUSION Hence, the elements presented and discussed in this short review demonstrated their relevance to the physiological control of NAFLD, opening perspectives for research to develop new strategy to treat fatty liver diseases.
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Affiliation(s)
- Camila Cristiane Pansa
- Departamento de Biologia Geral e Aplicada, Cellular Signalling and Gene Expression Laboratory, Universidade Estadual Paulista "Júlio de Mesquita Filho", Instituto de Biociências, Rio Claro, Brazil
| | - Letícia Ramos Molica
- Departamento de Biologia Geral e Aplicada, Cellular Signalling and Gene Expression Laboratory, Universidade Estadual Paulista "Júlio de Mesquita Filho", Instituto de Biociências, Rio Claro, Brazil
| | - Karen C M Moraes
- Departamento de Biologia Geral e Aplicada, Cellular Signalling and Gene Expression Laboratory, Universidade Estadual Paulista "Júlio de Mesquita Filho", Instituto de Biociências, Rio Claro, Brazil
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4
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Wajsbrot NB, Leite NC, Salles GF, Villela-Nogueira CA. Non-alcoholic fatty liver disease and the impact of genetic, epigenetic and environmental factors in the offspring. World J Gastroenterol 2022; 28:2890-2899. [PMID: 35978876 PMCID: PMC9280730 DOI: 10.3748/wjg.v28.i25.2890] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Revised: 03/20/2022] [Accepted: 05/14/2022] [Indexed: 02/06/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide and is strongly associated with metabolic deregulation. More recently, a significant impact of parental NAFLD in the offspring was demonstrated and has been widely discussed. However, pathogenetic pathways implicated in the inheritance by the offspring and relatives are still under debate. Probably, multiple mechanisms are involved as well as in NAFLD pathogenesis itself. Among the multifactorial involved mechanisms, genetic, epigenetic and environmental backgrounds are strongly related to NAFLD development in the offspring. Thus, based on recent evidence from the available literature concerning genetic, epigenetic and environmental disease modifiers, this review aimed to discuss the relationship between parental NAFLD and its impact on the offspring.
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Affiliation(s)
- Natalia Balassiano Wajsbrot
- Division of Hepatology, Clementino Fraga Filho University Hospital, Federal University of Rio de Janeiro, Rio de Janeiro 20941-913, Brazil
| | - Nathalie Carvalho Leite
- Division of Hepatology, Clementino Fraga Filho University Hospital, Federal University of Rio de Janeiro, Rio de Janeiro 20941-913, Brazil
| | - Gil F Salles
- Department of Internal Medicine, Medical School, Federal University of Rio de Janeiro, Rio de Janeiro 22750-240, Brazil
| | - Cristiane A Villela-Nogueira
- Department of Internal Medicine, Medical School, Federal University of Rio de Janeiro, Rio de Janeiro 22750-240, Brazil
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Heritability analysis of liver stiffness detected by ultrasound shear wave elastography: a twin study. Eur J Gastroenterol Hepatol 2021; 33:e766-e770. [PMID: 34284414 DOI: 10.1097/meg.0000000000002246] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Abstract
OBJECTIVES OF THE STUDY Nonalcoholic fatty liver disease (NAFLD) is a common condition with a subset of individuals developing liver fibrosis as a major risk factor for advanced liver disease. The contribution of genetic factors to this progression remains incompletely understood. Our aim was to analyze heritability in the development of liver fibrosis estimated by ultrasound shear wave elastography (SWE) in an asymptomatic adult twin cohort. METHODS In total 172 adult Hungarian twins (51 monozygotic and 36 dizygotic pairs; 63% women; mean age 54.9 ± 15.1 years) underwent B-mode ultrasonography to assess steatosis and SWE to determine Young's modulus as a noninvasive marker or liver fibrosis. RESULTS We identified 99 subjects with steatosis, which was mild in 46 subjects (46%), moderate in 52 subjects (52%) and severe in a single subject (1%). Mean Young's modulus was 7.58 ± 3.53 kPa in this slightly overweight study cohort (BMI: 25.7 ± 4.6 kg/m2). Univariate analysis adjusted for age, sex and BMI indicated no discernible role for genetic components in the presence of liver stiffness, whereas shared and unshared environmental effects accounted for 38.3% (95% confidence interval (CI), 17-56.1%) and 61.7% (95% CI, 43.9-83%). CONCLUSIONS Our findings do not support the heritability of liver stiffness in an asymptomatic, twin cohort with slight overweight and variable degree of steatosis, underscoring the importance of environmental factors in the development of NAFLD and liver fibrosis.
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Dong M, Liu S, Wang M, Wang Y, Xin Y, Xuan S. Relationship between AGT rs2493132 polymorphism and the risk of coronary artery disease in patients with NAFLD in the Chinese Han population. J Int Med Res 2021; 49:3000605211019263. [PMID: 34275374 PMCID: PMC8293844 DOI: 10.1177/03000605211019263] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Objective To investigate the relationship between angiotensin (AGT) rs2493132 gene polymorphism and the risk of developing non-alcoholic fatty liver disease (NAFLD) and coronary artery disease (CAD) in the Chinese Han population. Methods Polymerase chain reaction was performed to determine AGT genotypes. Anthropometric and clinical data were investigated and statistically analyzed in the clinical laboratory department of Qingdao Municipal Hospital. Results The AGT rs2493132 CT + TT genotype was an important risk factor for CAD in patients with NAFLD and NAFLD + CAD in healthy controls. The AGT rs2493132 T allele increased the risk of NAFLD + CAD in healthy controls. The AGT rs2493132 CT + TT genotype and T allele also significantly increased the risk of CAD in patients with NAFLD after adjustments for age, sex, and body mass index. In addition, AGT rs2493132 T allele carriers showed higher total cholesterol (TC) and low-density lipoprotein (LDL) levels compared with non-carriers. Conclusions The AGT rs2493132 CT + TT genotype and T allele significantly increased the risk of developing CAD in patients with NAFLD in the Chinese Han population. The AGT rs2493132 T allele was associated with increased serum TC and LDL levels.
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Affiliation(s)
- Mengzhen Dong
- Department of Infectious Disease, Qingdao Municipal Hospital, Qingdao University, Qingdao, China
| | - Shousheng Liu
- Clinical Research Center, Qingdao Municipal Hospital, Qingdao University, Qingdao, China.,Digestive Disease Key Laboratory of Qingdao, Qingdao, China
| | - Mengke Wang
- Department of Infectious Disease, Qingdao Municipal Hospital, Qingdao University, Qingdao, China
| | - Yifen Wang
- Department of Infectious Disease, Qingdao Municipal Hospital, Qingdao University, Qingdao, China
| | - Yongning Xin
- Department of Infectious Disease, Qingdao Municipal Hospital, Qingdao University, Qingdao, China.,Clinical Research Center, Qingdao Municipal Hospital, Qingdao University, Qingdao, China.,Digestive Disease Key Laboratory of Qingdao, Qingdao, China.,Department of Gastroenterology, Qingdao Municipal Hospital, Qingdao University, Qingdao, China
| | - Shiying Xuan
- Department of Infectious Disease, Qingdao Municipal Hospital, Qingdao University, Qingdao, China.,Digestive Disease Key Laboratory of Qingdao, Qingdao, China
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7
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Akkiz H, Taskin E, Karaogullarindan U, Delik A, Kuran S, Kutlu O. The influence of RS738409 I148M polymorphism of patatin-like phospholipase domain containing 3 gene on the susceptibility of non-alcoholic fatty liver disease. Medicine (Baltimore) 2021; 100:e25893. [PMID: 34106646 PMCID: PMC8133255 DOI: 10.1097/md.0000000000025893] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Accepted: 04/21/2021] [Indexed: 01/14/2023] Open
Abstract
We aimed to elucidate the frequency of polymorphic genotypes and alleles of patatin-like phospholipase domain containing 3 rs738409 polymorphism and its possible associations with non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis in a cohort from Turkey.We enrolled 200 patients diagnosed with NAFLD and genotyped for rs738409 I148M polymorphism by real-time polymerase chain reaction, particularly by melting curve analysis. SPSS analysis software was used for statistical significance. Continuous variable values were expressed as mean ± standard deviation. Significant statistical level was chosen as p = 0.05.Our results demonstrate in a cohort from Turkey that rs738409 C > G polymorphism (I148M) of patatin-like phospholipase domain containing 3 gene is significantly able to affect individuals to have NAFLD in unadjusted regression model.Consistent with the previous studies in other populations, our study group showed a significantly higher risk of having NAFLD in unadjusted regression model but not in the adjusted model indicating that non-genetic factors such as age and sex may be responsible for the association. However, independent studies need to validate our findings with a larger group of NAFLD patients, as well as in different ethnic cohorts.
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Affiliation(s)
- Hikmet Akkiz
- Cukurova University, Medical Faculty, Department of Gastroenterology, Adana
| | - Emre Taskin
- Karabuk University, Medical Faculty, Department of Medical Biology and Genetics, Karabuk
| | | | - Anil Delik
- Cukurova University, Faculty of Natural and Applied Science, Department of Biology, Adana
| | - Sedef Kuran
- Cukurova University, Medical Faculty, Department of Gastroenterology, Adana
| | - Ozlem Kutlu
- Sabanci University Nanotechnology Research and Application Center, Istanbul, Turkey
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8
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Choudhary NS, Duseja A. Genetic and epigenetic disease modifiers: non-alcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD). Transl Gastroenterol Hepatol 2021; 6:2. [PMID: 33409397 DOI: 10.21037/tgh.2019.09.06] [Citation(s) in RCA: 60] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2019] [Accepted: 09/04/2019] [Indexed: 12/12/2022] Open
Abstract
Inter-individual and inter-ethnic differences and difference in the severity and progression of liver disease among patients with non-alcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD) suggests the involvement of genetic and epigenetic factors in their pathogenesis. This article reviews the genetic and epigenetic modifiers in patients with NAFLD and ALD. Evidence regarding the genetic and epigenetic disease modifiers of NAFLD and ALD was reviewed by searching the available literature. Both genome wide association studies (GWAS) and candidate gene studies pertaining to the pathogenesis in both diseases were included. Clinical implications of the available information are also discussed. Several studies have shown association of both NAFLD and ALD with I148M PNPLA3 variant. In addition to the higher prevalence of hepatic steatosis, the I148M PNPLA3 variant is also associated with severity of liver disease and risk of hepatocellular carcinoma (HCC). TM6SF2 is the other genetic variant shown to be significantly associated with hepatic steatosis and cirrhosis in patients with NAFLD and ALD. The Membrane bound O-acyltransferase domain-containing 7 (MBOAT7) genetic variant is also associated with both NAFLD and ALD. In addition to these mutations, several variants related to the genes involved in glucose metabolism, insulin resistance, lipid metabolism, oxidative stress, inflammatory pathways, fibrosis have also been shown to be the disease modifiers in patients with NAFLD and ALD. Epigenetics involving several micro RNAs and DNA methylation could also modify the disease course in NAFLD and ALD. In conclusion the available literature suggests that genetics and epigenetics are involved in the pathogenesis of NAFLD and ALD which may affect the disease prevalence, severity and response to treatment in these patients.
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Affiliation(s)
- Narendra Singh Choudhary
- Institute of Liver Transplantation and Regenerative Medicine, Medanta, The Medicity, Gurgaon, Delhi (NCR), India
| | - Ajay Duseja
- Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
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9
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Brouwers MCGJ, de Graaf J, Simons N, Meex S, Ten Doeschate S, van Heertum S, Heidemann B, Luijten J, de Boer D, Schaper N, Stehouwer CDA, van Greevenbroek MMJ. Incidence of type 2 diabetes in familial combined hyperlipidemia. BMJ Open Diabetes Res Care 2020; 8:8/1/e001107. [PMID: 32193201 PMCID: PMC7103854 DOI: 10.1136/bmjdrc-2019-001107] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2019] [Revised: 02/12/2020] [Accepted: 02/22/2020] [Indexed: 12/13/2022] Open
Abstract
OBJECTIVE Familial combined hyperlipidemia (FCHL) is common among survivors of a premature myocardial infarction. FCHL patients are characterized by visceral obesity, fatty liver, and insulin resistance. The aim of the present study was to determine the incidence and determinants of type 2 diabetes (T2D) in a longitudinal cohort of FCHL pedigrees. RESEARCH DESIGN AND METHODS FCHL patients, their unaffected relatives and spouses included in our baseline cohort in 1998-2005 (n=596) were re-invited to determine the incidence of self-reported T2D (that was confirmed by medical records), used as the primary outcome measure. The Fatty Liver Index (FLI) and Homeostasis Model Assessment Insulin Resistance (HOMA2-IR) were used as markers of fatty liver and insulin resistance, respectively. A subset of the original cohort underwent ultrasound of the liver, and subcutaneous and visceral fat in 2002-2005 (n=275; 'ultrasound subcohort'). RESULTS Follow-up data (median: 15 years) was acquired for 76%. The incidence rate of T2D was significantly higher in FCHL patients compared with spouses (19.2 per 1000 person-years vs 2.8 per 1000 person-years; HR : 6.3, 95% CI: 2.4 to 16.8), whereas no differences were observed between unaffected relatives and spouses (HR: 0.9, 95% CI: 0.3 to 2.6). Cox's proportional hazard regression analyses showed that baseline HOMA2-IR and FLI≥60, but not waist circumference, BMI, or the FCHL affected state, were independently associated with incident T2D. Similar results were obtained in the ultrasound subcohort (median follow-up: 11 years), in which baseline HOMA2-IR and fatty liver (assessed by ultrasound) were independently associated with incident T2D. CONCLUSION This study further corroborates the suggestion that the liver plays a central role in the pathogenesis of cardiometabolic complications in FCHL. It supports periodical screening for T2D in this high-risk population.
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Affiliation(s)
- Martijn C G J Brouwers
- Department of Internal Medicine, Division of Endocrinology and Metabolic Disease, CARIM School for Cardiovascular Diseases, Maastricht University Medical Centre, Maastricht, The Netherlands
| | - Jacqueline de Graaf
- Department of Internal Medicine, Radboud Institute for Health Sciences, Radboudumc, Nijmegen, The Netherlands
| | - Nynke Simons
- Department of Internal Medicine, Division of Endocrinology and Metabolic Disease, CARIM School for Cardiovascular Diseases, Maastricht University Medical Centre, Maastricht, The Netherlands
- Department of Internal Medicine, Division of General Internal Medicine, Laboratory for Metabolism and Vascular Medicine, CARIM School for Cardiovascular Diseases, Maastricht University, Maastricht, The Netherlands
| | - Steven Meex
- Central Diagnostic Laboratory, Maastricht University Medical Centre, Maastricht, The Netherlands
| | - Sophie Ten Doeschate
- Department of Internal Medicine, Division of Endocrinology and Metabolic Disease, CARIM School for Cardiovascular Diseases, Maastricht University Medical Centre, Maastricht, The Netherlands
| | - Shadana van Heertum
- Department of Internal Medicine, Division of Endocrinology and Metabolic Disease, CARIM School for Cardiovascular Diseases, Maastricht University Medical Centre, Maastricht, The Netherlands
| | - Britt Heidemann
- Department of Internal Medicine, Division of Endocrinology and Metabolic Disease, CARIM School for Cardiovascular Diseases, Maastricht University Medical Centre, Maastricht, The Netherlands
| | - Jim Luijten
- Department of Internal Medicine, Division of Endocrinology and Metabolic Disease, CARIM School for Cardiovascular Diseases, Maastricht University Medical Centre, Maastricht, The Netherlands
| | - Douwe de Boer
- Central Diagnostic Laboratory, Maastricht University Medical Centre, Maastricht, The Netherlands
| | - Nicolaas Schaper
- Department of Internal Medicine, Division of Endocrinology and Metabolic Disease, CARIM School for Cardiovascular Diseases, Maastricht University Medical Centre, Maastricht, The Netherlands
| | - Coen D A Stehouwer
- Department of Internal Medicine, CARIM School for Cardiovascular Diseases, Maastricht University Medical Centre, Maastricht, The Netherlands
| | - Marleen M J van Greevenbroek
- Department of Internal Medicine, Division of General Internal Medicine, Laboratory for Metabolism and Vascular Medicine, CARIM School for Cardiovascular Diseases, Maastricht University, Maastricht, The Netherlands
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10
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Brouwers MCGJ, Simons N, Stehouwer CDA, Isaacs A. Non-alcoholic fatty liver disease and cardiovascular disease: assessing the evidence for causality. Diabetologia 2020; 63:253-260. [PMID: 31713012 PMCID: PMC6946734 DOI: 10.1007/s00125-019-05024-3] [Citation(s) in RCA: 86] [Impact Index Per Article: 17.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2019] [Accepted: 07/29/2019] [Indexed: 02/06/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is highly prevalent among individuals with type 2 diabetes. Although epidemiological studies have shown that NAFLD is associated with cardiovascular disease (CVD), it remains unknown whether NAFLD is an active contributor or an innocent bystander. Plasma lipids, low-grade inflammation, impaired fibrinolysis and hepatokines are potential mediators of the relationship between NAFLD and CVD. The Mendelian randomisation approach can help to make causal inferences. Studies that used common variants in PNPLA3, TM6SF2 and GCKR as instruments to investigate the relationship between NAFLD and coronary artery disease (CAD) have reported contrasting results. Variants in PNPLA3 and TM6SF2 were found to protect against CAD, whereas variants in GCKR were positively associated with CAD. Since all three genes have been associated with non-alcoholic steatohepatitis, the second stage of NAFLD, the question of whether low-grade inflammation is an important mediator of the relationship between NAFLD and CAD arises. In contrast, the differential effects of these genes on plasma lipids (i.e. lipid-lowering for PNPLA3 and TM6SF2, and lipid-raising for GCKR) strongly suggest that plasma lipids account for their differential effects on CAD risk. This concept has recently been confirmed in an extended set of 12 NAFLD susceptibility genes. From these studies it appears that plasma lipids are an important mediator between NAFLD and CVD risk. These findings have important clinical implications, particularly for the design of anti-NAFLD drugs that also affect lipid metabolism.
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Affiliation(s)
- Martijn C G J Brouwers
- Division of Endocrinology and Metabolic Disease, Department of Internal Medicine, Maastricht University Medical Centre, P. Debyelaan 25, 6229 HX, Maastricht, the Netherlands.
- Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, the Netherlands.
| | - Nynke Simons
- Division of Endocrinology and Metabolic Disease, Department of Internal Medicine, Maastricht University Medical Centre, P. Debyelaan 25, 6229 HX, Maastricht, the Netherlands
- Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, the Netherlands
- Laboratory for Metabolism and Vascular Medicine, Division of General Internal Medicine, Department of Internal Medicine, Maastricht University Medical Centre, Maastricht, the Netherlands
| | - Coen D A Stehouwer
- Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, the Netherlands
- Division of General Internal Medicine, Department of Internal Medicine, Maastricht University Medical Centre, Maastricht, the Netherlands
| | - Aaron Isaacs
- Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, the Netherlands
- Maastricht Centre for Systems Biology (MaCSBio), Maastricht University, Maastricht, the Netherlands
- Department of Biochemistry, Maastricht University, Maastricht, the Netherlands
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11
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Taghizadeh E, Esfehani RJ, Sahebkar A, Parizadeh SM, Rostami D, Mirinezhad M, Poursheikhani A, Mobarhan MG, Pasdar A. Familial combined hyperlipidemia: An overview of the underlying molecular mechanisms and therapeutic strategies. IUBMB Life 2019; 71:1221-1229. [PMID: 31271707 DOI: 10.1002/iub.2073] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2019] [Accepted: 05/03/2019] [Indexed: 12/30/2022]
Abstract
Among different types of dyslipidemia, familial combined hyperlipidemia (FCHL) is the most common genetic disorder, which is characterized by at least two different forms of lipid abnormalities: hypercholesterolemia and hypertriglyceridemia. FCHL is an important cause of cardiovascular diseases. FCHL is a heterogeneous condition linked with some metabolic defects that are closely associated with FCHL. These metabolic features include dysfunctional adipose tissue, delayed clearance of triglyceride-rich lipoproteins, overproduction of very low-density lipoprotein and hepatic lipids, and defect in the clearance of low-density lipoprotein particles. There are also some genes associated with FCHL such as those affecting the metabolism and clearance of plasma lipoprotein particles. Due to the high prevalence of FCHL especially in cardiovascular patients, targeted treatment is ideal but this necessitates identification of the genetic background of patients. This review describes the metabolic pathways and associated genes that are implicated in FCHL pathogenesis. We also review existing and novel treatment options for FCHL. © 2019 IUBMB Life, 71(9):1221-1229, 2019.
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Affiliation(s)
- Eskandar Taghizadeh
- Department of Medical Genetics, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.,Cellular and Molecular Research Center, Yasuj University of Medical Sciences, Yasuj, Iran
| | - Reza Jafarzadeh Esfehani
- Department of Medical Genetics, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.,Medical Genetics Research Centre, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Amirhossein Sahebkar
- Neurogenic Inflammation Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.,Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran.,School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Seyed Mostafa Parizadeh
- Metabolic Syndrome Research Centre, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Daryoush Rostami
- Department of School Allied, Zabol University of Medical Sciences, Zabol, Iran
| | - Mohammadreza Mirinezhad
- Department of Medical Genetics, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Arash Poursheikhani
- Department of Medical Genetics, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Majid Ghayour Mobarhan
- Metabolic Syndrome Research Centre, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Alireza Pasdar
- Department of Medical Genetics, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.,Medical Genetics Research Centre, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.,Division of Applied Medicine, Medical School, University of Aberdeen, Aberdeen, UK
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12
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The Epidemiology, Risk Profiling and Diagnostic Challenges of Nonalcoholic Fatty Liver Disease. MEDICINES 2019; 6:medicines6010041. [PMID: 30889791 PMCID: PMC6473603 DOI: 10.3390/medicines6010041] [Citation(s) in RCA: 71] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/18/2019] [Revised: 03/08/2019] [Accepted: 03/09/2019] [Indexed: 12/11/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) encompasses a wide spectrum of liver damage from the more prevalent (75%⁻80%) and nonprogressive nonalcoholic fatty liver (NAFL) category to its less common and more ominous subset, nonalcoholic steatohepatitis (NASH). NAFLD is now the most common cause of chronic liver disease in the developed world and is a leading indication for liver transplantation in United States (US). The global prevalence of NAFLD is estimated to be 25%, with the lowest prevalence in Africa (13.5%) and highest in the Middle East (31.8%) and South America (30.4%). The increasing incidence of NAFLD has been associated with the global obesity epidemic and manifestation of metabolic complications, including hypertension, diabetes, and dyslipidemia. The rapidly rising healthcare and economic burdens of NAFLD warrant institution of preventative and treatment measures in the high-risk sub-populations in an effort to reduce the morbidity and mortality associated with NAFLD. Genetic, demographic, clinical, and environmental factors may play a role in the pathogenesis of NAFLD. While NAFLD has been linked with various genetic variants, including PNPLA-3, TM6SF2, and FDFT1, environmental factors may predispose individuals to NAFLD as well. NAFLD is more common in older age groups and in men. With regards to ethnicity, in the US, Hispanics have the highest prevalence of NAFLD, followed by Caucasians and then African-Americans. NAFLD is frequently associated with the components of metabolic syndrome, such as type 2 diabetes mellitus (T2DM), obesity, hypertension, and dyslipidemia. Several studies have shown that the adoption of a healthy lifestyle, weight loss, and pro-active management of individual components of metabolic syndrome can help to prevent, retard or reverse NAFLD-related liver damage. Independently, NAFLD increases the risk of premature cardiovascular disease and associated mortality. For this reason, a case can be made for screening of NAFLD to facilitate early diagnosis and to prevent the hepatic and extra-hepatic complications in high risk sub-populations with morbid obesity, diabetes, and other metabolic risk factors.
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13
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Taghizadeh E, Mardani R, Rostami D, Taghizadeh H, Bazireh H, Hayat SMG. Molecular mechanisms, prevalence, and molecular methods for familial combined hyperlipidemia disease: A review. J Cell Biochem 2018; 120:8891-8898. [DOI: 10.1002/jcb.28311] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2018] [Accepted: 11/28/2018] [Indexed: 11/05/2022]
Affiliation(s)
- Eskandar Taghizadeh
- Department of Medical Genetics Faculty of Medicine, Mashhad University of Medical Sciences Mashhad Iran
- Cellular and Molecular Research Center, Yasuj University of Medical Sciences Yasuj Iran
| | - Rajab Mardani
- Department of Biochemistry Pasteur Institute of Iran Tehran Iran
| | - Daryoush Rostami
- Department of School Allied Zabol University of Medical Sciences Zabol Iran
| | - Hassan Taghizadeh
- Cellular and Molecular Research Center, Yasuj University of Medical Sciences Yasuj Iran
| | - Homa Bazireh
- Department of Industrial and Environmental Biotechnology National Institute of Genetic Engineering and Biotechnology Tehran Iran
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14
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Stender S, Smagris E, Lauridsen BK, Kofoed KF, Nordestgaard BG, Tybjærg-Hansen A, Pennacchio LA, Dickel DE, Cohen JC, Hobbs HH. Relationship between genetic variation at PPP1R3B and levels of liver glycogen and triglyceride. Hepatology 2018; 67:2182-2195. [PMID: 29266543 PMCID: PMC5991995 DOI: 10.1002/hep.29751] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2017] [Revised: 10/31/2017] [Accepted: 12/18/2017] [Indexed: 12/15/2022]
Abstract
UNLABELLED Genetic variation at rs4240624 on chromosome 8 is associated with an attenuated signal on hepatic computerized tomography, which has been attributed to changes in hepatic fat. The closest coding gene to rs4240624, PPP1R3B, encodes a protein that promotes hepatic glycogen synthesis. Here, we performed studies to determine whether the x-ray attenuation associated with rs4240624 is due to differences in hepatic glycogen or hepatic triglyceride content (HTGC). A sequence variant in complete linkage disequilibrium with rs4240624, rs4841132, was genotyped in the Dallas Heart Study (DHS), the Dallas Liver Study, and the Copenhagen Cohort (n = 112,428) of whom 1,539 had nonviral liver disease. The minor A-allele of rs4841132 was associated with increased hepatic x-ray attenuation (n = 1,572; P = 4 × 10-5 ), but not with HTGC (n = 2,674; P = 0.58). Rs4841132-A was associated with modest, but significant, elevations in serum alanine aminotransferase (ALT) in the Copenhagen Cohort (P = 3 × 10-4 ) and the DHS (P = 0.004), and with odds ratios for liver disease of 1.13 (95% CI, 0.97-1.31) and 1.23 (1.01-1.51), respectively. Mice lacking protein phosphatase 1 regulatory subunit 3B (PPP1R3B) were deficient in hepatic glycogen, whereas HTGC was unchanged. Hepatic overexpression of PPP1R3B caused accumulation of hepatic glycogen and elevated plasma levels of ALT, but did not change HTGC. CONCLUSION These observations are consistent with the notion that the minor allele of rs4841132 promotes a mild form of hepatic glycogenosis that is associated with hepatic injury. (Hepatology 2018;67:2182-2195).
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Affiliation(s)
- Stefan Stender
- Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390,Department of McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, TX 75390
| | - Eriks Smagris
- Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390
| | - Bo K. Lauridsen
- Department of Clinical Biochemistry, Copenhagen University Hospital, Copenhagen University Hospital, Copenhagen, DK
| | - Klaus F. Kofoed
- Department of Cardiology and Radiology, Rigshospitalet, Copenhagen University Hospital, Copenhagen University Hospital, Copenhagen, DK
| | - Børge G. Nordestgaard
- Department of Clinical Biochemistry and Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, Copenhagen University Hospital, Copenhagen, DK,The Copenhagen City Heart Study, Frederiksberg Hospital, Copenhagen University Hospital, Copenhagen, DK
| | - Anne Tybjærg-Hansen
- Department of Clinical Biochemistry, Copenhagen University Hospital, Copenhagen University Hospital, Copenhagen, DK,Department of Clinical Biochemistry and Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, Copenhagen University Hospital, Copenhagen, DK,The Copenhagen City Heart Study, Frederiksberg Hospital, Copenhagen University Hospital, Copenhagen, DK
| | | | | | - Jonathan C. Cohen
- Department of McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, TX 75390
| | - Helen H. Hobbs
- Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390,Department of McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, TX 75390,Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX, 75390
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15
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den Biggelaar LJCJ, Eussen SJPM, Sep SJS, Mari A, Ferrannini E, van Greevenbroek MM, van der Kallen CJ, Schalkwijk CG, Arts ICW, Stehouwer CDA, Dagnelie PC. Prospective associations of dietary carbohydrate, fat, and protein intake with β-cell function in the CODAM study. Eur J Nutr 2018. [PMID: 29525890 PMCID: PMC6437317 DOI: 10.1007/s00394-018-1644-y] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
PURPOSE Type 2 diabetes mellitus (T2DM) is characterized by both impaired pancreatic β-cell function (BCF) and insulin resistance. In the etiology of T2DM, BCF basically determines whether a person with a certain degree of insulin resistance develops T2DM, as β-cells are able to compensatorily increase insulin secretion. The effects of dietary intake on BCF are largely unknown. Our study aim was to investigate whether dietary macronutrient intake predicts BCF. METHODS Prospective data (median follow-up 7 years) of 303 individuals recruited from the CODAM study population (aged 40-70 years, 39% women) were analyzed. BCF was measured by C-peptide deconvolution and physiological modeling of data from a 5-point, 75-g, 2-h oral glucose tolerance test. Macronutrient intake was estimated by a 178-item Food Frequency Questionnaire. RESULTS Associations adjusted for relevant covariates of baseline macronutrient intake with model-derived parameters describing BCF (glucose sensitivity, rate sensitivity or potentiation) or C-peptidogenic index were detected for trans fat [standardized regression coefficient (95%-CI) glucose sensitivity - 0.14 (- 0.26, - 0.01)] per g, cholesterol [potentiation 0.20 (0.02, 0.37)] per 100 mg, dietary fiber [glucose sensitivity 0.21 (0.08, 0.33)] per 10 g, MUFA glucose sensitivity 0.16 (0.02, 0.31) per 10 g, and polysaccharide [potentiation - 0.24 (- 0.43, - 0.05), C-peptidogenic index - 0.16 (- 0.29 - 0.03); odds ratio lowest versus highest tertile (95%-CI) rate sensitivity 1.51 (1.06, 2.15)) per 50 g. CONCLUSIONS In this population at high risk for developing T2DM, polysaccharide and trans fat intake were associated with worse BCF, whereas increased intake of MUFA, dietary cholesterol, and fiber were associated with better BCF.
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Affiliation(s)
- Louise J C J den Biggelaar
- Department of Epidemiology, Maastricht University, P.O. Box 616, 6200 MD, Maastricht, The Netherlands.,School for Cardiovascular Diseases (CARIM), Maastricht University, Maastricht, The Netherlands.,Department of Internal Medicine, Maastricht University Medical Centre, Maastricht, The Netherlands
| | - Simone J P M Eussen
- Department of Epidemiology, Maastricht University, P.O. Box 616, 6200 MD, Maastricht, The Netherlands. .,School for Cardiovascular Diseases (CARIM), Maastricht University, Maastricht, The Netherlands. .,Care and Public Health Research Institute (CAPHRI), Maastricht University, Maastricht, The Netherlands. .,Department of Internal Medicine, Maastricht University Medical Centre, Maastricht, The Netherlands.
| | - Simone J S Sep
- Care and Public Health Research Institute (CAPHRI), Maastricht University, Maastricht, The Netherlands.,Centre of Expertise in Rehabilitation and Audiology, Adelante, Hoensbroek, The Netherlands.,Department of Internal Medicine, Maastricht University Medical Centre, Maastricht, The Netherlands
| | - Andrea Mari
- CNR Institute of Clinical Physiology, Pisa, Italy.,Department of Internal Medicine, Maastricht University Medical Centre, Maastricht, The Netherlands
| | - Ele Ferrannini
- CNR Institute of Neuroscience, Padova, Italy.,Department of Internal Medicine, Maastricht University Medical Centre, Maastricht, The Netherlands
| | - Marleen M van Greevenbroek
- School for Cardiovascular Diseases (CARIM), Maastricht University, Maastricht, The Netherlands.,Department of Internal Medicine, Maastricht University Medical Centre, Maastricht, The Netherlands
| | - Carla J van der Kallen
- School for Cardiovascular Diseases (CARIM), Maastricht University, Maastricht, The Netherlands.,Department of Internal Medicine, Maastricht University Medical Centre, Maastricht, The Netherlands
| | - Casper G Schalkwijk
- School for Cardiovascular Diseases (CARIM), Maastricht University, Maastricht, The Netherlands.,Department of Internal Medicine, Maastricht University Medical Centre, Maastricht, The Netherlands
| | - Ilja C W Arts
- School for Cardiovascular Diseases (CARIM), Maastricht University, Maastricht, The Netherlands.,Maastricht Centre for Systems Biology (MaCSBio), Maastricht University, Maastricht, The Netherlands
| | - Coen D A Stehouwer
- School for Cardiovascular Diseases (CARIM), Maastricht University, Maastricht, The Netherlands.,Department of Internal Medicine, Maastricht University Medical Centre, Maastricht, The Netherlands
| | - Pieter C Dagnelie
- Department of Epidemiology, Maastricht University, P.O. Box 616, 6200 MD, Maastricht, The Netherlands.,School for Cardiovascular Diseases (CARIM), Maastricht University, Maastricht, The Netherlands.,Care and Public Health Research Institute (CAPHRI), Maastricht University, Maastricht, The Netherlands.,Department of Internal Medicine, Maastricht University Medical Centre, Maastricht, The Netherlands
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16
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Abstract
Liver fibrosis arises because prolonged injury combined with excessive scar deposition within hepatic parenchyma arising from overactive wound healing response mediated by activated myofibroblasts. Fibrosis is the common end point for any type of chronic liver injury including alcoholic liver disease, nonalcoholic fatty liver disease, viral hepatitis, and cholestatic liver diseases. Although genetic influences are important, it is epigenetic mechanisms that have been shown to orchestrate many aspects of fibrogenesis in the liver. New discoveries in the field are leading toward the development of epigenetic biomarkers and targeted therapies. This review considers epigenetic mechanisms as well as recent advances in epigenetic programming in the context of hepatic fibrosis.
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Key Words
- CLD, chronic liver disease
- Chronic Liver Disease
- CpG, cytosine-phospho-guanine
- DNA Methylation
- DNMT, DNA methyltransferase
- Epigenetics
- HDAC, histone deacetylase
- HSC, hepatic stellate cell
- Histone Modifications
- Liver Fibrosis
- NAFLD, nonalcoholic fatty liver disease
- PPAR, peroxisome proliferator activated receptor
- TET, Ten Eleven Translocation
- miRNA, microRNA
- ncRNA, non-coding RNA
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Affiliation(s)
| | - Jelena Mann
- Correspondence Address correspondence to: Jelena Mann, PhD, Institute of Cellular Medicine, Faculty of Medical Sciences, 4th Floor, William Leech Building, Newcastle University, Framlington Place, Newcastle upon Tyne, NE2 4HH United Kingdom. fax: +44-191-208-0723.Institute of Cellular MedicineFaculty of Medical Sciences4th FloorWilliam Leech BuildingNewcastle UniversityFramlington PlaceNewcastle upon TyneNE2 4HH United Kingdom
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17
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den Biggelaar LJCJ, Sep SJS, Eussen SJPM, Mari A, Ferrannini E, van Greevenbroek MMJ, van der Kallen CJH, Schalkwijk CG, Stehouwer CDA, Dagnelie PC. Discriminatory ability of simple OGTT-based beta cell function indices for prediction of prediabetes and type 2 diabetes: the CODAM study. Diabetologia 2017; 60:432-441. [PMID: 27933333 PMCID: PMC6518926 DOI: 10.1007/s00125-016-4165-3] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2016] [Accepted: 11/11/2016] [Indexed: 12/26/2022]
Abstract
AIMS/HYPOTHESIS The hyperglycaemic clamp technique and the frequently sampled IVGTT are unsuitable techniques to assess beta cell function (BCF) in large cohorts. Therefore, the aim of this study was to evaluate the discriminatory ability of simple OGTT-based BCF indices for prediction of prediabetes (meaning impaired fasting glucose and/or impaired glucose tolerance) and type 2 diabetes. METHODS Glucose metabolism status was assessed by 2 h 75 g OGTT at baseline (n = 476, mean age 59.2 years, 38.7% women) and after 7 years of follow-up (n = 416) in the Cohort on Diabetes and Atherosclerosis Maastricht (CODAM) study (1999-2009). Baseline plasma glucose, insulin and C-peptide values during OGTTs were used to calculate 21 simple indices of BCF. Disposition indices (BCF index × Matsuda index), to compensate for the prevailing level of insulin resistance, were calculated for the BCF indices with the best discriminatory abilities. The discriminatory ability of the BCF indices was estimated by the area under the receiver operating characteristics curve (ROC AUC) with an outcome of incident prediabetes (n = 73) or type 2 diabetes (n = 60 and n = 18 cases, respectively, in individuals who were non-diabetic or had normal glucose metabolism at baseline). RESULTS For incident prediabetes (n = 73), all ROC AUCs were less than 70%, whereas for incident type 2 diabetes, I30/I0, CP30/CP0, ΔI30/ΔG30, ΔCP30/ΔG30 (where I, CP and G are the plasma concentrations of insulin, C-peptide and glucose, respectively, at the times indicated), and corrected insulin response at 30 min had ROC AUCs over 70%. In at-baseline non-diabetic individuals, disposition indices ΔI30/ΔG30, ΔCP30/ΔG30 and corrected insulin response at 30 min had ROC AUCs of over 80% for incident type 2 diabetes. Moreover, these BCF disposition indices had significantly better discriminatory abilities for incident type 2 diabetes than the Matsuda index alone. CONCLUSIONS/INTERPRETATION BCF indices reflecting early-phase insulin secretion have the best ability to discriminate individuals who will develop prediabetes and type 2 diabetes. Of these, ΔCP30/ΔG30, often referred to as the C-peptidogenic index, performed consistently well.
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Affiliation(s)
- Louise J C J den Biggelaar
- Department of Epidemiology, Maastricht University, PO Box 616, 6200 MD, Maastricht, the Netherlands.
- School for Cardiovascular Diseases (CARIM), Maastricht University, Maastricht, the Netherlands.
| | - Simone J S Sep
- School for Cardiovascular Diseases (CARIM), Maastricht University, Maastricht, the Netherlands
- Department of Internal Medicine, Maastricht University Medical Center, Maastricht, the Netherlands
| | - Simone J P M Eussen
- Department of Epidemiology, Maastricht University, PO Box 616, 6200 MD, Maastricht, the Netherlands
- School for Cardiovascular Diseases (CARIM), Maastricht University, Maastricht, the Netherlands
- School for Public Health and Primary Care (CAPHRI), Maastricht University, Maastricht, the Netherlands
| | - Andrea Mari
- CNR Institute of Neurosciences, Padua, Italy
| | | | - Marleen M J van Greevenbroek
- School for Cardiovascular Diseases (CARIM), Maastricht University, Maastricht, the Netherlands
- Department of Internal Medicine, Maastricht University Medical Center, Maastricht, the Netherlands
| | - Carla J H van der Kallen
- School for Cardiovascular Diseases (CARIM), Maastricht University, Maastricht, the Netherlands
- Department of Internal Medicine, Maastricht University Medical Center, Maastricht, the Netherlands
| | - Casper G Schalkwijk
- School for Cardiovascular Diseases (CARIM), Maastricht University, Maastricht, the Netherlands
- Department of Internal Medicine, Maastricht University Medical Center, Maastricht, the Netherlands
| | - Coen D A Stehouwer
- School for Cardiovascular Diseases (CARIM), Maastricht University, Maastricht, the Netherlands
- Department of Internal Medicine, Maastricht University Medical Center, Maastricht, the Netherlands
| | - Pieter C Dagnelie
- Department of Epidemiology, Maastricht University, PO Box 616, 6200 MD, Maastricht, the Netherlands
- School for Cardiovascular Diseases (CARIM), Maastricht University, Maastricht, the Netherlands
- School for Public Health and Primary Care (CAPHRI), Maastricht University, Maastricht, the Netherlands
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18
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Zegers D, Verrijken A, Francque S, de Freitas F, Beckers S, Aerts E, Ruppert M, Hubens G, Michielsen P, Van Hul W, Van Gaal LF. Screening for rare variants in the PNPLA3 gene in obese liver biopsy patients. Clin Res Hepatol Gastroenterol 2016; 40:715-721. [PMID: 27288299 DOI: 10.1016/j.clinre.2016.05.004] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2015] [Revised: 04/07/2016] [Accepted: 05/02/2016] [Indexed: 02/04/2023]
Abstract
BACKGROUND Previous research has clearly implicated the PNPLA3 gene in the etiology of nonalcoholic fatty liver disease as a polymorphism in the gene was found to be robustly associated to the disease. However, data on the involvement of rare PNPLA3 variants in the development of nonalcoholic fatty liver disease (NAFLD) is currently limited. Therefore, we performed an extensive mutation analysis study on a cohort of obese liver biopsy patients to determine PNPLA3 variation and its correlation with fatty liver disease. METHODS We screened the entire coding region of the PNPLA3 gene in DNA samples of 393 obese liver biopsy patients with varying degrees of fatty liver disease. Mutation analysis was performed by high-resolution melting curve analysis in combination with direct sequencing. RESULTS We identified several common polymorphisms as well as one rare synonymous variant (c.867G>A rs139896256), one rare intronic variant (c.979+13C>T) and 3 nonsynonymous coding variants (p.A76T, p.A104V and p.T200M) in the PNPLA3 gene. In silico analysis indicated that the p.A104V variant will probably have no functional effect, whereas for the p.A76T and p.T200M variant a possible pathogenic effect is suggested. CONCLUSION Overall, we showed that novel variants in PNPLA3 are very rare in our liver biopsy cohort, thereby indicating that their impact on the etiology of NAFLD is probably limited. Nevertheless, for the three rare coding variants that were identified in patients with advanced liver disease, further functional characterization will be essential to verify their potential disease causality.
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Affiliation(s)
- Doreen Zegers
- Department of Medical Genetics, University of Antwerp, Universiteitsplein 1, 2610 Antwerp, Belgium
| | - An Verrijken
- Department of Endocrinology, Diabetology and Metabolic Diseases, Antwerp University Hospital and University of Antwerp, Wilrijkstraat 10, 2650 Antwerp, Belgium
| | - Sven Francque
- Department of Gastroenterology and Hepatology, Antwerp University Hospital and University of Antwerp, Wilrijkstraat 10, 2650 Antwerp, Belgium
| | - Fenna de Freitas
- Department of Medical Genetics, University of Antwerp, Universiteitsplein 1, 2610 Antwerp, Belgium
| | - Sigri Beckers
- Department of Medical Genetics, University of Antwerp, Universiteitsplein 1, 2610 Antwerp, Belgium
| | - Evi Aerts
- Department of Medical Genetics, University of Antwerp, Universiteitsplein 1, 2610 Antwerp, Belgium
| | - Martin Ruppert
- Department of Abdominal Surgery, Antwerp University Hospital and University of Antwerp, Wilrijkstraat 10, 2650 Antwerp, Belgium
| | - Guy Hubens
- Department of Abdominal Surgery, Antwerp University Hospital and University of Antwerp, Wilrijkstraat 10, 2650 Antwerp, Belgium
| | - Peter Michielsen
- Department of Gastroenterology and Hepatology, Antwerp University Hospital and University of Antwerp, Wilrijkstraat 10, 2650 Antwerp, Belgium
| | - Wim Van Hul
- Department of Medical Genetics, University of Antwerp, Universiteitsplein 1, 2610 Antwerp, Belgium.
| | - Luc F Van Gaal
- Department of Endocrinology, Diabetology and Metabolic Diseases, Antwerp University Hospital and University of Antwerp, Wilrijkstraat 10, 2650 Antwerp, Belgium
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19
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Cui J, Chen CH, Lo MT, Schork N, Bettencourt R, Gonzalez MP, Bhatt A, Hooker J, Shaffer K, Nelson KE, Long MT, Brenner DA, Sirlin CB, Loomba R, for the Genetics of NAFLD in Twins. Shared genetic effects between hepatic steatosis and fibrosis: A prospective twin study. Hepatology 2016; 64:1547-1558. [PMID: 27315352 PMCID: PMC5090982 DOI: 10.1002/hep.28674] [Citation(s) in RCA: 64] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2016] [Revised: 05/08/2016] [Accepted: 05/29/2016] [Indexed: 12/14/2022]
Abstract
UNLABELLED Nonalcoholic fatty liver disease is associated with metabolic risk factors including hypertension and dyslipidemia and may progress to liver fibrosis. Studies have shown that hepatic steatosis and fibrosis are heritable, but whether they have a significant shared gene effect is unknown. This study examined the shared gene effects between hepatic steatosis and fibrosis and their associations with metabolic risk factors. This was a cross-sectional analysis of a prospective cohort of well-characterized, community-dwelling twins (45 monozygotic, 20 dizygotic twin pairs, 130 total subjects) from southern California. Hepatic steatosis was assessed with magnetic resonance imaging-proton density fat fraction and hepatic fibrosis with magnetic resonance elastography. A standard bivariate twin additive genetics and unique environment effects model was used to estimate the proportion of phenotypic variance between two phenotypes accounted for by additive genetic effects and individual-specific environmental effects. Genetic correlations estimated from this model represent the degree to which the genetic determinants of two phenotypes overlap. Mean (± standard deviation) age and body mass index were 47.1 (±21.9) years and 26.2 (±5.8) kg/m2 , respectively. Among the cohort, 20% (26/130) had hepatic steatosis (magnetic resonance imaging-proton density fat fraction ≥5%), and 8.2% (10/122) had hepatic fibrosis (magnetic resonance elastography ≥3 kPa). Blood pressure (systolic and diastolic), triglycerides, glucose, homeostatic model assessment of insulin resistance, insulin, hemoglobin A1c, and low high-density lipoprotein had significant shared gene effects with hepatic steatosis. Triglycerides, glucose, homeostatic model assessment of insulin resistance, insulin, hemoglobin A1c, and low high-density lipoprotein had significant shared gene effects with hepatic fibrosis. Hepatic steatosis and fibrosis had a highly significant shared gene effect of 0.756 (95% confidence interval 0.716-1, P < 0.0001). CONCLUSIONS Genes involved with steatosis pathogenesis may also be involved with fibrosis pathogenesis. (Hepatology 2016;64:1547-1558).
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Affiliation(s)
- Jeffrey Cui
- NAFLD Research Center, Department of Medicine, University of California at San Diego, La Jolla, CA, USA
| | - Chi-Hua Chen
- Department of Radiology, University of California at San Diego, La Jolla, CA, USA
| | - Min-Tzu Lo
- Department of Radiology, University of California at San Diego, La Jolla, CA, USA
| | | | - Ricki Bettencourt
- NAFLD Research Center, Department of Medicine, University of California at San Diego, La Jolla, CA, USA,Division of Epidemiology, Department of Family and Preventive Medicine, University of California at San Diego, La Jolla, CA
| | - Monica P Gonzalez
- NAFLD Research Center, Department of Medicine, University of California at San Diego, La Jolla, CA, USA
| | - Archana Bhatt
- NAFLD Research Center, Department of Medicine, University of California at San Diego, La Jolla, CA, USA
| | - Jonathan Hooker
- Liver Imaging Group, Department of Radiology, University of California at San Diego, La Jolla, CA
| | - Katherine Shaffer
- NAFLD Research Center, Department of Medicine, University of California at San Diego, La Jolla, CA, USA,Division of Gastroenterology, Department of Medicine, University of California at San Diego, La Jolla, CA
| | | | - Michelle T Long
- Division of Gastroenterology, Department of Medicine, Boston University School of Medicine, Boston, MA
| | - David A Brenner
- Division of Gastroenterology, Department of Medicine, University of California at San Diego, La Jolla, CA
| | - Claude B Sirlin
- Liver Imaging Group, Department of Radiology, University of California at San Diego, La Jolla, CA
| | - Rohit Loomba
- NAFLD Research Center, Department of Medicine, University of California at San Diego, La Jolla, CA. .,Division of Epidemiology, Department of Family and Preventive Medicine, University of California at San Diego, La Jolla, CA. .,Division of Gastroenterology, Department of Medicine, University of California at San Diego, La Jolla, CA.
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20
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Hardy T, Mann DA. Epigenetics in liver disease: from biology to therapeutics. Gut 2016; 65:1895-1905. [PMID: 27624887 PMCID: PMC5099193 DOI: 10.1136/gutjnl-2015-311292] [Citation(s) in RCA: 120] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2016] [Revised: 07/29/2016] [Accepted: 08/01/2016] [Indexed: 02/06/2023]
Abstract
Knowledge of the fundamental epigenetic mechanisms governing gene expression and cellular phenotype are sufficiently advanced that novel insights into the epigenetic control of chronic liver disease are now emerging. Hepatologists are in the process of shedding light on the roles played by DNA methylation, histone/chromatin modifications and non-coding RNAs in specific liver pathologies. Alongside these discoveries are advances in the technologies for the detection and quantification of epigenetic biomarkers, either directly from patient tissue or from body fluids. The premise for this review is to survey the recent advances in the field of liver epigenetics and to explore their potential for translation by industry and clinical hepatologists for the design of novel therapeutics and diagnostic/prognostic biomarkers. In particular, we present findings in the context of hepatocellular carcinoma, fibrosis and non-alcoholic fatty liver disease, where there is urgent unmet need for new clinical interventions and biomarkers.
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Affiliation(s)
- Timothy Hardy
- Fibrosis Laboratories, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK,Department of Gastroenterology and Hepatology, The Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
| | - Derek A Mann
- Fibrosis Laboratories, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK
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Zarrinpar A, Gupta S, Maurya MR, Subramaniam S, Loomba R. Serum microRNAs explain discordance of non-alcoholic fatty liver disease in monozygotic and dizygotic twins: a prospective study. Gut 2016; 65:1546-54. [PMID: 26002934 PMCID: PMC5089367 DOI: 10.1136/gutjnl-2015-309456] [Citation(s) in RCA: 71] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2015] [Accepted: 05/02/2015] [Indexed: 12/13/2022]
Abstract
OBJECTIVE In the setting where two individuals are genetically similar, epigenetic mechanisms could account for discordance in the presence or absence of non-alcoholic fatty liver disease (NAFLD). This study investigated if serum microRNAs (miRs) could explain discordance in NAFLD. DESIGN This is a cross-sectional analysis of a prospective cohort study of 40 (n=80) twin-pairs residing in Southern California. All participants underwent a standardised research visit, liver MRI using proton-density fat fraction to quantify fat content and miR profiling of their serum. RESULTS Among the 40 twin-pairs, there were 6 concordant for NAFLD, 28 were concordant for non-NAFLD and 6 were discordant for NAFLD. The prevalence of NAFLD was 22.5% (18/80). Within the six discordant twins, a panel of 10 miRs differentiated the twin with NAFLD from the one without. Two of these miRs, miR-331-3p and miR-30c, were also among the 21 miRs that were different between NAFLD and non-NAFLD groups (for miR-331-3p: 7.644±0.091 vs 8.057±0.071, respectively, p=0.004; for miR-30c: 10.013±0.126 vs 10.418±0.086, respectively, p=0.008). Both miRs were highly heritable (35.9% and 10.7%, respectively) and highly correlated with each other (R=0.90, p=2.2×10(-16)) suggesting involvement in a common mechanistic pathway. An interactome analysis of these two miRs showed seven common target genes. CONCLUSIONS Using a novel human twin-study design, we demonstrate that discordancy in liver fat content between the twins can be explained by miRs, and that they are heritable.
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Affiliation(s)
- Amir Zarrinpar
- NAFLD Translational Research Unit, University of California, San Diego, La Jolla, California, USA,Division of Gastroenterology, Department of Medicine, University of California, San Diego, La Jolla, California, USA
| | - Shakti Gupta
- Department of Bioengineering, San Diego Supercomputer Center, University of California, San Diego, La Jolla, California, USA
| | - Mano R Maurya
- Department of Bioengineering, San Diego Supercomputer Center, University of California, San Diego, La Jolla, California, USA
| | - Shankar Subramaniam
- Department of Bioengineering, San Diego Supercomputer Center, University of California, San Diego, La Jolla, California, USA,Departments of Computer Science & Engineering and Cellular & Molecular Medicine, University of California, San Diego, La Jolla, California, USA
| | - Rohit Loomba
- NAFLD Translational Research Unit, University of California, San Diego, La Jolla, California, USA,Division of Gastroenterology, Department of Medicine, University of California, San Diego, La Jolla, California, USA,Division of Epidemiology, Department of Family Medicine and Public Health, University of California, San Diego, La Jolla, California, USA
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22
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Zegers D, Verrijken A, Beckers S, Francque S, Van Camp JK, Aerts E, Ruppert M, Hubens G, Michielsen P, Van Hul W, Van Gaal LF. Association study of PNPLA2 gene with histological parameters of NAFLD in an obese population. Clin Res Hepatol Gastroenterol 2016; 40:333-339. [PMID: 26500201 DOI: 10.1016/j.clinre.2015.09.001] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2015] [Accepted: 09/08/2015] [Indexed: 02/04/2023]
Abstract
INTRODUCTION The prevalence of non-alcoholic fatty liver disease (NAFLD) and the closely associated metabolic syndrome is high and is related to risk factors such as obesity and type 2 diabetes. A genetic basis for NAFLD has been suggested, but only few causal genes have been identified. The most significant association reported to date is the robust association of the PNPLA3 I148M variant with susceptibility to NAFLD. We therefore hypothesized that the PNPLA2 gene might also be involved in NAFLD pathogenesis, because of its close sequence similarity with PNPLA3 and its possible involvement in ectopic fat accumulation. METHODS In this study, we investigated the association of PNPLA2 polymorphisms with the development of non-alcoholic fatty liver disease in a prospectively recruited Belgian obese population comprising 633 individuals with varying degrees of fatty liver disease. We selected 3 PNPLA2 SNPs for genotyping, including 2 tagSNPs that cover most information on common genetic variation in the selected region. RESULTS After performing linear regression analysis, we found that 2 of the analyzed PNPLA2 SNPs were associated with anthropometric and metabolic parameters. In our subcohort of patients that underwent liver biopsy (n=372/633 or 58.7%), we assessed the influence of the PNPLA2 variants on the severity of histologically determined liver damage, but we did not find convincing evidence for association. CONCLUSION Although we found evidence for moderate association between PNPLA2 tagSNPs and anthropometric and metabolic parameters in our cohort, no evidence for association between polymorphisms in the PNPLA2 gene and the presence and severity of NAFLD was identified.
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Affiliation(s)
- Doreen Zegers
- Department of Medical Genetics, University of Antwerp, Antwerp, Belgium
| | - An Verrijken
- Department of Endocrinology, Diabetology and Metabolic Diseases, Antwerp University Hospital and University of Antwerp, Antwerp, Belgium
| | - Sigri Beckers
- Department of Medical Genetics, University of Antwerp, Antwerp, Belgium
| | - Sven Francque
- Department of Gastroenterology and Hepatology, Antwerp University Hospital and University of Antwerp, Antwerp, Belgium
| | | | - Evi Aerts
- Department of Medical Genetics, University of Antwerp, Antwerp, Belgium
| | - Martin Ruppert
- Department of Abdominal Surgery, Antwerp University Hospital and University of Antwerp, Antwerp, Belgium
| | - Guy Hubens
- Department of Abdominal Surgery, Antwerp University Hospital and University of Antwerp, Antwerp, Belgium
| | - Peter Michielsen
- Department of Gastroenterology and Hepatology, Antwerp University Hospital and University of Antwerp, Antwerp, Belgium
| | - Wim Van Hul
- Department of Medical Genetics, University of Antwerp, Antwerp, Belgium.
| | - Luc F Van Gaal
- Department of Endocrinology, Diabetology and Metabolic Diseases, Antwerp University Hospital and University of Antwerp, Antwerp, Belgium
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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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24
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Loomba R, Schork N, Chen CH, Bettencourt R, Bhatt A, Ang B, Nguyen P, Hernandez C, Richards L, Salotti J, Lin S, Seki E, Nelson KE, Sirlin CB, Brenner D. Heritability of Hepatic Fibrosis and Steatosis Based on a Prospective Twin Study. Gastroenterology 2015; 149:1784-93. [PMID: 26299412 PMCID: PMC4663110 DOI: 10.1053/j.gastro.2015.08.011] [Citation(s) in RCA: 300] [Impact Index Per Article: 30.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/13/2015] [Accepted: 08/05/2015] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Little is known about the heritability of hepatic fibrosis, and the heritability of hepatic steatosis has not been assessed systematically in adults. We investigated the heritability of hepatic fibrosis and steatosis in a community-dwelling twin cohort. METHODS We performed a cross-sectional analysis of a cohort of well-characterized twins residing in Southern California including 60 pairs of twins (42 monozygotic and 18 dizygotic; average age, 45.7 ± 22.1 y; average body mass index, 26.4 ± 5.7 kg/m(2)). We collected data on medical history, physical examinations, fasting laboratory test results, and liver health; all participants underwent an advanced magnetic resonance imaging (MRI) examination of the liver from January 2012 through January 2015. Hepatic steatosis was quantified noninvasively by MRI and determined based on the proton-density fat fraction (MRI-PDFF); liver fibrosis was measured based on stiffness measured by magnetic resonance elastography. RESULTS Twenty-six of the 120 subjects (21.7%) had nonalcoholic fatty liver disease (defined as MRI-PDFF ≥ 5% after exclusion of other causes of hepatic steatosis). The presence of hepatic steatosis correlated between monozygotic twins (r(2) = 0.70; P < .0001) but not between dizygotic twins (r(2) = 0.36; P = .2). The level of liver fibrosis also correlated between monozygotic twins (r(2) = 0.48; P < .002) but not between dizygotic twins (r(2) = 0.12; P = .7). In multivariable models adjusted for age, sex, and ethnicity, the heritability of hepatic steatosis (based on MRI-PDFF) was 0.52 (95% confidence interval, 0.31-0.73; P < 1.1 × 10(-11)) and the heritability of hepatic fibrosis (based on liver stiffness) was 0.5 (95% confidence interval, 0.28-0.72; P <6.1 × 10(-11)). CONCLUSIONS A study of twins provides evidence that hepatic steatosis and hepatic fibrosis are heritable traits.
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Affiliation(s)
- Rohit Loomba
- NAFLD Translational Research Unit, University of California, San Diego, La Jolla, California; Division of Gastroenterology, Department of Medicine, University of California, San Diego, La Jolla, California; Division of Epidemiology, Department of Family Medicine and Public Health, University of California, San Diego, La Jolla, California.
| | - Nicholas Schork
- Human Biology, J. Craig Venter Institute, La Jolla, CA 92037
| | - Chi-Hua Chen
- Department of Radiology, University of California, San Diego, La Jolla, CA 92093
| | - Ricki Bettencourt
- NAFLD Translational Research Unit, University of California, San Diego, La Jolla, CA 92093
| | - Ana Bhatt
- NAFLD Translational Research Unit, University of California, San Diego, La Jolla, CA 92093
| | - Brandon Ang
- NAFLD Translational Research Unit, University of California, San Diego, La Jolla, CA 92093
| | - Phirum Nguyen
- NAFLD Translational Research Unit, University of California, San Diego, La Jolla, CA 92093
| | - Carolyn Hernandez
- NAFLD Translational Research Unit, University of California, San Diego, La Jolla, CA 92093
| | - Lisa Richards
- NAFLD Translational Research Unit, University of California, San Diego, La Jolla, CA 92093
| | - Joanie Salotti
- NAFLD Translational Research Unit, University of California, San Diego, La Jolla, CA 92093
| | - Steven Lin
- NAFLD Translational Research Unit, University of California, San Diego, La Jolla, CA 92093
| | - Ekihiro Seki
- Division of Gastroenterology, Department of Medicine, University of California, San Diego, La Jolla, CA 92093
| | - Karen E Nelson
- Human Biology, J. Craig Venter Institute, La Jolla, CA 92037
| | - Claude B Sirlin
- Liver Imaging Group, University of California, San Diego, La Jolla, CA 92093
| | - David Brenner
- Division of Gastroenterology, Department of Medicine, University of California, San Diego, La Jolla, CA 92093
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25
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Edelman D, Kalia H, Delio M, Alani M, Krishnamurthy K, Abd M, Auton A, Wang T, Wolkoff AW, Morrow BE. Genetic analysis of nonalcoholic fatty liver disease within a Caribbean-Hispanic population. Mol Genet Genomic Med 2015; 3:558-69. [PMID: 26740948 PMCID: PMC4694126 DOI: 10.1002/mgg3.168] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2015] [Revised: 07/07/2015] [Accepted: 07/09/2015] [Indexed: 12/18/2022] Open
Abstract
We explored potential genetic risk factors implicated in nonalcoholic fatty liver disease (NAFLD) within a Caribbean–Hispanic population in New York City. A total of 316 individuals including 40 subjects with biopsy‐proven NAFLD, 24 ethnically matched non‐NAFLD controls, and a 252 ethnically mixed random sampling of Bronx County, New York were analyzed. Genotype analysis was performed to determine allelic frequencies of 74 known single‐nucleotide polymorphisms (SNPs) associated with NAFLD risk based on previous genome‐wide association study (GWAS) and candidate gene studies. Additionally, the entire coding region of PNPLA3, a gene showing the strongest association to NAFLD was subjected to Sanger sequencing. Results suggest that both rare and common DNA variations in PNPLA3 and SAMM50 may be correlated with NAFLD in this small population study, while common DNA variations in CHUK and ERLIN1, may have a protective interaction. Common SNPs in ENPP1 and ABCC2 have suggestive association with fatty liver, but with less compelling significance. In conclusion, Hispanic patients of Caribbean ancestry may have different interactions with NAFLD genetic modifiers; therefore, further investigation with a larger sample size, into this Caribbean–Hispanic population is warranted.
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Affiliation(s)
- Deborah Edelman
- Department of GeneticsAlbert Einstein College of Medicine1301 Morris Park Ave.BronxNew York10461
| | - Harmit Kalia
- Division of Gastroenterology and Liver DiseasesMontefiore Medical Center and Albert Einstein College of MedicineBronxNew York10461
| | - Maria Delio
- Department of GeneticsAlbert Einstein College of Medicine1301 Morris Park Ave.BronxNew York10461
- Marion Bessin Liver Research CenterAlbert Einstein College of MedicineBronxNew York10461
| | - Mustafa Alani
- Division of Gastroenterology and Liver DiseasesMontefiore Medical Center and Albert Einstein College of MedicineBronxNew York10461
| | - Karthik Krishnamurthy
- Division of Gastroenterology and Liver DiseasesMontefiore Medical Center and Albert Einstein College of MedicineBronxNew York10461
| | - Mortadha Abd
- Division of Gastroenterology and Liver DiseasesMontefiore Medical Center and Albert Einstein College of MedicineBronxNew York10461
| | - Adam Auton
- Department of GeneticsAlbert Einstein College of Medicine1301 Morris Park Ave.BronxNew York10461
| | - Tao Wang
- Department of Epidemiology & Population HealthAlbert Einstein College of MedicineBronxNew York10461
| | - Allan W. Wolkoff
- Division of Gastroenterology and Liver DiseasesMontefiore Medical Center and Albert Einstein College of MedicineBronxNew York10461
- Marion Bessin Liver Research CenterAlbert Einstein College of MedicineBronxNew York10461
- Department of Anatomy and Structural BiologyAlbert Einstein College of MedicineBronxNew York10461
| | - Bernice E. Morrow
- Department of GeneticsAlbert Einstein College of Medicine1301 Morris Park Ave.BronxNew York10461
- Department of Anatomy and Structural BiologyAlbert Einstein College of MedicineBronxNew York10461
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Machado MV, Cortez-Pinto H. Non-alcoholic fatty liver disease: what the clinician needs to know. World J Gastroenterol 2014; 20:12956-80. [PMID: 25278691 PMCID: PMC4177476 DOI: 10.3748/wjg.v20.i36.12956] [Citation(s) in RCA: 157] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2014] [Revised: 04/21/2014] [Accepted: 05/25/2014] [Indexed: 02/06/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most frequent cause of liver disease in the Western world. Furthermore, it is increasing worldwide, paralleling the obesity pandemic. Though highly frequent, only about one fifth of affected subjects are at risk of developing the progressive form of the disease, non-alcoholic steatohepatitis with fibrosis. Even in the latter, liver disease is slowly progressive, though, since it is so prevalent, it is already the third cause of liver transplantation in the United States, and it is predicted to get to the top of the ranking in few years. Of relevance, fatty liver is also associated with increased overall mortality and particularly increased cardiovascular mortality. The literature and amount of published papers on NAFLD is increasing as fast as its prevalence, which makes it difficult to keep updated in this topic. This review aims to summarize the latest knowledge on NAFLD, in order to help clinicians understanding its pathogenesis and advances on diagnosis and treatment.
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27
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Larrieta-Carrasco E, Acuña-Alonzo V, Velázquez-Cruz R, Barquera-Lozano R, León-Mimila P, Villamil-Ramírez H, Menjivar M, Romero-Hidalgo S, Méndez-Sánchez N, Cárdenas V, Bañuelos-Moreno M, Flores YN, Quiterio M, Salmerón J, Sánchez-Muñoz F, Villarreal-Molina T, Aguilar-Salinas CA, Canizales-Quinteros S. PNPLA3 I148M polymorphism is associated with elevated alanine transaminase levels in Mexican Indigenous and Mestizo populations. Mol Biol Rep 2014; 41:4705-4711. [PMID: 24691744 DOI: 10.1007/s11033-014-3341-0] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2013] [Accepted: 03/21/2014] [Indexed: 02/06/2023]
Abstract
The patatin like phospholipase domain-containing (PNPLA3) I148M variant is the strongest genetic factor associated with elevated alanine transaminase (ALT) levels in different populations, particularly in Hispanics who have the highest 148M risk allele frequency reported to date. It has been suggested that Indigenous ancestry is associated with higher ALT levels in Mexicans. The aim of the present study was to assess the frequency of the PNPLA3 148M risk allele in Mexican indigenous and Mestizo individuals, and to examine its association with serum ALT levels. The study included a total of 1624 Mexican individuals: 919 Indigenous subjects from five different native groups and 705 Mexican Mestizo individuals (141 cases with ALT levels ≥ 40 U/L and 564 controls with ALT <40 U/L). The I148M polymorphism was genotyped by TaqMan assays. The frequency of elevated ALT levels in Indigenous populations was 18.7%, and varied according to obesity status: 14.4% in normal weight, 19.9% in overweight and 24.5% in obese individuals. The Mexican indigenous populations showed the highest reported frequency of the PNPLA3 148M risk allele (mean 0.73). The M148M genotype was significantly associated with elevated ALT levels in indigenous individuals (OR = 3.15, 95 % CI 1.91-5.20; P = 7.1 × 10(-6)) and this association was confirmed in Mexican Mestizos (OR = 2.24, 95% CI 1.50-3.33; P = 8.1 × 10(-5)). This is the first study reporting the association between M148M genotype and elevated ALT levels in Indigenous Mexican populations. The 148M allele risk may be considered an important risk factor for liver damage in Mexican indigenous and Mestizo populations.
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Affiliation(s)
- Elena Larrieta-Carrasco
- Departamento de Gastroenterología, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán (INCMNSZ), Mexico, Mexico
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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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Circulating PCSK9 is a strong determinant of plasma triacylglycerols and total cholesterol in homozygous carriers of apolipoprotein ε2. Clin Sci (Lond) 2014; 126:679-84. [DOI: 10.1042/cs20130556] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Plasma PCSK9, an important determinant of LDL-receptor degradation, is strongly related to total cholesterol and triacylglycerol levels in homozygous carriers of the apolipoprotein ε2 allele. This observation provides new insight into the pathogenesis of type III hyperlipidaemia and its treatment.
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30
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Larrieta-Carrasco E, León-Mimila P, Villarreal-Molina T, Villamil-Ramírez H, Romero-Hidalgo S, Jacobo-Albavera L, Gutiérrez-Vidal R, López-Contreras BE, Guillén-Pineda LE, Sánchez-Muñoz F, Bojalil R, Mejía-Domínguez AM, Méndez-Sánchez N, Domínguez-López A, Aguilar-Salinas CA, Canizales-Quinteros S. Association of the I148M/PNPLA3 variant with elevated alanine transaminase levels in normal-weight and overweight/obese Mexican children. Gene 2013; 520:185-188. [PMID: 23510779 DOI: 10.1016/j.gene.2013.03.038] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2013] [Accepted: 03/08/2013] [Indexed: 12/31/2022]
Abstract
BACKGROUND AND AIMS Non-alcoholic fatty liver disease (NAFLD) and elevated alanine transaminase (ALT) levels are common in obese Hispanic adults and children. Recently, a PNPLA3 gene variant (I148M) was strongly associated with NAFLD and higher ALT levels in obese adults, including Hispanics. The aims of this study were to estimate the frequency of elevated ALT levels, and to address the influence of obesity and PNPLA3/I148M on ALT levels in a general population sample of Mexican school-aged children. METHODS A total of 1037 non-related Mexican children aged 6 to 12 years were genotyped for the I148M variant. Anthropometric, clinical and metabolic parameters were collected from all participants. RESULTS Elevated ALT levels (>35 U/L) were more frequent in obese (26.9%) and overweight (9.3%) than in normal weight children (2.2%). The M148M genotype was significantly associated with elevated ALT levels in this population (OR=3.7, 95% CI 2.3-5.9; P=3.7×10(-8)), and children carrying the M148M genotype showed significantly lower HDL cholesterol levels and BMI z-core (P=0.036 and 0.015, respectively). On stratifying by BMI percentile, this genotype conferred a much greater risk of elevated ALT levels in normal weight (OR=19.9, 95% CI 2.5-157.7; P=0.005) than overweight and obese children (OR=3.4, 95% CI 1.3-8.9; P=0.014 and OR=3.1, 95% CI 1.7-5.5; P=1.4 x10(-4), respectively). CONCLUSIONS The I148M PNPLA3 variant is strongly associated with elevated ALT levels in normal weight and overweight/obese Mexican children. Thus, the M148M genotype may be considered as an important risk factor for liver damage in this population.
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Affiliation(s)
- Elena Larrieta-Carrasco
- Unidad de Biología Molecular y Medicina Genómica, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán (INCMNSZ), Mexico City, Mexico
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The genetic architecture of liver enzyme levels: GGT, ALT and AST. Behav Genet 2013; 43:329-39. [PMID: 23580007 DOI: 10.1007/s10519-013-9593-y] [Citation(s) in RCA: 115] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2012] [Accepted: 04/04/2013] [Indexed: 12/20/2022]
Abstract
High levels of liver enzymes GGT, ALT and AST are predictive of disease and all-cause mortality and can reflect liver injury, fatty liver and/or oxidative stress. Variation in GGT, ALT and AST levels is heritable. Moderation of the heritability of these liver enzymes by age and sex has not often been explored, and it is not clear to what extent non-additive genetic and shared environmental factors may play a role. To examine the genetic architecture of GGT, ALT and AST, plasma levels were assessed in a large sample of twins, their siblings, parents and spouses (N = 8,371; age range 18-90). For GGT and ALT, but not for AST, genetic structural equation modeling showed evidence for quantitative sex differences in the genetic architecture. There was no evidence for qualitative sex differences, i.e. the same genes were expressed in males and females. Both additive and non-additive genetic factors were important for GGT in females (total heritability h(2) 60 %) and AST in both sexes (total h(2) 43 %). The heritability of GGT in males and ALT for both sexes was due to additive effects only (GGT males 30 %; ALT males 40 %, females 22 %). Evidence emerged for shared environmental factors influencing GGT in the male offspring generation (variance explained 28 %). Thus, the same genes influence liver enzyme levels across sex and age, but their relative contribution to the variation in GGT and ALT differs in males and females and for GGT across age. Given adequate sample sizes these results suggest that genome-wide association studies may result in the detection of new susceptibility loci for liver enzyme levels when pooling results over sex and age.
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Pediatric non alcoholic fatty liver disease: old and new concepts on development, progression, metabolic insight and potential treatment targets. BMC Pediatr 2013; 13:40. [PMID: 23530957 PMCID: PMC3620555 DOI: 10.1186/1471-2431-13-40] [Citation(s) in RCA: 108] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2012] [Accepted: 03/18/2013] [Indexed: 12/12/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease in children. NAFLD has emerged to be extremely prevalent, and predicted by obesity and male gender. It is defined by hepatic fat infiltration >5% hepatocytes, in the absence of other causes of liver pathology. It includes a spectrum of disease ranging from intrahepatic fat accumulation (steatosis) to various degrees of necrotic inflammation and fibrosis (non-alcoholic steatohepatatis [NASH]). NAFLD is associated, in children as in adults, with severe metabolic impairments, determining an increased risk of developing the metabolic syndrome. It can evolve to cirrhosis and hepatocellular carcinoma, with the consequent need for liver transplantation. Both genetic and environmental factors seem to be involved in the development and progression of the disease, but its physiopathology is not yet entirely clear. In view of this mounting epidemic phenomenon involving the youth, the study of NAFLD should be a priority for all health care systems. This review provides an overview of current and new clinical-histological concepts of pediatric NAFLD, going through possible implications into patho-physiolocical and therapeutic perspectives.
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Tarnoki AD, Tarnoki DL, Bata P, Littvay L, Osztovits J, Jermendy G, Karlinger K, Lannert A, Preda I, Kiss RG, Molnar AA, Garami Z, Baffy G, Berczi V. Heritability of non-alcoholic fatty liver disease and association with abnormal vascular parameters: a twin study. Liver Int 2012; 32:1287-93. [PMID: 22651705 DOI: 10.1111/j.1478-3231.2012.02823.x] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2012] [Revised: 04/14/2012] [Accepted: 04/22/2012] [Indexed: 12/11/2022]
Abstract
BACKGROUND Non-alcoholic fatty liver disease (NAFLD) has been linked to increased cardiovascular morbidity. However, genetic factors have an unclear role in this condition. AIMS To analyse heritability of NAFLD and its association with abnormal vascular parameters in a large twin cohort. METHODS Anthropometric and lipid metabolic parameters were obtained from 208 adult Hungarian twins (63 monozygotic and 41 dizygotic pairs; 58 men and 150 women; age 43.7 ± 16.7 years). B-mode ultrasonography was performed to detect steatosis and categorize severity. Brachial and aortic augmentation indices and aortic pulse wave velocity were assessed using oscillometry (TensioMed Arteriograph). Carotid intima media thickness (IMT) was measured using ultrasonography on the proximal common, distal common and internal carotid arteries. RESULTS NAFLD was identified in 47 subjects (22.6%), of which 44 (93.6%) had mild and 3 (6.4%) had moderate steatosis. These subjects were older (age: 50.9 ± 14.3 vs. 41.5 ± 16.7 years, P < 0.001) and had a higher body mass index (BMI; 30.1 ± 5.2 vs. 24.6 ± 4.1 km/m(2) , P < 0.001) than non-NAFLD twins. Based on 91 same-sex twin pairs, heritability analysis indicated no discernible role for genetic components in the presence of NAFLD (95% confidence interval, 0.0-36.0%), while shared and unshared environmental effects accounted for 74.2% and 25.8% of variations adjusted for age and BMI. Augmentation indices and carotid IMT in twins with NAFLD were increased at most examined locations (P < 0.05-P < 0.001). CONCLUSION These findings do not support heritability of NAFLD, although it coexists with vascular parameters linked to increased cardiovascular risk, underscoring the importance and value of prevention in this very common disorder.
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Affiliation(s)
- Adam D Tarnoki
- Department of Radiology and Oncotherapy, Semmelweis University, Budapest, Hungary.
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Brouwers MCGJ, van Greevenbroek MMJ, Stehouwer CDA, de Graaf J, Stalenhoef AFH. The genetics of familial combined hyperlipidaemia. Nat Rev Endocrinol 2012; 8:352-62. [PMID: 22330738 DOI: 10.1038/nrendo.2012.15] [Citation(s) in RCA: 70] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
Almost 40 years after the first description of familial combined hyperlipidaemia (FCHL) as a discrete entity, the genetic and metabolic basis of this prevalent disease has yet to be fully unveiled. In general, two strategies have been applied to elucidate its complex genetic background, the candidate-gene and the linkage approach, which have yielded an extensive list of genes associated with FCHL or its related traits, with a variable degree of scientific evidence. Some genes influence the FCHL phenotype in many pedigrees, whereas others are responsible for the affected state in only one kindred, thereby adding to the genetic and phenotypic heterogeneity of FCHL. This Review outlines the individual genes that have been described in FCHL and how these genes can be incorporated into the current concept of metabolic pathways resulting in FCHL: adipose tissue dysfunction, hepatic fat accumulation and overproduction, disturbed metabolism and delayed clearance of apolipoprotein-B-containing particles. Genes that affect metabolism and clearance of plasma lipoprotein particles have been most thoroughly studied. The adoption of new traits, in addition to the classic plasma lipid traits, could aid in the identification of new genes implicated in other pathways in FCHL. Moreover, systems genetic analysis, which integrates genetic polymorphisms with data on gene expression levels, lipidomics or metabolomics, will attribute functions to genetic variants in addition to revealing new genes.
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Affiliation(s)
- Martijn C G J Brouwers
- Department of Internal Medicine and Endocrinology, Maastricht University Medical Centre, P. Debyelaan 25, 6229 HX, Maastricht, The Netherlands
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Shia WC, Ku TH, Tsao YM, Hsia CH, Chang YM, Huang CH, Chung YC, Hsu SL, Liang KW, Hsu FR. Genetic copy number variants in myocardial infarction patients with hyperlipidemia. BMC Genomics 2011; 12 Suppl 3:S23. [PMID: 22369086 PMCID: PMC3333183 DOI: 10.1186/1471-2164-12-s3-s23] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
BACKGROUND Cardiovascular disease is the chief cause of death in Taiwan and many countries, of which myocardial infarction (MI) is the most serious condition. Hyperlipidemia appears to be a significant cause of myocardial infarction, because it causes atherosclerosis directly. In recent years, copy number variation (CNV) has been analyzed in genomewide association studies of complex diseases. In this study, CNV was analyzed in blood samples and SNP arrays from 31 myocardial infarction patients with hyperlipidemia. RESULTS We identified seven CNV regions that were associated significantly with hyperlipidemia and myocardial infarction in our patients through multistage analysis (P<0.001), at 1p21.3, 1q31.2 (CDC73), 1q42.2 (DISC1), 3p21.31 (CDCP1), 10q11.21 (RET) 12p12.3 (PIK3C2G) and 16q23.3 (CDH13), respectively. In particular, the CNV region at 10q11.21 was examined by quantitative real-time PCR, the results of which were consistent with microarray findings. CONCLUSIONS Our preliminary results constitute an alternative method of evaluating the relationship between CNV regions and cardiovascular disease. These susceptibility CNV regions may be used as biomarkers for early-stage diagnosis of hyperlipidemia and myocardial infarction, rendering them valuable for further research and discussion.
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Affiliation(s)
- Wei-Chung Shia
- Department of Information Engineering and Computer Science, Feng Chia University, Taichung City, Taiwan
| | - Tien-Hsiung Ku
- Department of Anesthesia, Changhua Christian Hospital, Changhua County, Taiwan
| | - Yu-Ming Tsao
- Department of Computer Science, National Chiao Tung University, Hsinchu, Taiwan
| | - Chien-Hsun Hsia
- Department of Cardiovascular Medicine, Changhua Christian Hospital, Changhua County, Taiwan
| | - Yung-Ming Chang
- Department of Cardiovascular Medicine, Changhua Christian Hospital, Changhua County, Taiwan
| | - Ching-Hui Huang
- Department of Cardiovascular Medicine, Changhua Christian Hospital, Changhua County, Taiwan
| | - Yeh-Ching Chung
- Department of Computer Science, National Tsing Hua University, Hsinchu, Taiwan
| | - Shih-Lan Hsu
- Department of Medical Education and Research, Taichung Veterans General Hospital, Taichung City, Taiwan
| | - Kae-Woei Liang
- Department of Cardiovascular Medicine, Taichung Veterans General Hospital, Taichung City, Taiwan
| | - Fang-Rong Hsu
- Department of Information Engineering and Computer Science, Feng Chia University, Taichung City, Taiwan
- Master's Program in Biomedical Informatics and Biomedical Engineering, Feng Chia University, Taichung City, Taiwan
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Plasma proprotein convertase subtilisin kexin type 9 is a heritable trait of familial combined hyperlipidaemia. Clin Sci (Lond) 2011; 121:397-403. [DOI: 10.1042/cs20110129] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
The aim of the present study was to investigate the relationship between circulating PCSK9 (proprotein convertase subtilisin kexin type 9) and FCHL (familial combined hyperlipidaemia) and, when positive, to determine the strength of its heritability. Plasma PCSK9 levels were measured in FCHL patients (n=45), NL (normolipidaemic) relatives (n=139) and their spouses (n=72). In addition, 11 FCHL patients were treated with atorvastatin to study the response in PCSK9 levels. PCSK9 levels were higher in FCHL patients compared with NL relatives and spouses: 96.1 compared with 78.7 and 82.0 ng/ml (P=0.004 and P=0.002 respectively). PCSK9 was significantly associated with both TAG (triacylglycerol) and apolipoprotein B levels (P<0.001). The latter relationship was accounted for by LDL (low-density lipoprotein)–apolipoprotein B (r=0.31, P=0.02), not by VLDL (very-low-density lipoprotein)–apolipoprotein B (r=0.09, P=0.49) in a subgroup of subjects (n=59). Heritability calculations for PCSK9 using SOLAR and FCOR software yielded estimates of 67–84% respectively (P<0.0001). PCSK9 increased from 122 to 150 ng/ml in 11 FCHL patients treated with atorvastatin (40 mg) once daily for 8 weeks (P=0.018). In conclusion, plasma PCSK9 is a heritable trait associated with both FCHL diagnostic hallmarks. These results, combined with the significant rise in PCSK9 levels after statin therapy, warrant further studies in order to unravel the exact role of PCSK9 in the pathogenesis and treatment of this highly prevalent genetic dyslipidaemia.
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Jacobs M, van Greevenbroek MMJ, van der Kallen CJH, Ferreira I, Feskens EJM, Jansen EHJM, Schalkwijk CG, Stehouwer C. The association between the metabolic syndrome and alanine amino transferase is mediated by insulin resistance via related metabolic intermediates (the Cohort on Diabetes and Atherosclerosis Maastricht [CODAM] study). Metabolism 2011; 60:969-75. [PMID: 21040936 DOI: 10.1016/j.metabol.2010.09.006] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2010] [Revised: 09/15/2010] [Accepted: 09/15/2010] [Indexed: 01/04/2023]
Abstract
The metabolic syndrome is associated with nonalcoholic fatty liver disease (NAFLD) as well as with insulin resistance, inflammatory adipokines, endothelial dysfunction, and higher plasma levels of nonesterified fatty acids (NEFA), all of which may also affect the development of NAFLD. Therefore, we investigated to what extent the association between the metabolic syndrome and alanine aminotransferase (ALT, as a surrogate of NAFLD) can be explained by different metabolic intermediates of the metabolic syndrome. Cross-sectional analyses were performed in 434 subjects from the Cohort on Diabetes and Atherosclerosis Maastricht study (264 men; mean age, 59.5 ± 7.1 years). We used multiple linear regression analyses to investigate the association between the metabolic syndrome and ALT and the mediation role of potential mediators herein. The mediators considered were insulin resistance (homeostasis model assessment), an inflammatory adipokine score (based on interleukin-6, serum amyloid A, intercellular adhesion molecule, adiponectin, and leptin), an endothelial dysfunction score (based on E-selectin, vascular cell adhesion molecule, and von Willebrand factor), and plasma levels of NEFA. All analyses were adjusted for age, sex, smoking, alcohol consumption, and use of medication. Subjects with the metabolic syndrome (53.7%) had significantly higher levels of ALT (β = 0.67 SD [95% confidence interval, 0.49-0.85], P < .001). Adjustment for insulin resistance attenuated this difference by 77.3% (to 0.15 SD [-0.04 to 0.35]). Attenuation by adipose tissue-associated inflammation, endothelial dysfunction, and NEFA was more modest (20.7%, 13.1%, and 9.5%, respectively). Part of the attenuation by NEFA, but not of the other mediators, was additional to that of insulin resistance. Insulin resistance constitutes a key pathophysiological mechanism in the association between the metabolic syndrome and NAFLD (measured as ALT), which may operate through adipose tissue-associated inflammation and endothelial dysfunction and to a lesser extent through NEFA, which may have an independent role in the development of NAFLD in subjects with the metabolic syndrome.
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Affiliation(s)
- Marjon Jacobs
- Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands
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Miller M, Stone NJ, Ballantyne C, Bittner V, Criqui MH, Ginsberg HN, Goldberg AC, Howard WJ, Jacobson MS, Kris-Etherton PM, Lennie TA, Levi M, Mazzone T, Pennathur S. Triglycerides and cardiovascular disease: a scientific statement from the American Heart Association. Circulation 2011; 123:2292-333. [PMID: 21502576 DOI: 10.1161/cir.0b013e3182160726] [Citation(s) in RCA: 1325] [Impact Index Per Article: 94.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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van Greevenbroek MMJ, Jacobs M, van der Kallen CJH, Vermeulen VMMJ, Jansen EHJM, Schalkwijk CG, Ferreira I, Feskens EJM, Stehouwer CDA. The cross-sectional association between insulin resistance and circulating complement C3 is partly explained by plasma alanine aminotransferase, independent of central obesity and general inflammation (the CODAM study). Eur J Clin Invest 2011; 41:372-9. [PMID: 21114489 DOI: 10.1111/j.1365-2362.2010.02418.x] [Citation(s) in RCA: 54] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Complement C3, a central component of the innate immune system is increased in subjects with obesity and type 2 diabetes and is a novel risk factor for cardiovascular disease. We hypothesized that the strong association between insulin resistance and circulating amounts of C3 may be related to hepatic fat accumulation -independent of central obesity itself and of a general low-grade inflammatory response. RESEARCH QUESTION To what extent is the association between insulin resistance and C3 explained by plasma levels of alanine aminotransferase (ALT) as a surrogate of hepatic fat accumulation. METHODS Cross-sectional analyses conducted in the Cohort on Diabetes and Atherosclerosis Maastricht (CODAM) study. Analyses were restricted to subjects with none-to-moderate alcohol consumption (n = 453, 61·4% men). Multiple linear regression analyses were used to investigate the association between HOMA2IR (main determinant) and circulating complement C3 (main outcome), and the mediating role of ALT herein. All analyses were adjusted for age, sex, presence of type 2 diabetes mellitus or heart disease, use of medication, smoking, alcohol consumption, waist circumference and inflammation. RESULTS Insulin resistance (estimated as HOMA2IR) was strongly associated with circulating C3 (standardized regression coefficient β 0·40 [95% CI: 0·30; 0·49]) and also with ALT (β 0·44 [0·34; 0·54]), both adjusted for the above-mentioned covariates. The association between HOMA2IR and C3 was attenuated after further adjustment for ALT (β decreased to 0·34 [0·24; 0·44]). CONCLUDING REMARKS Plasma ALT can explain 14·2% of the strong association between insulin resistance and circulating concentrations of complement C3, independent of central obesity and general inflammation.
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Hooper AJ, Adams LA, Burnett JR. Genetic determinants of hepatic steatosis in man. J Lipid Res 2011; 52:593-617. [PMID: 21245030 DOI: 10.1194/jlr.r008896] [Citation(s) in RCA: 98] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Hepatic steatosis is one of the most common liver disorders in the general population. The main cause of hepatic steatosis is nonalcoholic fatty liver disease (NAFLD), representing the hepatic component of the metabolic syndrome, which is characterized by type 2 diabetes, obesity, and dyslipidemia. Insulin resistance and excess adiposity are considered to play key roles in the pathogenesis of NAFLD. Although the risk factors for NAFLD are well established, the genetic basis of hepatic steatosis is largely unknown. Here we review recent progress on genomic variants and their association with hepatic steatosis and discuss the potential impact of these genetic studies on clinical practice. Identifying the genetic determinants of hepatic steatosis will lead to a better understanding of the pathogenesis and progression of NAFLD.
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Affiliation(s)
- Amanda J Hooper
- Department of Core Clinical Pathology and Biochemistry, Royal Perth Hospital, Perth, Australia
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Brouwers MCGJ, de Graaf J, van Greevenbroek MMJ, Schaper N, Stehouwer CDA, Stalenhoef AFH. Novel drugs in familial combined hyperlipidemia: lessons from type 2 diabetes mellitus. Curr Opin Lipidol 2010; 21:530-8. [PMID: 20739883 DOI: 10.1097/mol.0b013e32833ea9ec] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
PURPOSE OF REVIEW Familial combined hyperlipidemia (FCHL) and type 2 diabetes mellitus (T2DM) are prevalent entities that share many features of the metabolic syndrome. Recent findings suggest that FCHL and T2DM are less distinct than initially anticipated, which could offer new insights for their therapeutic approach. RECENT FINDINGS Genetic association studies have provided evidence for a common genetic background (upstream transcription factor 1, activating transcription factor 6, transcription factor 7-like 2 and hepatocyte nuclear factor 4 alpha) between FCHL and T2DM. The metabolic overlap can be illustrated by the presence of ectopic fat accumulation and insulin resistance (muscle, adipose tissue and liver). We have shown that FCHL patients are at increased risk to develop T2DM. This indicates that both entities are not static, but instead the former is able to migrate to the latter as insulin resistance progresses. Given these new findings, it can be anticipated that FCHL patients could also benefit from insulin-sensitizing therapy such as pioglitazone and metformin. Indeed, pilot studies have demonstrated that pioglitazone might be advantageous in FCHL patients. SUMMARY Recent studies suggest that FCHL patients have an increased risk to develop T2DM, which has important clinical implications. Further studies are necessary to evaluate whether FCHL patients can be protected from new-onset T2DM and premature cardiovascular events with insulin-sensitizing therapy.
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MESH Headings
- Adipose Tissue/drug effects
- Adipose Tissue/metabolism
- Cholesterol, LDL/genetics
- Cholesterol, LDL/metabolism
- Diabetes Mellitus, Type 2/complications
- Diabetes Mellitus, Type 2/drug therapy
- Diabetes Mellitus, Type 2/genetics
- Diabetes Mellitus, Type 2/metabolism
- Drug Discovery
- Fatty Liver/genetics
- Fatty Liver/metabolism
- Genetic Predisposition to Disease
- Humans
- Hyperlipidemia, Familial Combined/complications
- Hyperlipidemia, Familial Combined/drug therapy
- Hyperlipidemia, Familial Combined/genetics
- Hyperlipidemia, Familial Combined/metabolism
- Insulin/metabolism
- Insulin Resistance/genetics
- Male
- Metabolic Syndrome/etiology
- Metabolic Syndrome/genetics
- Metabolic Syndrome/metabolism
- Metformin/administration & dosage
- Models, Biological
- Obesity/genetics
- Obesity/metabolism
- Pioglitazone
- Risk Factors
- Thiazolidinediones/administration & dosage
- Transcription Factors/genetics
- Transcription Factors/metabolism
- Triglycerides/genetics
- Triglycerides/metabolism
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Affiliation(s)
- Martijn C G J Brouwers
- Laboratory of Vascular Medicine and Metabolism, Department of Internal Medicine, Divisions of General Internal Medicine and Endocrinology, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands
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Tilg H, Moschen A. Update on nonalcoholic fatty liver disease: genes involved in nonalcoholic fatty liver disease and associated inflammation. Curr Opin Clin Nutr Metab Care 2010; 13:391-6. [PMID: 20473151 DOI: 10.1097/mco.0b013e32833a87cc] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
PURPOSE OF REVIEW Nonalcoholic fatty liver disease (NAFLD) is one of the most prevalent liver diseases worldwide. Advanced age, extensive overweight and a number of features of the metabolic syndrome are associated with NAFLD severity. The cause of NAFLD is considered multifactorial with a substantial genetic component. RECENT FINDINGS Family members of children with NAFLD demonstrate a higher risk for NAFLD. Whereas such an association only suggests that familial factors are major determinants of whether or not an individual will develop NAFLD, recent genome-wide association studies were able to identify first candidate genes. An allele in patatin-like phospholipase 3, encoding a protein of unknown function with homology to lipid acyl hydrolases, is strongly associated with increased hepatic fat and inflammation. Apolipoprotein C3 gene variants are also associated with NAFLD and insulin resistance. Several other genetic variants have been identified, although with less convincing evidence. These genetic variants involve molecules regulating insulin signaling, lipid metabolism, oxidative stress or fibrogenesis. Furthermore, genetic variants of several cytokines and adipocytokines have been associated with NAFLD. SUMMARY Several genetic factors such as patatin-like phospholipase 3 or apolipoprotein C3 have been recently characterized in NAFLD. Further studies to identify their interaction with environmental factors are eagerly warranted.
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Affiliation(s)
- Herbert Tilg
- Christian Doppler Research Laboratory for Gut Inflammation, Innsbruck Medical University, Innsbruck, Austria.
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Abstract
Non-alcoholic fatty liver disease (NAFLD), the most common chronic liver disease in the Western world, is tightly associated with obesity and metabolic syndrome. NAFLD entails an increased cardiometabolic and liver-related risk, the latter regarding almost exclusively non-alcoholic steatohepatitis (NASH), the progressive form of NAFLD. Pathogenetic models encompass altered hepatic lipid partitioning and adipokine action, increased oxidative stress, free fatty acid lipotoxicity. On this basis, lifestyle-, drug- or surgically induced weight loss, insulin sensitizers, antioxidants, lipid-lowering drugs have been evaluated in NAFLD/NASH. Most trials are small, of short duration, nonrandomized, without histological end points, thus limiting assessment of long-term safety and efficacy of proposed treatments. All NAFLD patients should be evaluated for their metabolic, cardiovascular and liver-related risk. Liver biopsy remains the gold standard for staging NAFLD, but non-invasive methods are under intense development. Weight loss through lifestyle intervention is the initial approach, because of established efficacy on NAFLD-associated cardiometabolic abnormalities, and to emerging benefits on necroinflammation and overall disease activity in NASH. Bariatric surgery warrants further evaluation before it can be routinely considered in morbidly obese NASH. Larger- and longer-duration randomized trials assessing safety and benefits of drugs on patient-oriented outcomes are needed before pharmacological treatment can be routinely recommended for NASH.
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Affiliation(s)
- G Musso
- Gradenigo Hospital, Turin, Italy.
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Brouwers MCGJ, van Greevenbroek MMJ, Cantor RM. Heritability of nonalcoholic fatty liver disease. Gastroenterology 2009; 137:1536. [PMID: 19717129 DOI: 10.1053/j.gastro.2009.03.065] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2009] [Accepted: 03/13/2009] [Indexed: 01/13/2023]
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Hirano T, Nohtomi K, Sato Y, Kamata K, Ito Y. Small dense LDL-cholesterol determined by a simple precipitation assay for screening familial combined hyperlipidemia. Atherosclerosis 2009; 205:603-7. [DOI: 10.1016/j.atherosclerosis.2009.01.009] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2008] [Revised: 01/07/2009] [Accepted: 01/09/2009] [Indexed: 10/21/2022]
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Yan X, Xu L, Qi J, Liang X, Ma C, Guo C, Zhang L, Sun W, Zhang J, Wei X, Gao L. sTRAIL levels and TRAIL gene polymorphisms in Chinese patients with fatty liver disease. Immunogenetics 2009; 61:551-6. [PMID: 19629467 DOI: 10.1007/s00251-009-0389-4] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2009] [Accepted: 07/10/2009] [Indexed: 01/12/2023]
Abstract
Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a member of the TNF superfamily, and has been identified as a novel mediator of fatty liver disease (FLD). The aim of our study was to further investigate the relationship between TRAIL and FLD. We found that soluble TRAIL (sTRAIL) concentrations in non-alcoholic FLD (NAFLD) patients were significantly higher than those of controls, and that sTRAIL levels positively correlated with triglyceride concentrations in NAFLD patients. Our results also indicated that the AA/TT genotypes of TRAIL at 1525/1595 engendered a lower risk of FLD attack and a less severe form of steatosis for NAFLD patients in Chinese population. This study provides a means to test for susceptibility to FLD and may assist in the diagnosis of FLD. In addition, we found that 1525G/A and 1595C/T sites were in complete linkage disequilibrium in Chinese population. This might indicate a haplotype with high genetic frequency of TRAIL.
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Affiliation(s)
- Xiaohua Yan
- Department of Immunology, Shandong University School of Medicine, 44# Wenhua Xi Road, Jinan, 250012, People's Republic of China
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Wagenknecht LE, Scherzinger AL, Stamm ER, Hanley AJG, Norris JM, Chen YDI, Bryer-Ash M, Haffner SM, Rotter JI. Correlates and heritability of nonalcoholic fatty liver disease in a minority cohort. Obesity (Silver Spring) 2009; 17:1240-6. [PMID: 19584882 PMCID: PMC2709735 DOI: 10.1038/oby.2009.4] [Citation(s) in RCA: 85] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is associated with obesity and insulin resistance. The condition disproportionately affects Hispanic Americans. The aims of this study were to examine the risk factors and heritability of NAFLD in 795 Hispanic American and 347 African-American adults participating in the Insulin Resistance Atherosclerosis Study (IRAS) Family Study. Computed tomography (CT) scans of the abdomen were evaluated centrally for measures of liver-spleen (LS) density ratio and abdominal fat distribution. Other measures included insulin sensitivity (SI) calculated from a frequently sampled intravenous glucose tolerance test and various laboratory measures. Statistical models which adjust for familial relationships were estimated separately for the two ethnic groups. Heritability was calculated using a variance components approach. The mean age of the cohort was 49 years (range 22-84); 66% were female. NAFLD (LS ratio<1) was more common in Hispanic Americans (24%) than African Americans (10%). NAFLD was independently associated with SI and visceral adipose tissue (VAT) area in both ethnic groups, although the proportion of explained variance was considerably higher in the Hispanic models. Adiponectin contributed significantly in the African-American models whereas triglycerides (TGs) and plasminogen activator inhibitor 1 (PAI-1) contributed only in the Hispanic models. Liver density was modestly heritable in both ethnic groups (h2 approximately 0.35). In summary, the prevalence of NAFLD was twofold greater in Hispanic than African Americans. Certain correlates of NAFLD were similar between the ethnic groups, whereas others were distinct. NAFLD was modestly heritable. These findings suggest that NAFLD may have a differing environmental and/or genetic basis in these ethnic groups.
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Affiliation(s)
- Lynne E Wagenknecht
- Division of Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA.
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Lusis J, Mar-Heyming RA. Caution on the Interpretation of Plasma Fatty Acid Composition as a Proxy Marker for SCD1 Activity: Particular Implications for Using the 16:1/16:0 Ratio in QTL Studies Involving Hyperlipidemic Patients. Arterioscler Thromb Vasc Biol 2008. [DOI: 10.1161/atvbaha.108.170043] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Affiliation(s)
- Jake Lusis
- UCLA School of Medicine, Department of Medicine, Microbiolog, and Human Genetics, Los Angeles, Calif
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Brouwers MCGJ, van Greevenbroek MMJ, Vermeulen VMMJ, van Lin JMJP, van der Kallen CJH, de Bruin TWA. Five-year follow-up of waist circumference, insulin and ALT levels in familial combined hyperlipidaemia. Clin Sci (Lond) 2007; 113:375-81. [PMID: 17564583 DOI: 10.1042/cs20070101] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
FCHL (familial combined hyperlipidaemia), an entity with many features of the metabolic syndrome, is characterized by changes in cholesterol and triacylglycerol (triglyceride) phenotype over time. The present study was conducted to investigate the relationship of ALT (alanine aminotransferase) levels, used as a surrogate marker for the amount of hepatic fat, with the switch in triacylglycerol phenotype and the increased susceptibility to develop hypertriglyceridaemia in FCHL. BMI (body mass index), waist circumference and plasma triacylglycerols, insulin and ALT levels were measured in 145 FCHL family members and 54 spouses at baseline and after a 5-year follow-up. A switch from normotriglyceridaemia to hypertriglyceridaemia or vice versa, as observed in 22 of 145 FCHL family members, was associated with changes in plasma ALT levels (P=0.001), but not with insulin levels or waist circumference. At 5 years of follow-up, an intra-individual relationship was observed between waist circumference and plasma triacylglycerols, insulin and ALT levels. For each waist circumference, FCHL patients, but not their NL (normolipidaemic) relatives, exhibited higher triacylglycerol and insulin levels than spouses (P<0.001). Remarkably, both FCHL patients and the NL relatives had higher ALT levels for each waist circumference compared with spouses (P<0.001 for FCHL patients, and P=0.035 for NL relatives). In conclusion, the present study shows that the longitudinal relationship of abdominal obesity–ALT is more specific for all FCHL family members, i.e. patients and their NL relatives, than the relationship of abdominal obesity–triacylglycerols. Additionally, the association of ALT with the switch in triacylglycerol phenotype suggests a central role of the liver in the pathogenesis of FCHL.
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Affiliation(s)
- Martijn C G J Brouwers
- Department of Medicine, University Hospital Maastricht, University of Maastricht, Maastricht, The Netherlands.
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