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Pirola CJ, Sookoian S. Drug repurposing in MASLD and MASH-cirrhosis: Targets and treatment approaches based on pathways analysis. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2024; 207:193-206. [PMID: 38942537 DOI: 10.1016/bs.pmbts.2024.01.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/30/2024]
Abstract
Designing and predicting novel drug targets to accelerate drug discovery for treating metabolic dysfunction-associated steatohepatitis (MASH)-cirrhosis is a challenging task. The presence of superimposed (nested) and co-occurring clinical and histological phenotypes, namely MASH and cirrhosis, may partly explain this. Thus, in this scenario, each sub-phenotype has its own set of pathophysiological mechanisms, triggers, and processes. Here, we used gene/protein and set enrichment analysis to predict druggable pathways for the treatment of MASH-cirrhosis. Our findings indicate that the pathogenesis of MASH-cirrhosis can be explained by perturbations in multiple, simultaneous, and overlapping molecular processes. In this scenario, each sub-phenotype has its own set of pathophysiological mechanisms, triggers, and processes. Therefore, we used systems biology modeling to provide evidence that MASH and cirrhosis paradoxically present unique and distinct as well as common disease mechanisms, including a network of molecular targets. More importantly, pathway analysis revealed straightforward results consistent with modulation of the immune response, cell cycle control, and epigenetic regulation. In conclusion, the selection of potential therapies for MASH-cirrhosis should be guided by a better understanding of the underlying biological processes and molecular perturbations that progressively damage liver tissue and its underlying structure. Therapeutic options for patients with MASH may not necessarily be of choice for MASH cirrhosis. Therefore, the biology of the disease and the processes associated with its natural history must be at the forefront of the decision-making process.
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Affiliation(s)
- Carlos J Pirola
- Systems Biology of Complex Diseases, Centro de Investigación Traslacional en Salud, Universidad Maimónides, Buenos Aires, Argentina; Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina.
| | - Silvia Sookoian
- Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina; Clinical and Molecular Hepatology, Centro de Investigación Traslacional en Salud, Universidad Maimónides, Buenos Aires, Argentina; Facultad de Ciencias de la Salud, Universidad Maimónides, Buenos Aires, Argentina.
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Pirola CJ, Sookoian S. Advances in our understanding of the molecular heterogeneity of fatty liver disease: toward informed treatment decision making. Expert Rev Gastroenterol Hepatol 2023; 17:317-324. [PMID: 36912694 DOI: 10.1080/17474124.2023.2191190] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 03/14/2023]
Abstract
INTRODUCTION nonalcoholic fatty liver disease (NAFLD) is a complex disorder resulting from intricate relationships with diverse cardiometabolic risk factors and environmental factors. NAFLD may result in severe chronic liver damage and potentially declining liver function. AREAS COVERED Accumulated knowledge over the last decade indicates that the disease trajectory presents substantial heterogeneity. In addition, overlapping features with the diseases of the metabolic syndrome, combined with heterogeneity in disease mechanisms, further complicates NAFLD diagnosis and prognosis, and hampers progress in biomarker and pharmacological discoveries. Here, we explore solving the heterogeneous clinical landscape of NAFLD by cluster analysis of molecular signatures that serve as a proxy for disease stratification into molecular sub-types. First, we collected information on NAFLD and metabolic syndrome-associated protein-coding genes by data mining the literature. Next, we performed pathways enrichment and cluster analyses to decipher and dissect the different patterns of phenotypic heterogeneity. Our approach showed unique biological pathways for every clinical subtype/group, namely NAFLD + obesity, NAFLD + arterial hypertension, NAFLD + dyslipidemia, and NAFLD + type 2 diabetes. EXPERT OPINION Patients with NAFLD may be benefited by a better understanding of the disease biology, which involves 'dissection' of the molecular sub-phenotypes that drive the disease progression.
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Affiliation(s)
- Carlos J Pirola
- Systems Biology of Complex Diseases, Centro de Altos Estudios En Ciencias Humanas Y de la Salud (CAECIHS), Universidad Abierta Interamericana, Consejo Nacional de Investigaciones Científicas Y Técnicas (CONICET), Buenos Aires, Argentina
| | - Silvia Sookoian
- Clinical and Molecular Hepatology, Centro de Altos Estudios En Ciencias Humanas Y de la Salud (CAECIHS), Universidad Abierta Interamericana, Consejo Nacional de Investigaciones Científicas Y Técnicas (CONICET), Buenos Aires, Argentina
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Pirola CJ, Sookoian S. Repurposing drugs to target nonalcoholic steatohepatitis: Auranofin, a gold-organic molecule complex for the treatment of a specifc complex trait. Clin Mol Hepatol 2022; 28:806-809. [PMID: 35989091 PMCID: PMC9597216 DOI: 10.3350/cmh.2022.0208] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2022] [Accepted: 08/18/2022] [Indexed: 01/05/2023] Open
Affiliation(s)
- Carlos J. Pirola
- Institute of Medical Research A Lanari, School of Medicine, University of Buenos Aires, Ciudad Autónoma de Buenos Aires, Argentina,Department of Molecular Genetics and Biology of Complex Diseases, National Scientific and Technical Research Council (CONICET)-University of Buenos Aires, Institute of Medical Research (IDIM), Ciudad Autónoma de Buenos Aires, Argentina,Corresponding author : Carlos J. Pirola Institute of Medical Research A Lanari, School of Medicine, University of Buenos Aires, Combatientes de Malvinas 3150, Ciudad Autónoma de Buenos Aires 1427, Argentina Tel: +54-11-5287388, E-mail:
| | - Silvia Sookoian
- Institute of Medical Research A Lanari, School of Medicine, University of Buenos Aires, Ciudad Autónoma de Buenos Aires, Argentina,Department of Clinical and Molecular Hepatology, National Scientific and Technical Research Council (CONICET)-University of Buenos Aires, Institute of Medical Research (IDIM), Ciudad Autónoma de Buenos Aires, Argentina,Silvia Sookoian Institute of Medical Research A Lanari, School of Medicine, University of Buenos Aires, Combatientes de Malvinas 3150, Ciudad Autónoma de Buenos Aires 1427, Argentina Tel: +54-11-52873905, E-mail:
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Pirola CJ, Salatino A, Sookoian S. Pleiotropy within gene variants associated with nonalcoholic fatty liver disease and traits of the hematopoietic system. World J Gastroenterol 2021; 27:305-320. [PMID: 33584064 PMCID: PMC7852588 DOI: 10.3748/wjg.v27.i4.305] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/09/2020] [Revised: 12/19/2020] [Accepted: 12/28/2020] [Indexed: 02/06/2023] Open
Abstract
Genome-wide association studies of complex diseases, including nonalcoholic fatty liver disease (NAFLD), have demonstrated that a large number of variants are implicated in the susceptibility of multiple traits — a phenomenon known as pleiotropy that is increasingly being explored through phenome-wide association studies. We focused on the analysis of pleiotropy within variants associated with hematologic traits and NAFLD. We used information retrieved from large public National Health and Nutrition Examination Surveys, Genome-wide association studies, and phenome-wide association studies based on the general population and explored whether variants associated with NAFLD also present associations with blood cell-related traits. Next, we applied systems biology approaches to assess the potential biological connection/s between genes that predispose affected individuals to NAFLD and nonalcoholic steatohepatitis, and genes that modulate hematological-related traits—specifically platelet count. We reasoned that this analysis would allow the identification of potential molecular mediators that link NAFLD with platelets. Genes associated with platelet count are most highly expressed in the liver, followed by the pancreas, heart, and muscle. Conversely, genes associated with NAFLD presented high expression levels in the brain, lung, spleen, and colon. Functional mapping, gene prioritization, and functional analysis of the most significant loci (P < 1 × 10-8) revealed that loci involved in the genetic modulation of platelet count presented significant enrichment in metabolic and energy balance pathways. In conclusion, variants in genes influencing NAFLD exhibit pleiotropic associations with hematologic traits, particularly platelet count. Likewise, significant enrichment of related genes with variants influencing platelet traits was noted in metabolic-related pathways. Hence, this approach yields novel mechanistic insights into NAFLD pathogenesis.
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Affiliation(s)
- Carlos Jose Pirola
- Department of Molecular Genetics and Biology of Complex Diseases, National Scientific and Technical Research Council (CONICET), University of Buenos Aires, Institute of Medical Research (IDIM), Ciudad Autónoma de Buenos Aires C1427ARO, Argentina
- Institute of Medical Research A Lanari, University of Buenos Aires, School of Medicine, Ciudad Autónoma de Buenos Aires, Ciudad Autónoma de Buenos Aires C1427ARO, Argentina
| | - Adrian Salatino
- Department of Molecular Genetics and Biology of Complex Diseases, National Scientific and Technical Research Council (CONICET), University of Buenos Aires, Institute of Medical Research (IDIM), Ciudad Autónoma de Buenos Aires C1427ARO, Argentina
- Institute of Medical Research A Lanari, University of Buenos Aires, School of Medicine, Ciudad Autónoma de Buenos Aires, Ciudad Autónoma de Buenos Aires C1427ARO, Argentina
| | - Silvia Sookoian
- Institute of Medical Research A Lanari, University of Buenos Aires, School of Medicine, Ciudad Autónoma de Buenos Aires, Ciudad Autónoma de Buenos Aires C1427ARO, Argentina
- Department of Clinical and Molecular Hepatology, National Scientific and Technical Research Council (CONICET), University of Buenos Aires, Institute of Medical Research (IDIM), Ciudad Autónoma de Buenos Aires C1427ARO, Argentina
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Restrepo RJ, Lim RW, Korthuis RJ, Shukla SD. Binge alcohol alters PNPLA3 levels in liver through epigenetic mechanism involving histone H3 acetylation. Alcohol 2017; 60:77-82. [PMID: 28433418 DOI: 10.1016/j.alcohol.2017.01.009] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2016] [Accepted: 01/10/2017] [Indexed: 02/06/2023]
Abstract
The human PNPLA3 (patatin-like phospholipase domain-containing 3) gene codes for a protein which is highly expressed in adipose tissue and liver, and is implicated in lipid homeostasis. While PNPLA3 protein contains regions homologous to functional lipolytic proteins, the regulation of its tissue expression is reflective of lipogenic genes. A naturally occurring genetic variant of PNPLA3 in humans has been linked to increased susceptibility to alcoholic liver disease. We have examined the modulatory effect of alcohol on PNPLA3 protein and mRNA expression as well as the association of its gene promoter with acetylated histone H3K9 by chromatin immunoprecipitation (ChIP) assay in rat hepatocytes in vitro, and in vivo in mouse and rat models of acute binge, chronic, and chronic followed by acute binge ethanol administration. Protein expression of PNPLA3 was significantly increased by alcohol in all three models used. PNPLA3 mRNA also increased, albeit to a varying degree. ChIP assay using H3AcK9 antibody showed increased association with the promoter of PNPLA3 in hepatocytes and in mouse liver. This was less evident in rat livers in vivo except under chronic treatment. It is concluded for the first time that histone acetylation plays a role in the modulation of PNPLA3 levels in the liver exposed to binge ethanol both in vitro and in vivo.
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Sookoian S, Pirola CJ. Genetic predisposition in nonalcoholic fatty liver disease. Clin Mol Hepatol 2017; 23:1-12. [PMID: 28268262 PMCID: PMC5381829 DOI: 10.3350/cmh.2016.0109] [Citation(s) in RCA: 164] [Impact Index Per Article: 20.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2016] [Accepted: 11/04/2016] [Indexed: 12/12/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease whose prevalence has reached global epidemic proportions. Although the disease is relatively benign in the early stages, when severe clinical forms, including nonalcoholic steatohepatitis (NASH), cirrhosis and even hepatocellular carcinoma, occur, they result in worsening the long-term prognosis. A growing body of evidence indicates that NAFLD develops from a complex process in which many factors, including genetic susceptibility and environmental insults, are involved. In this review, we focused on the genetic component of NAFLD, with special emphasis on the role of genetics in the disease pathogenesis and natural history. Insights into the topic of the genetic susceptibility in lean individuals with NAFLD and the potential use of genetic tests in identifying individuals at risk are also discussed.
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Affiliation(s)
- Silvia Sookoian
- Department of Clinical and Molecular Hepatology, Institute of Medical Research A Lanari-IDIM, University of Buenos Aires - National Scientific and Technical Research Council (CONICET), Ciudad Autónoma de Buenos Aires, Argentina
| | - Carlos J Pirola
- Department of Molecular Genetics and Biology of Complex Diseases, Institute of Medical Research A Lanari-IDIM, University of Buenos Aires - National Scientific and Technical Research Council (CONICET), Ciudad Autónoma de Buenos Aires, Argentina
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Lonardo A, Sookoian S, Pirola CJ, Targher G. Non-alcoholic fatty liver disease and risk of cardiovascular disease. Metabolism 2016; 65:1136-1150. [PMID: 26477269 DOI: 10.1016/j.metabol.2015.09.017] [Citation(s) in RCA: 165] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2015] [Revised: 08/17/2015] [Accepted: 09/19/2015] [Indexed: 02/06/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) has become the leading cause of chronic liver diseases worldwide, causing considerable liver-related mortality and morbidity. During the past decade, it has also become increasingly evident that NAFLD is a multisystem disease that affects many extra-hepatic organ systems, including the heart and the vascular system. In this updated clinical review, we discuss the rapidly expanding body of clinical and epidemiological evidence that supports a strong association of NAFLD with cardiovascular diseases (CVDs) and other functional and structural myocardial abnormalities. We also discuss some recently published data that correlate NAFLD due to specific genetic polymorphisms with the risk of CVDs. Finally, we briefly examine the assessment tools for estimating the global CVD risk in patients with NAFLD as well as the conventional and the more innovative pharmacological approaches for the treatment of CVD risk in this group of patients.
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Affiliation(s)
- Amedeo Lonardo
- Outpatient Liver Clinic and Division of Internal Medicine, Department of Biomedical, Metabolic and Neural Sciences, NOCSAE, Baggiovara, Azienda USL and University of Modena and Reggio Emilia, Modena, Italy
| | - Silvia Sookoian
- Department of Clinical and Molecular Hepatology, Institute of Medical Research A Lanari-IDIM, University of Buenos Aires-National Scientific and Technical Research Council (CONICET), Ciudad Autónoma de Buenos Aires, Argentina
| | - Carlos J Pirola
- Department of Molecular Genetics and Biology of Complex Diseases, Institute of Medical Research A Lanari-IDIM, University of Buenos Aires-National Scientific and Technical Research Council (CONICET), Ciudad Autónoma de Buenos Aires, Argentina
| | - Giovanni Targher
- Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, University and Azienda Ospedaliera Universitaria Integrata of Verona, Verona, Italy.
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Abstract
Genome-wide association studies (GWAS) in the field of liver diseases have revealed previously unknown pathogenic loci and generated new biological hypotheses. In 2008, a GWAS performed in a population-based sample study, where hepatic liver fat content was measured by magnetic spectroscopy, showed a strong association between a variant (rs738409 C>G p.I148M) in the patatin-like phospholipase domain containing 3 (PNPLA3) gene and nonalcoholic fatty liver disease. Further replication studies have shown robust associations between PNPLA3 and steatosis, fibrosis/cirrhosis, and hepatocellular carcinoma on a background of metabolic, alcoholic, and viral insults. The PNPLA3 protein has lipase activity towards triglycerides in hepatocytes and retinyl esters in hepatic stellate cells. The I148M substitution leads to a loss of function promoting triglyceride accumulation in hepatocytes. Although PNPLA3 function has been extensively studied, the molecular mechanisms leading to hepatic fibrosis and carcinogenesis remain unclear. This unsuspected association has highlighted the fact that liver fat metabolism may have a major impact on the pathophysiology of liver diseases. Conversely, alone, this locus may have limited predictive value with regard to liver disease outcomes in clinical practice. Additional studies at the genome-wide level will be required to identify new variants associated with liver damage and cancer to explain a greater proportion of the heritability of these phenotypes. Thus, incorporating PNPLA3 and other genetic variants in combination with clinical data will allow for the development of tailored predictive models. This attractive approach should be evaluated in prospective cohorts.
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Ueyama M, Nishida N, Korenaga M, Korenaga K, Kumagai E, Yanai H, Adachi H, Katsuyama H, Moriyama S, Hamasaki H, Sako A, Sugiyama M, Aoki Y, Imamura M, Murata K, Masaki N, Kawaguchi T, Torimura T, Hyogo H, Aikata H, Ito K, Sumida Y, Kanazawa A, Watada H, Okamoto K, Honda K, Kon K, Kanto T, Mizokami M, Watanabe S. The impact of PNPLA3 and JAZF1 on hepatocellular carcinoma in non-viral hepatitis patients with type 2 diabetes mellitus. J Gastroenterol 2016; 51:370-379. [PMID: 26337813 DOI: 10.1007/s00535-015-1116-6] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2015] [Accepted: 08/14/2015] [Indexed: 02/04/2023]
Abstract
BACKGROUND Type 2 diabetes mellitus (T2DM) is an established independent risk factor for hepatocellular carcinoma (HCC). T2DM is associated with non-alcoholic steatohepatitis (NASH), which is a major cause of non-HBV and non-HCV-related HCC; nevertheless, it has been difficult to identify those patients with T2DM who have a high risk of developing HCC. The aim of this study was to identify genetic determinants that predispose T2DM patients to HCC by genotyping T2DM susceptibility loci and PNPLA3. METHODS We recruited 389 patients with T2DM who satisfied the following three criteria: negative for HBs-Ag and anti-HCV Ab, alcohol intake <60 g/day, and history of T2DM >10 years. These patients were divided into two groups: T2DM patients with HCC (DM-HCC, n = 59) or those without HCC (DM-non-HCC, n = 330). We genotyped 51 single-nucleotide polymorphisms (SNPs) previously reported as T2DM or NASH susceptibility loci (PNPLA3) compared between the DM-HCC and DM-non-HCC groups with regard to allele frequencies at each SNP. RESULTS The SNP rs738409 located in PNPLA3 was the greatest risk factor associated with HCC. The frequency of the PNPLA3 G allele was significantly higher among DM-HCC individuals than DM-non-HCC individuals (OR 2.53, p = 1.05 × 10(-5)). Among individuals homozygous for the PNPLA3 G allele (n = 115), the frequency of the JAZF1 rs864745 G allele was significantly higher among DM-HCC individuals than DM-non-HCC individuals (OR 3.44, p = 0.0002). CONCLUSIONS PNPLA3 and JAZF1 were associated with non-HBV and non-HCV-related HCC development among Japanese patients with T2DM.
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Affiliation(s)
- Misuzu Ueyama
- The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, 1-7-1 Kohnodai, Ichikawa, Chiba, 272-8516, Japan
- Department of Gastroenterology, Juntendo University School of Medicine, Bunkyo-Ku, Tokyo, Japan
| | - Nao Nishida
- The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, 1-7-1 Kohnodai, Ichikawa, Chiba, 272-8516, Japan
| | - Masaaki Korenaga
- The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, 1-7-1 Kohnodai, Ichikawa, Chiba, 272-8516, Japan.
| | - Keiko Korenaga
- The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, 1-7-1 Kohnodai, Ichikawa, Chiba, 272-8516, Japan
| | - Erina Kumagai
- The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, 1-7-1 Kohnodai, Ichikawa, Chiba, 272-8516, Japan
- Department of Gastroenterology, Juntendo University School of Medicine, Bunkyo-Ku, Tokyo, Japan
| | - Hidekatsu Yanai
- Department of Internal Medicine, National Center for Global Health and Medicine Kohnodai Hospital, Ichikawa, Chiba, Japan
| | - Hiroki Adachi
- Department of Internal Medicine, National Center for Global Health and Medicine Kohnodai Hospital, Ichikawa, Chiba, Japan
| | - Hisayuki Katsuyama
- Department of Internal Medicine, National Center for Global Health and Medicine Kohnodai Hospital, Ichikawa, Chiba, Japan
| | - Sumie Moriyama
- Department of Internal Medicine, National Center for Global Health and Medicine Kohnodai Hospital, Ichikawa, Chiba, Japan
| | - Hidetaka Hamasaki
- Department of Internal Medicine, National Center for Global Health and Medicine Kohnodai Hospital, Ichikawa, Chiba, Japan
| | - Akahito Sako
- Department of Internal Medicine, National Center for Global Health and Medicine Kohnodai Hospital, Ichikawa, Chiba, Japan
| | - Masaya Sugiyama
- The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, 1-7-1 Kohnodai, Ichikawa, Chiba, 272-8516, Japan
| | - Yoshihiko Aoki
- The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, 1-7-1 Kohnodai, Ichikawa, Chiba, 272-8516, Japan
| | - Masatoshi Imamura
- The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, 1-7-1 Kohnodai, Ichikawa, Chiba, 272-8516, Japan
| | - Kazumoto Murata
- The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, 1-7-1 Kohnodai, Ichikawa, Chiba, 272-8516, Japan
| | - Naohiko Masaki
- The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, 1-7-1 Kohnodai, Ichikawa, Chiba, 272-8516, Japan
| | - Takumi Kawaguchi
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
| | - Takuji Torimura
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
| | - Hideyuki Hyogo
- Department of Gastroenterology and Metabolism, Hiroshima University, Hiroshima, Japan
| | - Hiroshi Aikata
- Department of Gastroenterology and Metabolism, Hiroshima University, Hiroshima, Japan
| | - Kiyoaki Ito
- Division of Gastroenterology, Department of Internal Medicine, Aichi Medical University School of Medicine, Nagakute, Japan
| | - Yoshio Sumida
- Center for Digestive and Liver Diseases, Nara City Hospital, Nara, Japan
- Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kamigyo-ku, Kyoto, Japan
| | - Akio Kanazawa
- Department of Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, Bunkyo-Ku, Tokyo, Japan
| | - Hirotaka Watada
- Department of Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, Bunkyo-Ku, Tokyo, Japan
| | - Koji Okamoto
- Department of Nephrology and Endocrinology, Department of Hemodialysis and Apheresis, University Hospital, The University of Tokyo, Tokyo, Japan
| | - Kenjiro Honda
- Department of Nephrology and Endocrinology, Department of Hemodialysis and Apheresis, University Hospital, The University of Tokyo, Tokyo, Japan
| | - Kazuyoshi Kon
- Department of Gastroenterology, Juntendo University School of Medicine, Bunkyo-Ku, Tokyo, Japan
| | - Tatsuya Kanto
- The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, 1-7-1 Kohnodai, Ichikawa, Chiba, 272-8516, Japan
| | - Masashi Mizokami
- The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, 1-7-1 Kohnodai, Ichikawa, Chiba, 272-8516, Japan
| | - Sumio Watanabe
- Department of Gastroenterology, Juntendo University School of Medicine, Bunkyo-Ku, Tokyo, Japan
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Brouwer WP, van der Meer AJ, Boonstra A, Pas SD, de Knegt RJ, de Man RA, Hansen BE, ten Kate FJW, Janssen HLA. The impact of PNPLA3 (rs738409 C>G) polymorphisms on liver histology and long-term clinical outcome in chronic hepatitis B patients. Liver Int 2015; 35:438-47. [PMID: 25284145 DOI: 10.1111/liv.12695] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2014] [Accepted: 09/22/2014] [Indexed: 12/21/2022]
Abstract
BACKGROUND & AIMS We aimed to assess the association between the patatin-like phospholipase domain-containing-3 (PNPLA3) I148M polymorphism, liver histology and long-term outcome in chronic hepatitis B (CHB) patients. METHODS We enrolled 531 consecutive treatment naïve CHB patients diagnosed from 1985 to 2012 with an available liver biopsy for reassessment, and sample for genetic testing. Data on all-cause mortality and hepatocellular carcinoma (HCC) at long-term follow-up were obtained from national database registries. RESULTS The prevalence of steatohepatitis increased with PNPLA3 CC (14%), CG (20%) and GG (43%) (P < 0.001). The association was altered by both gender (P = 0.010) and overweight (P = 0.015): the effect of PNPLA3 on steatohepatitis was most pronounced among non-overweight females (adjusted OR 13.4, 95%CI: 3.7-51.6, P < 0.001), and non-overweight males (adjusted OR 2.4, 95%CI: 1.4-4.3, P = 0.002). Furthermore, PNPLA3 GG genotype was associated with iron depositions (OR 2.8, 95%CI: 1.2-6.4, P = 0.014) and lobular inflammation (OR 2.2, 95%CI: 1.1-4.5, P = 0.032), but not with advanced fibrosis (OR 1.1, 95%CI: 0.7-1.8, P = 0.566). The median follow-up was 10.1 years (interquartile range 5.6 - 15.8), during which 13 patients developed HCC and 28 died. Steatohepatitis was associated with all-cause mortality [Hazard ratio (HR) 3.1, 95%CI: 1.3-7.3, P = 0.006] and HCC (HR 2.8, 95%CI: 0.9-9.2, P = 0.078), but no significant association was observed for PNPLA3. CONCLUSIONS In this cohort of biopsied CHB patients, PNPLA3 was independently associated with steatosis, steatohepatitis, lobular inflammation and iron depositions, but not with advanced fibrosis, HCC development or all-cause mortality. The effect of PNPLA3 on steatohepatitis was particularly pronounced among female patients without severe overweight.
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Affiliation(s)
- Willem P Brouwer
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, The Netherlands
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Sookoian S, Pirola CJ. Liver enzymes, metabolomics and genome-wide association studies: From systems biology to the personalized medicine. World J Gastroenterol 2015; 21:711-725. [PMID: 25624707 PMCID: PMC4299326 DOI: 10.3748/wjg.v21.i3.711] [Citation(s) in RCA: 202] [Impact Index Per Article: 20.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/04/2014] [Revised: 10/18/2014] [Accepted: 12/16/2014] [Indexed: 02/06/2023] Open
Abstract
For several decades, serum levels of alanine (ALT) and aspartate (AST) aminotransferases have been regarded as markers of liver injury, including a wide range of etiologies from viral hepatitis to fatty liver. The increasing worldwide prevalence of metabolic syndrome and cardiovascular disease revealed that transaminases are strong predictors of type 2 diabetes, coronary heart disease, atherothrombotic risk profile, and overall risk of metabolic disease. Therefore, it is plausible to suggest that aminotransferases are surrogate biomarkers of “liver metabolic functioning” beyond the classical concept of liver cellular damage, as their enzymatic activity might actually reflect key aspects of the physiology and pathophysiology of the liver function. In this study, we summarize the background information and recent findings on the biological role of ALT and AST, and review the knowledge gained from the application of genome-wide approaches and “omics” technologies that uncovered new concepts on the role of aminotransferases in human diseases and systemic regulation of metabolic functions. Prediction of biomolecular interactions between the candidate genes recently discovered to be associated with plasma concentrations of liver enzymes showed interesting interconnectivity nodes, which suggest that regulation of aminotransferase activity is a complex and highly regulated trait. Finally, links between aminotransferase genes and metabolites are explored to understand the genetic contributions to the metabolic diversity.
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Sookoian S, Pirola CJ. Personalizing care for nonalcoholic fatty liver disease patients: what are the research priorities? Per Med 2014; 11:735-743. [PMID: 29764046 DOI: 10.2217/pme.14.44] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a common chronic liver disease whose prevalence has reached global epidemic proportions, not only in adults but also in children. From a clinical point of view, NAFLD stems a myriad of challenges to physicians, researchers and patients. In this study, we revise the current knowledge and recent insights on NAFLD pathogenesis and diagnosis in the context of a personalized perspective with special focus on the following issues: noninvasive biomarkers for the evaluation of disease severity and progression, lifestyle-related patients' recommendations, risk prediction of disease by genetic testing, management of NAFLD-associated comorbidities and patient-oriented therapeutic intervention strategies.
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Affiliation(s)
- Silvia Sookoian
- Department of Clinical & Molecular Hepatology, Institute of Medical Research A Lanari-IDIM, University of Buenos Aires - National Scientific and Technical Research Council (CONICET), Ciudad Autónoma de Buenos Aires, Argentina
| | - Carlos J Pirola
- Department of Molecular Genetics & Biology of Complex Diseases, Institute of Medical Research A Lanari-IDIM, University of Buenos Aires - National Scientific & Technical Research Council (CONICET), Ciudad Autónoma de Buenos Aires, Argentina
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Hao L, Ito K, Huang KH, Sae-tan S, Lambert JD, Ross AC. Shifts in dietary carbohydrate-lipid exposure regulate expression of the non-alcoholic fatty liver disease-associated gene PNPLA3/adiponutrin in mouse liver and HepG2 human liver cells. Metabolism 2014; 63:1352-62. [PMID: 25060692 PMCID: PMC4175036 DOI: 10.1016/j.metabol.2014.06.016] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2014] [Revised: 05/24/2014] [Accepted: 06/17/2014] [Indexed: 02/07/2023]
Abstract
OBJECTIVE Patatin-like phospholipase domain containing 3 (PNPLA3, adiponutrin) has been identified as a modifier of lipid metabolism. To better understand the physiological role of PNPLA3/adiponutrin, we have investigated its regulation in intact mice and human hepatocytes under various nutritional/metabolic conditions. MATERIAL/METHODS PNPLA3 gene expression was determined by real-time PCR in liver of C57BL/6 mice after dietary treatments and in HepG2 cells exposed to various nutritional/metabolic stimuli. Intracellular lipid content was determined in HepG2 cells after siRNA-mediated knockdown of PNPLA3. RESULTS In vivo, mice fed a high-carbohydrate (HC) liquid diet had elevated hepatic lipid content, and PNPLA3 mRNA and protein expression, compared to chow-fed mice. Elevated expression was completely abrogated by addition of unsaturated lipid emulsion to the HC diet. By contrast, in mice with high-fat diet-induced steatosis, Pnpla3 expression did not differ compared to low-fat fed mice. In HepG2 cells, Pnpla3 expression was reversibly suppressed by glucose depletion and increased by glucose refeeding, but unchanged by addition of insulin and glucagon. Several unsaturated fatty acids each significantly decreased Pnpla3 mRNA, similar to lipid emulsion in vivo. However, Pnpla3 knockdown in HepG2 cells did not alter total lipid content in high glucose- or oleic acid-treated cells. CONCLUSIONS Our results provide evidence that PNPLA3 expression is an early signal/signature of carbohydrate-induced lipogenesis, but its expression is not associated with steatosis per se. Under lipogenic conditions due to high-carbohydrate feeding, certain unsaturated fatty acids can effectively suppress both lipogenesis and PNPLA3 expression, both in vivo and in a hepatocyte cell line.
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Affiliation(s)
- Lei Hao
- Department of Nutritional Sciences, The Pennsylvania State University, University Park, PA 16802 USA
| | - Kyoko Ito
- Department of Nutritional Sciences, The Pennsylvania State University, University Park, PA 16802 USA
| | - Kuan-Hsun Huang
- Department of Nutritional Sciences, The Pennsylvania State University, University Park, PA 16802 USA
| | - Sudathip Sae-tan
- Department of Food Science, The Pennsylvania State University, University Park, PA 16802 USA
| | - Joshua D Lambert
- Department of Food Science, The Pennsylvania State University, University Park, PA 16802 USA
| | - A Catharine Ross
- Department of Nutritional Sciences, The Pennsylvania State University, University Park, PA 16802 USA; Center for Immunology and Infectious Disease, The Pennsylvania State University, University Park, PA 16802 USA.
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14
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Liu YL, Patman GL, Leathart JBS, Piguet AC, Burt AD, Dufour JF, Day CP, Daly AK, Reeves HL, Anstee QM. Carriage of the PNPLA3 rs738409 C >G polymorphism confers an increased risk of non-alcoholic fatty liver disease associated hepatocellular carcinoma. J Hepatol 2014; 61:75-81. [PMID: 24607626 DOI: 10.1016/j.jhep.2014.02.030] [Citation(s) in RCA: 410] [Impact Index Per Article: 37.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2013] [Revised: 02/26/2014] [Accepted: 02/27/2014] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Subtle inter-patient genetic variation and environmental factors combine to determine disease progression in non-alcoholic fatty liver disease (NAFLD). Carriage of the PNPLA3 rs738409 c.444C >G minor allele (encoding the I148M variant) has been robustly associated with advanced NAFLD. Although most hepatocellular carcinoma (HCC) is related to chronic viral hepatitis or alcoholic liver disease, the incidence of NAFLD-related HCC is increasing. We examined whether rs738409 C >G was associated with HCC-risk in patients with NAFLD. METHODS PNPLA3 rs738409 genotype was determined by allelic discrimination in 100 European Caucasians with NAFLD-related HCC and 275 controls with histologically characterised NAFLD. RESULTS Genotype frequencies were significantly different between NAFLD-HCC cases (CC=28, CG=43, GG=29) and NAFLD-controls (CC=125, CG=117, GG=33) (p=0.0001). In multivariate analysis adjusted for age, gender, diabetes, BMI, and presence of cirrhosis, carriage of each copy of the rs738409 minor (G) allele conferred an additive risk for HCC (adjusted OR 2.26 [95% CI 1.23-4.14], p=0.0082), with GG homozygotes exhibiting a 5-fold [1.47-17.29], p=0.01 increased risk over CC. When compared to the UK general population (1958 British Birth Cohort, n=1476), the risk-effect was more pronounced (GC vs. CC: unadjusted OR 2.52 [1.55-4.10], p=0.0002; GG vs. CC: OR 12.19 [6.89-21.58], p<0.0001). CONCLUSIONS Carriage of the PNPLA3 rs738409 C >G polymorphism is not only associated with greater risk of progressive steatohepatitis and fibrosis but also of HCC. If validated, these findings suggest that PNPLA3 genotyping has the potential to contribute to multi-factorial patient-risk stratification, identifying those to whom HCC surveillance may be targeted.
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Affiliation(s)
- Y-L Liu
- Institute of Cellular Medicine, The Medical School, Newcastle University, Newcastle upon Tyne, UK
| | - G L Patman
- Northern Institute for Cancer Research, The Medical School, Newcastle University, Newcastle upon Tyne, UK
| | - J B S Leathart
- Institute of Cellular Medicine, The Medical School, Newcastle University, Newcastle upon Tyne, UK
| | - A-C Piguet
- University Clinic of Visceral Surgery and Medicine, Inselspital Bern, Bern, Switzerland
| | - A D Burt
- Institute of Cellular Medicine, The Medical School, Newcastle University, Newcastle upon Tyne, UK
| | - J-F Dufour
- University Clinic of Visceral Surgery and Medicine, Inselspital Bern, Bern, Switzerland
| | - C P Day
- Institute of Cellular Medicine, The Medical School, Newcastle University, Newcastle upon Tyne, UK
| | - A K Daly
- Institute of Cellular Medicine, The Medical School, Newcastle University, Newcastle upon Tyne, UK
| | - H L Reeves
- Northern Institute for Cancer Research, The Medical School, Newcastle University, Newcastle upon Tyne, UK.
| | - Q M Anstee
- Institute of Cellular Medicine, The Medical School, Newcastle University, Newcastle upon Tyne, UK
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