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Norden-Krichmar TM, Rotroff D, Schwantes-An TH, Bataller R, Goldman D, Nagy LE, Liangpunsakul S. Genomic approaches to explore susceptibility and pathogenesis of alcohol use disorder and alcohol-associated liver disease. Hepatology 2025; 81:1595-1606. [PMID: 37796138 PMCID: PMC10985049 DOI: 10.1097/hep.0000000000000617] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2023] [Accepted: 08/13/2023] [Indexed: 10/06/2023]
Abstract
Excessive alcohol use is a major risk factor for the development of an alcohol use disorder (AUD) and contributes to a wide variety of other medical illnesses, including alcohol-associated liver disease (ALD). Both AUD and ALD are complex and causally interrelated diseases, and multiple factors other than alcohol consumption are implicated in the disease pathogenesis. While the underlying pathophysiology of AUD and ALD is complex, there is substantial evidence for a genetic susceptibility of both diseases. Current genome-wide association studies indicate that the genes associated with clinical AUD only poorly overlap with the genes identified for heavy drinking and, in turn, neither overlap with the genes identified for ALD. Uncovering the main genetic factors will enable us to identify molecular drivers underlying the pathogenesis, discover potential targets for therapy, and implement patient care early in disease progression. In this review, we described multiple genomic approaches and their implications to investigate the susceptibility and pathogenesis of both AUD and ALD. We concluded our review with a discussion of the knowledge gaps and future research on genomic studies in these 2 diseases.
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Affiliation(s)
| | - Daniel Rotroff
- Department of Quantitative Health Sciences, Cleveland Clinic, Cleveland, OH
| | - Tae-Hwi Schwantes-An
- Department of Medical & Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN
| | - Ramon Bataller
- Liver Unit, Institut of Digestive and Metabolic Diseases, Hospital Clinic, Barcelona, Spain
- Institut d’Investigacions Biomediques August Pi i Sunyer (IDIBAPS)
| | - David Goldman
- Laboratory of Neurogenetics and Office of the Clinical Director, National Institute on Alcohol Abuse and Alcoholism, Rockville, MD
| | - Laura E. Nagy
- Center for Liver Disease Research, Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, OH
- Gastroenterology and Hepatology, Cleveland Clinic, Cleveland, OH
- Department of Molecular Medicine, Case Western Reserve University, Cleveland, OH
| | - Suthat Liangpunsakul
- Division of Gastroenterology and Hepatology, Department of Medicine, Indianapolis, IN
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN
- Roudebush Veterans Administration Medical Center, Indianapolis, IN
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Sato S, Iino C, Sasada T, Furusawa K, Yoshida K, Sawada K, Mikami T, Fukuda S, Nakaji S, Sakuraba H. A 4-year cohort study of the effects of PNPLA3 rs738409 genotypes on liver fat and fibrosis and gut microbiota in a non-fatty liver population. Environ Health Prev Med 2025; 30:17. [PMID: 40074353 PMCID: PMC11925709 DOI: 10.1265/ehpm.24-00365] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2024] [Accepted: 02/07/2025] [Indexed: 03/14/2025] Open
Abstract
BACKGROUND Many factors are associated with the development and progression of liver fat and fibrosis; however, genetics and the gut microbiota are representative factors. Moreover, recent studies have indicated a link between host genes and the gut microbiota. This study investigated the effect of patatin-like phospholipase domain-containing 3 (PNPLA3) rs738409 (C > G), which has been reported to be most involved in the onset and progression of fatty liver, on liver fat and fibrosis in a cohort study related to gut microbiota in a non-fatty liver population. METHODS This cohort study included 214 participants from the health check-up project in 2018 and 2022 who had non-fatty liver with controlled attenuation parameter (CAP) values <248 dB/m by FibroScan and were non-drinkers. Changes in CAP values and liver stiffness measurement (LSM), liver-related items, and gut microbiota from 2018 to 2022 were investigated separately for PNPLA3 rs738409 CC, CG, and GG genotypes. RESULTS Baseline values showed no difference among the PNPLA3 rs738409 genotypes for any of the measurement items. From 2018 to 2022, the PNPLA3 rs738409 CG and GG genotype groups showed a significant increase in CAP and body mass index; no significant change was observed in the CC genotype group. LSM increased in all genotypes, but the rate of increase was highest in the GG genotype, followed by the CG and CC genotypes. Fasting blood glucose levels increased in all genotypes; however, HOMA-IR (Homeostasis Model Assessment of Insulin Resistance) increased significantly only in the GG genotype. HDL (high-density lipoprotein) and LDL (low-density lipoprotein) cholesterol levels significantly increased in all genotypes, whereas triglycerides did not show any significant changes in any genotype. As for the gut microbiota, the relative abundance of Feacalibacterium in the PNPLA3 rs738409 GG genotype decreased by 2% over 4 years, more than 2-fold compared to CC and GG genotypes. Blautia increased significantly in the CC group. CONCLUSION The results suggest that PNPLA3 G-allele carriers of non-fatty liver develop liver fat and fibrosis due to not only obesity and insulin resistance but also the deterioration of gut microbiota, which may require a relatively long course of time, even years.
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Affiliation(s)
- Satoshi Sato
- Department of Gastroenterology, Hematology and Clinical Immunology, Hirosaki University Graduate School of Medicine, Hirosaki 036-8562, Japan
| | - Chikara Iino
- Department of Gastroenterology, Hematology and Clinical Immunology, Hirosaki University Graduate School of Medicine, Hirosaki 036-8562, Japan
| | - Takafumi Sasada
- Department of Gastroenterology, Hematology and Clinical Immunology, Hirosaki University Graduate School of Medicine, Hirosaki 036-8562, Japan
| | - Keisuke Furusawa
- Department of Gastroenterology, Hematology and Clinical Immunology, Hirosaki University Graduate School of Medicine, Hirosaki 036-8562, Japan
| | - Kenta Yoshida
- Department of Gastroenterology, Hematology and Clinical Immunology, Hirosaki University Graduate School of Medicine, Hirosaki 036-8562, Japan
| | - Kaori Sawada
- Department of Preemptive Medicine, Hirosaki University Graduate School of Medicine, Hirosaki 036-8562, Japan
| | - Tatsuya Mikami
- Department of Preemptive Medicine, Hirosaki University Graduate School of Medicine, Hirosaki 036-8562, Japan
| | - Shinsaku Fukuda
- Department of Preemptive Medicine, Hirosaki University Graduate School of Medicine, Hirosaki 036-8562, Japan
| | - Shigeyuki Nakaji
- Department of Preemptive Medicine, Hirosaki University Graduate School of Medicine, Hirosaki 036-8562, Japan
| | - Hirotake Sakuraba
- Department of Gastroenterology, Hematology and Clinical Immunology, Hirosaki University Graduate School of Medicine, Hirosaki 036-8562, Japan
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Sato S, Iino C, Sasada T, Soma G, Furusawa K, Yoshida K, Sawada K, Mikami T, Fukuda S, Nakaji S, Sakuraba H. An epidemiological study on the factors including genetic polymorphism influencing ALT >30 U/L and liver fibrosis progression in metabolic dysfunction-associated steatotic liver disease among the general population. JGH Open 2024; 8:e70043. [PMID: 39713746 PMCID: PMC11659511 DOI: 10.1002/jgh3.70043] [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: 06/19/2024] [Revised: 09/29/2024] [Accepted: 10/07/2024] [Indexed: 12/24/2024]
Abstract
Background and Aim Identifying the factors contributing to the progression of metabolic dysfunction-associated steatotic liver disease (MASLD), a lifestyle-related disease, is crucial for preventing future liver-related deaths. This study aimed to epidemiologically investigate factors, including single-nucleotide polymorphisms (SNPs) associated with alanine aminotransferase (ALT) levels >30 U/L and potential risk factors for liver fibrosis, in a general population cohort of patients with MASLD. Methods Among 1059 participants in the health checkup project, 228 who were diagnosed with MASLD were analyzed. Liver fat content and stiffness were measured using FibroScan, and 13 SNPs associated with non-alcoholic fatty liver disease (NAFLD) were measured in addition to other clinical parameters. Results In the multivariate analysis, male sex, younger age, and high triglyceride levels were significant risk factors for ALT levels >30 U/L (P-value < 0.05). Furthermore, among the 13 SNPs measured, only the GG genotypes of patatin-like phospholipase domain-containing 3 gene (PNPLA3) rs738409 and rs2896019 were significant risk factors for ALT levels >30 U/L (P-value 0.004 and 0.007). The GG genotypes of PNPLA3 rs738409 and rs2896019 had higher FibroScan-aspartate aminotransferase (FAST) and APRI scores than the CC + CG and TT + TG genotypes (P-value < 0.05). In addition, multivariate analysis revealed that the GG genotypes of rs738409 and rs2896019 were significant risk factors independent of cardiovascular metabolic risk for patients with MASLD (P-value 0.038 and 0.021). Conclusion An individualized treatment approach is warranted for patients with MASLD due to the influence of various factors on its progression, including genetic factors and lifestyle diseases.
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Affiliation(s)
- Satoshi Sato
- Department of Gastroenterology, Hematology and Clinical ImmunologyHirosaki University Graduate School of MedicineHirosakiJapan
| | - Chikara Iino
- Department of Gastroenterology, Hematology and Clinical ImmunologyHirosaki University Graduate School of MedicineHirosakiJapan
| | - Takafumi Sasada
- Department of Gastroenterology, Hematology and Clinical ImmunologyHirosaki University Graduate School of MedicineHirosakiJapan
| | - Go Soma
- Department of Gastroenterology, Hematology and Clinical ImmunologyHirosaki University Graduate School of MedicineHirosakiJapan
| | - Keisuke Furusawa
- Department of Gastroenterology, Hematology and Clinical ImmunologyHirosaki University Graduate School of MedicineHirosakiJapan
| | - Kenta Yoshida
- Department of Gastroenterology, Hematology and Clinical ImmunologyHirosaki University Graduate School of MedicineHirosakiJapan
| | - Kaori Sawada
- Department of Preemptive MedicineHirosaki University Graduate School of MedicineHirosakiJapan
| | - Tatsuya Mikami
- Department of Preemptive MedicineHirosaki University Graduate School of MedicineHirosakiJapan
| | - Shinsaku Fukuda
- Department of Preemptive MedicineHirosaki University Graduate School of MedicineHirosakiJapan
| | - Shigeyuki Nakaji
- Department of Preemptive MedicineHirosaki University Graduate School of MedicineHirosakiJapan
| | - Hirotake Sakuraba
- Department of Gastroenterology, Hematology and Clinical ImmunologyHirosaki University Graduate School of MedicineHirosakiJapan
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Sato S, Iino C, Sasada T, Soma G, Furusawa K, Yoshida K, Sawada K, Mikami T, Nakaji S, Sakuraba H, Fukuda S. Epidemiological Study on the Interaction between the PNPLA3 (rs738409) and Gut Microbiota in Metabolic Dysfunction-Associated Steatotic Liver Disease. Genes (Basel) 2024; 15:1172. [PMID: 39336763 PMCID: PMC11430940 DOI: 10.3390/genes15091172] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2024] [Revised: 08/31/2024] [Accepted: 09/02/2024] [Indexed: 09/30/2024] Open
Abstract
Many factors are associated with the development and progression of metabolic dysfunction-associated steatotic liver disease (MASLD); however, genetics and gut microbiota are representative factors. Recent studies have highlighted the link between host genes and the gut microbiota. Although there have been many studies on the separate effects of single nucleotide polymorphisms (SNPs) and gut bacteria on MASLD, few epidemiological studies have examined how SNPs and gut bacteria interact in the development and progression of MASLD. This study aimed to investigate the association between PNPLA3 rs738409, a representative MASLD-related SNP, and gut bacteria in MASLD using a cross-sectional study of the general population. The 526 participants (318 normal and 208 MASLD groups) were grouped into the PNPLA3 rs738409 SNP, CC, CG, and GG genotypes, and the differences in the gut microbiota were investigated in each group. The PNPLA3 rs738409 CC and CG genotypes were associated with decreased Blautia and Ruminococcaceae in the MASLD group. They were negatively correlated with controlled attenuation parameter levels, body mass index, serum blood glucose, and triglycerides. In contrast, there was no association between the normal and MASLD groups and the gut bacteria in the PNPLA3 rs738409, the GG genotype group. This finding implies that dietary interventions and probiotics may be more effective in preventing and treating MASLD in individuals with the PNPLA3 rs738409 CC and CG genotypes. In contrast, their efficacy may be limited in those with the GG genotype.
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Affiliation(s)
- Satoshi Sato
- Department of Gastroenterology, Hematology, and Clinical Immunology, Hirosaki University Graduate School of Medicine, Hirosaki 036-8562, Japan
| | - Chikara Iino
- Department of Gastroenterology, Hematology, and Clinical Immunology, Hirosaki University Graduate School of Medicine, Hirosaki 036-8562, Japan
| | - Takafumi Sasada
- Department of Gastroenterology, Hematology, and Clinical Immunology, Hirosaki University Graduate School of Medicine, Hirosaki 036-8562, Japan
| | - Go Soma
- Department of Gastroenterology, Hematology, and Clinical Immunology, Hirosaki University Graduate School of Medicine, Hirosaki 036-8562, Japan
| | - Keisuke Furusawa
- Department of Gastroenterology, Hematology, and Clinical Immunology, Hirosaki University Graduate School of Medicine, Hirosaki 036-8562, Japan
| | - Kenta Yoshida
- Department of Gastroenterology, Hematology, and Clinical Immunology, Hirosaki University Graduate School of Medicine, Hirosaki 036-8562, Japan
| | - Kaori Sawada
- Department of Preemptive Medicine, Hirosaki University Graduate School of Medicine, Hirosaki 036-8562, Japan
| | - Tatsuya Mikami
- Department of Preemptive Medicine, Hirosaki University Graduate School of Medicine, Hirosaki 036-8562, Japan
| | - Shigeyuki Nakaji
- Department of Preemptive Medicine, Hirosaki University Graduate School of Medicine, Hirosaki 036-8562, Japan
| | - Hirotake Sakuraba
- Department of Gastroenterology, Hematology, and Clinical Immunology, Hirosaki University Graduate School of Medicine, Hirosaki 036-8562, Japan
| | - Shinsaku Fukuda
- Department of Gastroenterology, Hematology, and Clinical Immunology, Hirosaki University Graduate School of Medicine, Hirosaki 036-8562, Japan
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Zhang L, El-Shabrawi M, Baur LA, Byrne CD, Targher G, Kehar M, Porta G, Lee WS, Lefere S, Turan S, Alisi A, Weiss R, Faienza MF, Ashraf A, Sundaram SS, Srivastava A, De Bruyne R, Kang Y, Bacopoulou F, Zhou YH, Darma A, Lupsor-Platon M, Hamaguchi M, Misra A, Méndez-Sánchez N, Ng NBH, Marcus C, Staiano AE, Waheed N, Alqahtani SA, Giannini C, Ocama P, Nguyen MH, Arias-Loste MT, Ahmed MR, Sebastiani G, Poovorawan Y, Al Mahtab M, Pericàs JM, Reverbel da Silveira T, Hegyi P, Azaz A, Isa HM, Lertudomphonwanit C, Farrag MI, Nugud AAA, Du HW, Qi KM, Mouane N, Cheng XR, Al Lawati T, Fagundes EDT, Ghazinyan H, Hadjipanayis A, Fan JG, Gimiga N, Kamal NM, Ștefănescu G, Hong L, Diaconescu S, Li M, George J, Zheng MH. An international multidisciplinary consensus on pediatric metabolic dysfunction-associated fatty liver disease. MED 2024; 5:797-815.e2. [PMID: 38677287 DOI: 10.1016/j.medj.2024.03.017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2023] [Revised: 02/20/2024] [Accepted: 03/26/2024] [Indexed: 04/29/2024]
Abstract
BACKGROUND Non-alcoholic fatty liver disease (NAFLD) is highly prevalent in children and adolescents, particularly those with obesity. NAFLD is considered a hepatic manifestation of the metabolic syndrome due to its close associations with abdominal obesity, insulin resistance, and atherogenic dyslipidemia. Experts have proposed an alternative terminology, metabolic dysfunction-associated fatty liver disease (MAFLD), to better reflect its pathophysiology. This study aimed to develop consensus statements and recommendations for pediatric MAFLD through collaboration among international experts. METHODS A group of 65 experts from 35 countries and six continents, including pediatricians, hepatologists, and endocrinologists, participated in a consensus development process. The process encompassed various aspects of pediatric MAFLD, including epidemiology, mechanisms, screening, and management. FINDINGS In round 1, we received 65 surveys from 35 countries and analyzed these results, which informed us that 73.3% of respondents agreed with 20 draft statements while 23.8% agreed somewhat. The mean percentage of agreement or somewhat agreement increased to 80.85% and 15.75%, respectively, in round 2. The final statements covered a wide range of topics related to epidemiology, pathophysiology, and strategies for screening and managing pediatric MAFLD. CONCLUSIONS The consensus statements and recommendations developed by an international expert panel serve to optimize clinical outcomes and improve the quality of life for children and adolescents with MAFLD. These findings emphasize the need for standardized approaches in diagnosing and treating pediatric MAFLD. FUNDING This work was funded by the National Natural Science Foundation of China (82070588, 82370577), the National Key R&D Program of China (2023YFA1800801), National High Level Hospital Clinical Research Funding (2022-PUMCH-C-014), the Wuxi Taihu Talent Plan (DJTD202106), and the Medical Key Discipline Program of Wuxi Health Commission (ZDXK2021007).
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Affiliation(s)
- Le Zhang
- Department of Paediatrics, Affiliated Children's Hospital of Jiangnan University (Wuxi Children's Hospital), Wuxi, China
| | - Mortada El-Shabrawi
- Department of Pediatrics and Pediatric Hepatology, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Louise A Baur
- Children's Hospital Westmead Clinical School, Sydney Medical School, The University of Sydney, Sydney, NSW, Australia; Sydney School of Public Health, The University of Sydney, Sydney, NSW, Australia
| | - Christopher D Byrne
- Nutrition and Metabolism, Faculty of Medicine, University of Southampton, Southampton, UK; National Institute for Health and Care Research Southampton Biomedical Research Centre, University Hospital Southampton, Southampton, UK
| | - Giovanni Targher
- Department of Medicine, University of Verona, Verona, Italy; Metabolic Diseases Research Unit, IRCCS Sacro Cuore - Don Calabria Hospital, Negrar di Valpolicella, Italy
| | - Mohit Kehar
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Children's Hospital of Eastern Ontario, Department of Pediatrics, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada
| | - Gilda Porta
- Pediatric Hepatology, Transplant Unit, Hospital Sírio-Libanês, Hospital Municipal Infantil Menino Jesus, Sau Paulo, Brazil
| | - Way Seah Lee
- Department of Paediatrics, Faculty of Medicine, University Malaya, Kuala Lumpur, Malaysia
| | - Sander Lefere
- Hepatology Research Unit, Department Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium; Liver Research Center Ghent, Ghent University, Ghent, Belgium
| | - Serap Turan
- Pediatric Endocrinology and Diabetes, Marmara University School of Medicine, Istanbul, Turkey
| | - Anna Alisi
- Research Unit of Molecular Genetics of Complex Phenotypes, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
| | - Ram Weiss
- Department of Pediatrics, Ruth Children's Hospital, Rambam Medical Center and the Bruce Rappaport School of Medicine, Technion, Haifa, Israel
| | - Maria Felicia Faienza
- Pediatric Unit, Department of Precision and Regenerative Medicine and Ionian Area, University of Bari "Aldo Moro", Bari, Italy
| | - Ambika Ashraf
- Division of Pediatric Endocrinology and Diabetes, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Shikha S Sundaram
- Section of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Pediatric Liver Center, Children's Hospital Colorado, University of Colorado School of Medicine and Anschutz Medical Campus, Aurora, CO, USA
| | - Anshu Srivastava
- Department of Pediatric Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - Ruth De Bruyne
- Department of Pediatric Gastroenterology, Hepatology and Nutrition, Ghent University Hospital, Ghent, Belgium
| | - Yunkoo Kang
- Department of Pediatrics, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea
| | - Flora Bacopoulou
- Center for Adolescent Medicine and UNESCO Chair in Adolescent Health Care, Aghia Sophia Children's Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece; University Research Institute of Maternal and Child Health & Precision Medicine, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Yong-Hai Zhou
- Department of Pediatrics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
| | - Andy Darma
- Department of Pediatrics, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia
| | - Monica Lupsor-Platon
- Department of Medical Imaging, "Iuliu Hatieganu" University of Medicine and Pharmacy, Cluj-Napoca, Romania; "Prof. Dr. O. Fodor" Regional Institute of Gastroenterology and Hepatology, Cluj-Napoca, Romania
| | - Masahide Hamaguchi
- Department of Endocrinology and Metabolism, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kyoto, Japan
| | - Anoop Misra
- Fortis-C-DOC Centre of Excellence for Diabetes, Metabolic Diseases and Endocrinology, New Delhi, India; National Diabetes, Obesity and Cholesterol Foundation (N-DOC), New Delhi, India; Diabetes Foundation, New Delhi, India
| | - Nahum Méndez-Sánchez
- Liver Research Unit, Medica Sur Clinic and Foundation and Faculty of Medicine, National Autonomous University of Mexico, Mexico City, Mexico
| | - Nicholas Beng Hui Ng
- Department of Paediatrics, Khoo Teck Puat - National University Children's Medical Institute, National University Hospital, Singapore, Singapore; Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Claude Marcus
- Department of Clinical Science, Intervention and Technology, Division of Pediatrics, Karolinska Institutet, Stockholm, Sweden
| | | | - Nadia Waheed
- Department of Pediatrics, Shaheed Zulfiqar Ali Bhutto Medical University, Pakistan Institute of Medical Sciences, Islamabad, Pakistan
| | - Saleh A Alqahtani
- Organ Transplantation Center of Excellence, King Faisal Specialist Hospital & Research Center, Riyadh, Saudi Arabia; Division of Gastroenterology and Hepatology, Johns Hopkins University, Baltimore, MD, USA
| | - Cosimo Giannini
- Department of Pediatrics, University of Chieti, Chieti, Italy
| | - Ponsiano Ocama
- Department of Internal Medicine, School of Medicine, Makerere University College of Health Sciences, Kampala, Uganda
| | - Mindie H Nguyen
- Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University Medical Center, Palo Alto, CA, USA; Department of Epidemiology and Population Health, Stanford University, Stanford, CA, USA
| | - Maria Teresa Arias-Loste
- Hospital Universitario Marqués de Valdecilla, Gastroenterology and Hepatology Department, Clinical and Translational Research in Digestive Diseases, Instituto de Investigación Marqués de Valdecilla (IDIVAL), Santander, Spain
| | - Mohamed Rabea Ahmed
- Department of Pediatrics, Jahra Hospital, Kuwait and Department of Pediatrics, National Hepatology and Tropical Medicine Research Institute (NHTMRI), Cairo, Egypt
| | - Giada Sebastiani
- Division of Gastroenterology and Hepatology and Division of Infectious Diseases, McGill University Health Centre, Montreal, QC, Canada
| | - Yong Poovorawan
- Centre of Excellence in Clinical Virology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Mamun Al Mahtab
- Department of Hepatology, Bangabandhu Sheikh Mujib Medical University, Shahbag, Dhaka, Bangladesh
| | - Juan M Pericàs
- Liver Unit, Vall d'Hebron University Hospital, Vall d'Hebron Institute for Research (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain; Centros de Investigación Biomédica en Red, Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain
| | | | - Peter Hegyi
- Institute for Translational Medicine, Medical School, University of Pécs, Pécs, Hungary; Center for Translational Medicine, Semmelweis University, Budapest, Hungary; Institute of Pancreatic Diseases, Semmelweis University, Budapest, Hungary
| | - Amer Azaz
- Sheikh Khalifa Medical City, Abu Dhabi, United Arab Emirates
| | - Hasan M Isa
- Pediatric Department, Salmaniya Medical Complex and Pediatric Department, Arabian Gulf University, Manama, Bahrain
| | - Chatmanee Lertudomphonwanit
- Division of Gastroenterology, Department of Paediatrics, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Mona Issa Farrag
- Department of Pediatrics and Pediatric Hepatology, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Ahmed Abd Alwahab Nugud
- Department of Pediatrics and Pediatric Hepatology, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Hong-Wei Du
- Department of Paediatrics, First Hospital of Jilin University, Changchun, China
| | - Ke-Min Qi
- Laboratory of Nutrition and Development, Key Laboratory of Major Diseases in Children, Ministry of Education, Beijing Pediatric Research Institute, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, China
| | - Nezha Mouane
- Department of Pediatric Gastroenterology Hepatology and Nutrition, Academic Children's Hospital Ibn Sina, Mohammed V University, Rabat, Morocco
| | - Xin-Ran Cheng
- Department of Paediatric Genetics, Endocrinology and Metabolism, Chengdu Women's and Children's Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | | | - Eleonora D T Fagundes
- Department of Pediatrics, Federal University of Minas Gerais, Belo Horizonte, Brazil
| | - Hasmik Ghazinyan
- Department of Hepatology, Nikomed Medical Center, Yerevan, Armenia
| | | | - Jian-Gao Fan
- Department of Gastroenterology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai Key Lab of Pediatric Gastroenterology and Nutrition, Shanghai, China
| | - Nicoleta Gimiga
- Clinical Department of Pediatric Gastroenterology, "St. Mary" Emergency Children's Hospital, Iași, Romania; Faculty of Medicine, "Grigore T. Popa" University of Medicine and Pharmacy, Iași, Romania
| | - Naglaa M Kamal
- Department of Pediatrics and Pediatric Hepatology, Faculty of Medicine, Cairo University, Cairo, Egypt; Pediatric Hepatology and Gastroenterology, Alhada Armed Forces Hospital, Taif, Saudi Arabia
| | - Gabriela Ștefănescu
- Department of Gastroenterology, "Grigore T. Popa" University of Medicine and Pharmacy, Iași, Romania
| | - Li Hong
- Department of Clinical Nutrition, Shanghai Children's Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Smaranda Diaconescu
- Medical-Surgical Department, Faculty of Medicine, University "Titu Maiorescu", Bucuresti, Romania
| | - Ming Li
- Key Laboratory of Endocrinology of National Health Commission, Department of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jacob George
- Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital, University of Sydney, Sydney, NSW, Australia.
| | - Ming-Hua Zheng
- MAFLD Research Center, Department of Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China; Institute of Hepatology, Wenzhou Medical University, Wenzhou, China; Key Laboratory of Diagnosis and Treatment for the Development of Chronic Liver Disease in Zhejiang Province, Wenzhou, China.
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6
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Bril F, Kalavalapalli S, Lomonaco R, Frye R, Godinez Leiva E, Cusi K. Insulin resistance is an integral feature of MASLD even in the presence of PNPLA3 variants. JHEP Rep 2024; 6:101092. [PMID: 39022386 PMCID: PMC11252529 DOI: 10.1016/j.jhepr.2024.101092] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/04/2024] [Revised: 03/29/2024] [Accepted: 04/03/2024] [Indexed: 07/20/2024] Open
Abstract
Background & Aims It has been postulated that carriers of PNPLA3 I148M (CG [Ile/Met] or GG [Met/Met]) develop metabolic dysfunction-associated steatotic liver disease (MASLD) in the absence of insulin resistance or metabolic syndrome. However, the relationship between insulin resistance and MASLD according to the PNPLA3 allele has not been carefully assessed. Methods A total of 204 participants were recruited and underwent PNPLA3 genotyping, an oral glucose tolerance test, liver proton magnetic resonance spectroscopy and percutaneous liver biopsy if diagnosed with MASLD. A subgroup of patients (n = 55) had an euglycemic hyperinsulinemic clamp with glucose tracer infusion. Results As expected, patients with the CG/GG genotype had worse intrahepatic triglyceride content and worse liver histology. However, regardless of PNPLA3 genotype, patients with a diagnosis of MASLD had severe whole-body insulin resistance (Matsuda index, an estimation of insulin resistance in glucose metabolic pathways) and fasting and postprandial adipose tissue insulin resistance (Adipo-IR index and free fatty acid suppression during the oral glucose tolerance test, respectively, as measures of insulin resistance in lipolytic metabolic pathways) compared to patients without MASLD. Moreover, for the same amount of liver fat accumulation, insulin resistance was similar in patients with genotypes CC vs. CG/GG. In multiple regression analyses, A1c and Adipo-IR were associated with the presence of MASLD and advanced liver fibrosis, independently of PNPLA3 genotype. Conclusions PNPLA3 variant carriers with MASLD are equally insulin resistant as non-carriers with MASLD at the level of the liver, muscle, and adipose tissue. This calls for reframing "PNPLA3 MASLD" as an insulin-resistant condition associated with increased hepatic susceptibility to metabolic insults, such as obesity or diabetes, wherein early identification and aggressive intervention are warranted to reverse metabolic dysfunction and prevent disease progression. Impact and implications It has been proposed that the PNPLA3 G allele is associated with the presence of metabolic dysfunction-associated steatotic liver disease (MASLD) in the absence of insulin resistance. However, our results suggest that regardless of PNPLA3 alleles, the presence of insulin resistance is necessary for the development of MASLD. This calls for reframing patients with "PNPLA3 MASLD" not as insulin sensitive, but on the contrary, as an insulin-resistant population with increased hepatic susceptibility to metabolic insults, such as obesity or diabetes.
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Affiliation(s)
- Fernando Bril
- Division of Endocrinology, Diabetes and Metabolism, University of Alabama at Birmingham. 510 20 Street South, FOT 825A, 35233, Birmingham, AL, USA
- Division of Endocrinology, Diabetes and Metabolism, University of Florida, Gainesville, FL, USA. 1600 Archer Road, Room H2, 32610, Gainesville, FL, USA
| | - Srilaxmi Kalavalapalli
- Division of Endocrinology, Diabetes and Metabolism, University of Florida, Gainesville, FL, USA. 1600 Archer Road, Room H2, 32610, Gainesville, FL, USA
| | - Romina Lomonaco
- Division of Endocrinology, Diabetes and Metabolism, University of Florida, Gainesville, FL, USA. 1600 Archer Road, Room H2, 32610, Gainesville, FL, USA
| | - Reginald Frye
- Center for Pharmacogenomics, University of Florida, Gainesville, FL, USA; Currently at College of Pharmacy, University of Tennessee Health Science Center, USA
| | - Eddison Godinez Leiva
- Division of Endocrinology, Diabetes and Metabolism, University of Florida, Gainesville, FL, USA. 1600 Archer Road, Room H2, 32610, Gainesville, FL, USA
| | - Kenneth Cusi
- Division of Endocrinology, Diabetes and Metabolism, University of Florida, Gainesville, FL, USA. 1600 Archer Road, Room H2, 32610, Gainesville, FL, USA
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Ignat M, Stefanescu H. Non-Invasive Biomarkers for Differentiating Alcohol Associated Hepatitis from Acute Decompensation in Patients with ALD. J Clin Med 2024; 13:3747. [PMID: 38999313 PMCID: PMC11242687 DOI: 10.3390/jcm13133747] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2024] [Revised: 06/17/2024] [Accepted: 06/22/2024] [Indexed: 07/14/2024] Open
Abstract
Alcohol-associated hepatitis (AH) is the most severe form of alcohol-related liver disease. The natural course of alcohol-related liver disease is influenced by heavy alcohol consumption and abstinence periods. Differentiating between AH and decompensated cirrhosis (DC) could be extremely challenging in clinical practice due to clinical and bioclinical similarities. The severity of AH is made on bioclinical grounds, the severe form necessitating corticotherapy treatment. Liver biopsy is still the standard of care for establishing the diagnosis in atypical presentations. The pathogenesis of AH is an interplay between gene expression, cytokine dysregulation, the immune system and the gut microbiota. Non-invasive tests are increasingly and widely used for the purpose of early diagnosis and reliable prognostication. The non-invasive tests are emerging in concordance with disease pathogenesis. In this review, we describe the non-invasive tools that can distinguish AH from DC. We outline the available cut-offs and their performance in diagnosis and prognosis, as well as in assessing the treatment response to corticotherapy. Promising circulating biomarkers like keratin 18, microRNAs and sphingolipids will be in the review.
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Affiliation(s)
- Mina Ignat
- Regional Institute of Gastroenterology and Hepatology "Prof. Dr. O. Fodor", 400394 Cluj-Napoca, Romania
- Faculty of Medicine, University of Medicine and Pharmacy "Iuliu Hatieganu", 400347 Cluj-Napoca, Romania
| | - Horia Stefanescu
- Regional Institute of Gastroenterology and Hepatology "Prof. Dr. O. Fodor", 400394 Cluj-Napoca, Romania
- Faculty of Medicine, University of Medicine and Pharmacy "Iuliu Hatieganu", 400347 Cluj-Napoca, Romania
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8
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Tarantino G, Citro V. What are the common downstream molecular events between alcoholic and nonalcoholic fatty liver? Lipids Health Dis 2024; 23:41. [PMID: 38331795 PMCID: PMC10851522 DOI: 10.1186/s12944-024-02031-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2023] [Accepted: 01/25/2024] [Indexed: 02/10/2024] Open
Abstract
Liver fat storage, also called hepatic steatosis, is increasingly common and represents a very frequent diagnosis in the medical field. Excess fat is not without consequences. In fact, hepatic steatosis contributes to the progression toward liver fibrosis. There are two main types of fatty liver disease, alcoholic fatty liver disease (AFLD) and nonalcoholic fatty liver disease (NAFLD). Although AFLD and NAFLD are similar in their initial morphological features, both conditions involve the same evolutive forms. Moreover, there are various common mechanisms underlying both diseases, including alcoholic liver disease and NAFLD, which are commonalities. In this Review, the authors explore similar downstream signaling events involved in the onset and progression of the two entities but not completely different entities, predominantly focusing on the gut microbiome. Downstream molecular events, such as the roles of sirtuins, cytokeratins, adipokines and others, should be considered. Finally, to complete the feature, some new tendencies in the therapeutic approach are presented.
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Affiliation(s)
| | - Vincenzo Citro
- Department of General Medicine, Umberto I Hospital, Nocera Inferiore, SA, 84014, Italy
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9
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Tauriainen MM, Csader S, Lankinen M, Lo KK, Chen C, Lahtinen O, El-Nezamy H, Laakso M, Schwab U. PNPLA3 Genotype and Dietary Fat Modify Concentrations of Plasma and Fecal Short Chain Fatty Acids and Plasma Branched-Chain Amino Acids. Nutrients 2024; 16:261. [PMID: 38257154 PMCID: PMC10819939 DOI: 10.3390/nu16020261] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2023] [Revised: 12/11/2023] [Accepted: 12/25/2023] [Indexed: 01/24/2024] Open
Abstract
The GG genotype of the Patatin-like phosphatase domain-containing 3 (PNPLA3), dietary fat, short-chain fatty acids (SCFA) and branched-chain amino acids (BCAA) are linked with non-alcoholic fatty liver disease. We studied the impact of the quality of dietary fat on plasma (p) and fecal (f) SCFA and p-BCAA in men homozygous for the PNPLA3 rs738409 variant (I148M). Eighty-eight randomly assigned men (age 67.8 ± 4.3 years, body mass index 27.1 ± 2.5 kg/m2) participated in a 12-week diet intervention. The recommended diet (RD) group followed the National and Nordic nutrition recommendations for fat intake. The average diet (AD) group followed the average fat intake in Finland. The intervention resulted in a decrease in total p-SCFAs and iso-butyric acid in the RD group (p = 0.041 and p = 0.002). Valeric acid (p-VA) increased in participants with the GG genotype regardless of the diet (RD, 3.6 ± 0.6 to 7.0 ± 0.6 µmol/g, p = 0.005 and AD, 3.8 ± 0.3 to 9.7 ± 8.5 µmol/g, p = 0.015). Also, genotype relation to p-VA was seen statistically significantly in the RD group (CC: 3.7 ± 0.4 to 4.2 ± 1.7 µmol/g and GG: 3.6 ± 0.6 to 7.0 ± 0.6 µmol/g, p = 0.0026 for time and p = 0.004 for time and genotype). P-VA, unlike any other SCFA, correlated positively with plasma gamma-glutamyl transferase (r = 0.240, p = 0.025). Total p-BCAAs concentration changed in the AD group comparing PNPLA3 CC and GG genotypes (CC: 612 ± 184 to 532 ± 149 µmol/g and GG: 587 ± 182 to 590 ± 130 µmol/g, p = 0.015 for time). Valine decreased in the RD group (p = 0.009), and leucine decreased in the AD group (p = 0.043). RD decreased total fecal SCFA, acetic acid (f-AA), and butyric acid (f-BA) in those with CC genotype (p = 0.006, 0.013 and 0.005, respectively). Our results suggest that the PNPLA3 genotype modifies the effect of dietary fat modification for p-VA, total f-SCFA, f-AA and f-BA, and total p-BCAA.
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Affiliation(s)
- Milla-Maria Tauriainen
- Department of Medicine, Endoscopy Unit, Kuopio University Hospital, 70029 Kuopio, Finland
- Institute of Public Health and Clinical Nutrition, University of Eastern Finland, 70210 Kuopio, Finland (M.L.); (H.E.-N.); (U.S.)
| | - Susanne Csader
- Institute of Public Health and Clinical Nutrition, University of Eastern Finland, 70210 Kuopio, Finland (M.L.); (H.E.-N.); (U.S.)
| | - Maria Lankinen
- Institute of Public Health and Clinical Nutrition, University of Eastern Finland, 70210 Kuopio, Finland (M.L.); (H.E.-N.); (U.S.)
| | - Kwun Kwan Lo
- School of Biological Sciences, University of Hong Kong, Pokfulam, Hong Kong, China; (K.K.L.); (C.C.)
| | - Congjia Chen
- School of Biological Sciences, University of Hong Kong, Pokfulam, Hong Kong, China; (K.K.L.); (C.C.)
| | - Olli Lahtinen
- Diagnostic Imaging Centre, Department of Clinical Radiology, Kuopio University Hospital, 70029 Kuopio, Finland;
| | - Hani El-Nezamy
- Institute of Public Health and Clinical Nutrition, University of Eastern Finland, 70210 Kuopio, Finland (M.L.); (H.E.-N.); (U.S.)
- School of Biological Sciences, University of Hong Kong, Pokfulam, Hong Kong, China; (K.K.L.); (C.C.)
| | - Markku Laakso
- Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland, 70211 Kuopio, Finland;
- Department of Medicine, Kuopio University Hospital, 70029 Kuopio, Finland
| | - Ursula Schwab
- Institute of Public Health and Clinical Nutrition, University of Eastern Finland, 70210 Kuopio, Finland (M.L.); (H.E.-N.); (U.S.)
- Department of Medicine, Endocrinology and Clinical Nutrition, Kuopio University Hospital, 70029 Kuopio, Finland
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10
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Yazıcı D, Demir SÇ, Sezer H. Insulin Resistance, Obesity, and Lipotoxicity. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2024; 1460:391-430. [PMID: 39287860 DOI: 10.1007/978-3-031-63657-8_14] [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: 09/19/2024]
Abstract
Lipotoxicity, originally used to describe the destructive effects of excess fat accumulation on glucose metabolism, causes functional impairments in several metabolic pathways, both in adipose tissue and peripheral organs, like liver, heart, pancreas, and muscle. Ectopic lipid accumulation in the kidneys, liver, and heart has important clinical counterparts like diabetic nephropathy in type 2 diabetes mellitus, obesity-related glomerulopathy, nonalcoholic fatty liver disease, and cardiomyopathy. Insulin resistance due to lipotoxicity indirectly lead to reproductive system disorders, like polycystic ovary syndrome. Lipotoxicity has roles in insulin resistance and pancreatic beta-cell dysfunction. Increased circulating levels of lipids and the metabolic alterations in fatty acid utilization and intracellular signaling have been related to insulin resistance in muscle and liver. Different pathways, like novel protein kinase c pathways and the JNK-1 pathway, are involved as the mechanisms of how lipotoxicity leads to insulin resistance in nonadipose tissue organs, such as liver and muscle. Mitochondrial dysfunction plays a role in the pathogenesis of insulin resistance. Endoplasmic reticulum stress, through mainly increased oxidative stress, also plays an important role in the etiology of insulin resistance, especially seen in non-alcoholic fatty liver disease. Visceral adiposity and insulin resistance both increase the cardiometabolic risk, and lipotoxicity seems to play a crucial role in the pathophysiology of these associations.
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Affiliation(s)
- Dilek Yazıcı
- Koç University Medical School, Section of Endocrinology and Metabolism, Koç University Hospital, Topkapi, Istanbul, Turkey.
| | - Selin Çakmak Demir
- Koç University Medical School, Section of Endocrinology and Metabolism, Koç University Hospital, Topkapi, Istanbul, Turkey
| | - Havva Sezer
- Koç University Medical School, Section of Endocrinology and Metabolism, Koç University Hospital, Topkapi, Istanbul, Turkey
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11
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Sohal A, Chaudhry H, Kowdley KV. Genetic Markers Predisposing to Nonalcoholic Steatohepatitis. Clin Liver Dis 2023; 27:333-352. [PMID: 37024211 DOI: 10.1016/j.cld.2023.01.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/08/2023]
Abstract
The growing prevalence of nonalcoholic fatty liver disease (NAFLD) has sparked interest in understanding genetics and epigenetics associated with the development and progression of the disease. A better understanding of the genetic factors related to progression will be beneficial in the risk stratification of patients. These genetic markers can also serve as potential therapeutic targets in the future. In this review, we focus on the genetic markers associated with the progression and severity of NAFLD.
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Affiliation(s)
- Aalam Sohal
- Liver Institute Northwest, 3216 Northeast 45th Place Suite 212, Seattle, WA 98105, USA
| | - Hunza Chaudhry
- Department of Internal Medicine, UCSF Fresno, 155 North Fresno Street, Fresno, CA 93722, USA
| | - Kris V Kowdley
- Liver Institute Northwest, 3216 Northeast 45th Place Suite 212, Seattle, WA 98105, USA; Elson S. Floyd College of Medicine, Washington State University, WA, USA.
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12
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Odriozola A, Santos-Laso A, Del Barrio M, Cabezas J, Iruzubieta P, Arias-Loste MT, Rivas C, Duque JCR, Antón Á, Fábrega E, Crespo J. Fatty Liver Disease, Metabolism and Alcohol Interplay: A Comprehensive Review. Int J Mol Sci 2023; 24:ijms24097791. [PMID: 37175497 PMCID: PMC10178387 DOI: 10.3390/ijms24097791] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Revised: 04/05/2023] [Accepted: 04/07/2023] [Indexed: 05/15/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease worldwide, and its incidence has been increasing in recent years because of the high prevalence of obesity and metabolic syndrome in the Western population. Alcohol-related liver disease (ArLD) is the most common cause of cirrhosis and constitutes the leading cause of cirrhosis-related deaths worldwide. Both NAFLD and ArLD constitute well-known causes of liver damage, with some similarities in their pathophysiology. For this reason, they can lead to the progression of liver disease, being responsible for a high proportion of liver-related events and liver-related deaths. Whether ArLD impacts the prognosis and progression of liver damage in patients with NAFLD is still a matter of debate. Nowadays, the synergistic deleterious effect of obesity and diabetes is clearly established in patients with ArLD and heavy alcohol consumption. However, it is still unknown whether low to moderate amounts of alcohol are good or bad for liver health. The measurement and identification of the possible synergistic deleterious effect of alcohol consumption in the assessment of patients with NAFLD is crucial for clinicians, since early intervention, advising abstinence and controlling cardiovascular risk factors would improve the prognosis of patients with both comorbidities. This article seeks to perform a comprehensive review of the pathophysiology of both disorders and measure the impact of alcohol consumption in patients with NAFLD.
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Affiliation(s)
- Aitor Odriozola
- Gastroenterology and Hepatology Department, Clinical and Translational Research in Digestive Diseases, Valdecilla Research Institute (IDIVAL), Marqués de Valdecilla Universitary Hospital, Av. Valdecilla 25, 39008 Santander, Cantabria, Spain
| | - Alvaro Santos-Laso
- Gastroenterology and Hepatology Department, Clinical and Translational Research in Digestive Diseases, Valdecilla Research Institute (IDIVAL), Marqués de Valdecilla Universitary Hospital, Av. Valdecilla 25, 39008 Santander, Cantabria, Spain
| | - María Del Barrio
- Gastroenterology and Hepatology Department, Clinical and Translational Research in Digestive Diseases, Valdecilla Research Institute (IDIVAL), Marqués de Valdecilla Universitary Hospital, Av. Valdecilla 25, 39008 Santander, Cantabria, Spain
| | - Joaquín Cabezas
- Gastroenterology and Hepatology Department, Clinical and Translational Research in Digestive Diseases, Valdecilla Research Institute (IDIVAL), Marqués de Valdecilla Universitary Hospital, Av. Valdecilla 25, 39008 Santander, Cantabria, Spain
| | - Paula Iruzubieta
- Gastroenterology and Hepatology Department, Clinical and Translational Research in Digestive Diseases, Valdecilla Research Institute (IDIVAL), Marqués de Valdecilla Universitary Hospital, Av. Valdecilla 25, 39008 Santander, Cantabria, Spain
| | - María Teresa Arias-Loste
- Gastroenterology and Hepatology Department, Clinical and Translational Research in Digestive Diseases, Valdecilla Research Institute (IDIVAL), Marqués de Valdecilla Universitary Hospital, Av. Valdecilla 25, 39008 Santander, Cantabria, Spain
| | - Coral Rivas
- Gastroenterology and Hepatology Department, Clinical and Translational Research in Digestive Diseases, Valdecilla Research Institute (IDIVAL), Marqués de Valdecilla Universitary Hospital, Av. Valdecilla 25, 39008 Santander, Cantabria, Spain
| | - Juan Carlos Rodríguez Duque
- Gastroenterology and Hepatology Department, Clinical and Translational Research in Digestive Diseases, Valdecilla Research Institute (IDIVAL), Marqués de Valdecilla Universitary Hospital, Av. Valdecilla 25, 39008 Santander, Cantabria, Spain
| | - Ángela Antón
- Gastroenterology and Hepatology Department, Clinical and Translational Research in Digestive Diseases, Valdecilla Research Institute (IDIVAL), Marqués de Valdecilla Universitary Hospital, Av. Valdecilla 25, 39008 Santander, Cantabria, Spain
| | - Emilio Fábrega
- Gastroenterology and Hepatology Department, Clinical and Translational Research in Digestive Diseases, Valdecilla Research Institute (IDIVAL), Marqués de Valdecilla Universitary Hospital, Av. Valdecilla 25, 39008 Santander, Cantabria, Spain
| | - Javier Crespo
- Gastroenterology and Hepatology Department, Clinical and Translational Research in Digestive Diseases, Valdecilla Research Institute (IDIVAL), Marqués de Valdecilla Universitary Hospital, Av. Valdecilla 25, 39008 Santander, Cantabria, Spain
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Nádasdi Á, Gál V, Masszi T, Somogyi A, Firneisz G. PNPLA3 rs738409 risk genotype decouples TyG index from HOMA2-IR and intrahepatic lipid content. Cardiovasc Diabetol 2023; 22:64. [PMID: 36944955 PMCID: PMC10031960 DOI: 10.1186/s12933-023-01792-w] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Accepted: 03/06/2023] [Indexed: 03/23/2023] Open
Abstract
BACKGROUND Recent reports suggested a different predictive value for TyG index compared to HOMA-IR in coronary artery calcification (CAC) and other atherosclerotic outcomes, despite that both indices are proposed as surrogate markers of insulin resistance. We hypothesized a key role for liver pathology as an explanation and therefore assessed the relationship among the two indices and the intrahepatic lipid content stratified by PNPLA3 rs738409 genotypes as a known non-alcoholic fatty liver disease (NAFLD) genetic risk. METHODS Thirty-nine women from a prior GDM-genetic study were recalled with PNPLA3 rs738409 CC and GG genotypes for metabolic phenotyping and to assess hepatic triglyceride content (HTGC). 75 g OGTT was performed, fasting lipid, glucose, insulin levels and calculated insulin resistance indices (TyG and HOMA2-IR) were used. HTGC was measured by MR based methods. Mann-Whitney-U, χ2 and for the correlation analysis Spearman rank order tests were applied. RESULTS The PNPLA3 rs738409 genotype had a significant effect on the direct correlation between the HOMA2-IR and TyG index: the correlation (R = 0.52, p = 0.0054) found in the CC group was completely abolished in those with the GG (NAFLD) risk genotype. In addition, the HOMA2-IR correlated with HTGC in the entire study population (R = 0.69, p < 0.0001) and also separately in both genotypes (CC R = 0.62, p = 0.0006, GG: R = 0.74, p = 0.0058). In contrast, the correlation between TyG index and HTGC was only significant in rs738409 CC genotype group (R = 0.42, p = 0.0284) but not in GG group. A similar pattern was observed in the correlation between TG and HTGC (CC: R = 0.41, p = 0.0335), when the components of the TyG index were separately assessed. CONCLUSIONS PNPLA3 rs738409 risk genotype completely decoupled the direct correlation between two surrogate markers of insulin resistance: TyG and HOMA2-IR confirming our hypothesis. The liver lipid content increased in parallel with the HOMA2-IR independent of genotype, in contrast to the TyG index where the risk genotype abolished the correlation. This phenomenon seems to be related to the nature of hepatic fat accumulation and to the different concepts establishing the two insulin resistance markers.
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Affiliation(s)
- Ákos Nádasdi
- Translational Medicine Institute, Faculty of Medicine, Semmelweis University, Budapest, Hungary
- Department of Internal Medicine and Haematology, Faculty of Medicine, Semmelweis University, Budapest, Hungary
| | - Viktor Gál
- Brain Imaging Centre, Research Centre for Natural Sciences, Eötvös Loránd Research Network, Budapest, Hungary
- Medical Imaging Centre, Faculty of Medicine, Semmelweis University, Budapest, Hungary
| | - Tamás Masszi
- Department of Internal Medicine and Haematology, Faculty of Medicine, Semmelweis University, Budapest, Hungary
| | - Anikó Somogyi
- Department of Internal Medicine and Haematology, Faculty of Medicine, Semmelweis University, Budapest, Hungary
| | - Gábor Firneisz
- Translational Medicine Institute, Faculty of Medicine, Semmelweis University, Budapest, Hungary.
- Department of Internal Medicine and Haematology, Faculty of Medicine, Semmelweis University, Budapest, Hungary.
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Fecal Metagenomics and Metabolomics Identifying Microbial Signatures in Non-Alcoholic Fatty Liver Disease. Int J Mol Sci 2023; 24:ijms24054855. [PMID: 36902288 PMCID: PMC10002933 DOI: 10.3390/ijms24054855] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Revised: 02/28/2023] [Accepted: 03/01/2023] [Indexed: 03/06/2023] Open
Abstract
The frequency of non-alcoholic fatty liver disease (NAFLD) has intensified, creating diagnostic challenges and increasing the need for reliable non-invasive diagnostic tools. Due to the importance of the gut-liver axis in the progression of NAFLD, studies attempt to reveal microbial signatures in NAFLD, evaluate them as diagnostic biomarkers, and to predict disease progression. The gut microbiome affects human physiology by processing the ingested food into bioactive metabolites. These molecules can penetrate the portal vein and the liver to promote or prevent hepatic fat accumulation. Here, the findings of human fecal metagenomic and metabolomic studies relating to NAFLD are reviewed. The studies present mostly distinct, and even contradictory, findings regarding microbial metabolites and functional genes in NAFLD. The most abundantly reproducing microbial biomarkers include increased lipopolysaccharides and peptidoglycan biosynthesis, enhanced degradation of lysine, increased levels of branched chain amino acids, as well as altered lipid and carbohydrate metabolism. Among other causes, the discrepancies between the studies may be related to the obesity status of the patients and the severity of NAFLD. In none of the studies, except for one, was diet considered, although it is an important factor driving gut microbiota metabolism. Future studies should consider diet in these analyses.
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Wang D, Xu Y, Zhu Z, Li Y, Li X, Li Y, Shen H, Wu W, Liu Y, Han C. Changes in the global, regional, and national burdens of NAFLD from 1990 to 2019: A systematic analysis of the global burden of disease study 2019. Front Nutr 2022; 9:1047129. [PMID: 36618688 PMCID: PMC9811393 DOI: 10.3389/fnut.2022.1047129] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2022] [Accepted: 11/30/2022] [Indexed: 12/24/2022] Open
Abstract
Background Understanding the burdens and trends of non-alcoholic fatty liver disease (NAFLD) is necessary for developing effective intervention strategies. In this study, Global Burden of Disease (GBD) 2019 study data were extracted and analyzed to elucidate trends of NAFLD. Methods The prevalence, incidence, disability-adjusted life year (DALY), and death rates of NAFLD in geographic populations worldwide from 1990 to 2019 were extracted from the GBD 2019 study data. The global temporal trend of NAFLD from 1990 to 2019 was evaluated using estimated annual percentage changes (EAPCs) and age-standardized rates. Results Globally, between 1999 and 2019, the age-standardized prevalence rate of NAFLD increased, with EAPCs of 0.77 [95% CI (0.69, 0.85)], whereas the DALY and Death rates decreased, with EAPCs of -0.82 [95% CI (-0.92, -0.71)], and -0.67 [95% CI (-0.76, -0.58)], respectively. Geographically, the age-standardized prevalence rate showed the most serious upward trend in high-income North America with an EAPC of 0.98 [95% CI (0.95, 1.02)], and the age-standardized incidence rate showed an upward trend in Central Asia with an EAPC of 3.17 [95% CI (2.2, 2.49)]. The most significant upward trend of DALY and death rates appeared in Eastern Europe, with EAPCs of 4.06 [95% CI (3.31, 4.82)], and 3.36 [95% CI (2.77, 3.96)], respectively. At the country level, the age-standardized rates showed an upward trend in Armenia, Belarus, and Republic of Korea. Regarding age groups, the percentage change of prevalence was the highest in the 40 to 44 group [0.29 (0.26, 0.34)] from 1990 to 2019; the percentage change of incidence was the highest in the 85 to 89 group [0.46 (0.12, 0.71)] from 1990 to 2019; the percentage change of DALY was the highest in the 80 to 84 group [0.25 (0.11, 0.39)] from 1990 to 2019; and the percentage change of death rate was the highest in the 15 to 19 group [0.36 (0.17, 0.60)] from 1990 to 2019. The percentage change of prevalence of liver cancer due to NASH was the highest in the group of 85 to 89, whereas those of incidence, DALY, and death were the highest in the group above 95 from 1990 to 2019. Regarding the sociodemographic index (SDI), the highest age-standardized prevalence, incidence, and Death rates of NAFLD occurred in middle-SDI countries, and the highest DALY rates of NAFLD occurred in low-SDI countries. Conclusion Global NAFLD burdens have increased since 1990. Our findings provide a reference for policymakers to reduce the burden of NAFLD, especially in middle and low-SDI countries.
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Affiliation(s)
- Dan Wang
- Department of Clinical Nutrition and Metabolism, Affiliated Zhongshan Hospital of Dalian University, Dalian, China
| | - Yanbing Xu
- Department of Clinical Nutrition and Metabolism, Affiliated Zhongshan Hospital of Dalian University, Dalian, China
| | - Zizhao Zhu
- Department of General Surgery, The Sixth People’s Hospital of Shenyang, Shenyang, China
| | - Yanliang Li
- Departments of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, IL, United States
| | - Xiaowen Li
- Department of Clinical Nutrition and Metabolism, Affiliated Zhongshan Hospital of Dalian University, Dalian, China
| | - Yike Li
- Department of Clinical Nutrition and Metabolism, Affiliated Zhongshan Hospital of Dalian University, Dalian, China
| | - Hui Shen
- Department of Clinical Nutrition and Metabolism, Affiliated Zhongshan Hospital of Dalian University, Dalian, China
| | - Wei Wu
- Department of General Surgery, The Sixth People’s Hospital of Shenyang, Shenyang, China
| | - Yazhuo Liu
- Department of Clinical Nutrition and Metabolism, Affiliated Zhongshan Hospital of Dalian University, Dalian, China,*Correspondence: Yazhuo Liu,
| | - Cheng Han
- Department of Clinical Nutrition and Metabolism, Affiliated Zhongshan Hospital of Dalian University, Dalian, China,Cheng Han,
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Alsaif F, Al-hamoudi W, Alotaiby M, Alsadoon A, Almayouf M, Almadany H, Abuhaimed J, Ghufran N, Merajuddin A, Ali Khan I. Molecular Screening via Sanger Sequencing of the Genetic Variants in Non-Alcoholic Fatty Liver Disease Subjects in the Saudi Population: A Hospital-Based Study. Metabolites 2022; 12:metabo12121240. [PMID: 36557278 PMCID: PMC9784496 DOI: 10.3390/metabo12121240] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2022] [Revised: 11/29/2022] [Accepted: 12/03/2022] [Indexed: 12/13/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is one of the most common liver diseases, along with steatosis and non-alcoholic steatohepatitis (NASH), and is associated with cirrhosis and hepatocellular carcinoma. Candidate gene and genome-wide association studies have validated the relationships between NAFLD, NASH, PNPLA3, TM6SF2, and HFE. The present study utilized five polymorphisms in three genes: PNPLA3 (I148M and K434E) TM6SF2 (E167K), and HFE (H63D and C282Y), based on undocumented case−control studies in the Saudi Arabian population. A total of 95 patients with NAFLD and 78 non-NAFLD subjects were recruited. Genomic DNA was isolated, and polymerase chain reaction and Sanger sequencing were performed using specific primers for the I148M, K434E, E167K, H63D, and C282Y. NAFLD subjects were older when compared to controls and showed the significant association (p = 0.0001). Non-significant association was found between gender (p = 0.26). However, both weight and BMI were found to be associated. Hardy−Weinberg equilibrium analysis confirmed that H63D, I148M, and K434E polymorphisms were associated. Genotype analysis showed only K434E variant was associated with NAFLD and non-NAFLD (OR-2.16; 95% CI: 1.08−4.31; p = 0.02). However, other polymorphisms performed with NAFLD and NASH were not associated (p > 0.05), and similar analysis was found when ANOVA was performed (p > 0.05). In conclusion, we confirmed that K434E polymorphism showed a positive association in the Saudi population.
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Affiliation(s)
- Faisal Alsaif
- Surgery Department, College of Medicine, King Saud University, Riyadh 12372, Saudi Arabia
- Molecular Genetic Pathology Unit, Pathology Department, College of Medicine, King Saud University, Riyadh 12372, Saudi Arabia
| | - Waleed Al-hamoudi
- Molecular Genetic Pathology Unit, Pathology Department, College of Medicine, King Saud University, Riyadh 12372, Saudi Arabia
- Medicine Department, College of Medicine, King Saud University, Riyadh 12372, Saudi Arabia
| | - Maram Alotaiby
- Molecular Genetic Pathology Unit, Pathology Department, College of Medicine, King Saud University, Riyadh 12372, Saudi Arabia
- Laboratories and Blood Bank Services Ministry of Health, Riyadh 12746, Saudi Arabia
- Correspondence: (M.A.); (I.A.K.)
| | - Amani Alsadoon
- Liver Disease Research Center, King Saud University Medical City, Riyadh 12746, Saudi Arabia
| | - Mohammed Almayouf
- Surgery Department, College of Medicine, Prince Sattam bin Abdulaziz University, Riyadh 11942, Saudi Arabia
| | - Hadeel Almadany
- Surgery Department, College of Medicine, King Saud University, Riyadh 12372, Saudi Arabia
| | - Jawahir Abuhaimed
- College of Medicine, Al-Faisal University, Riyadh P.O. Box 400, Saudi Arabia
| | - Noman Ghufran
- Molecular Genetic Pathology Unit, Pathology Department, College of Medicine, King Saud University, Riyadh 12372, Saudi Arabia
| | - Ahmed Merajuddin
- Molecular Genetic Pathology Unit, Pathology Department, College of Medicine, King Saud University, Riyadh 12372, Saudi Arabia
- Research and Development Unit, Adela Inc. 610, University of Avenue, Toronto, ON M5G 2R5, Canada
| | - Imran Ali Khan
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Saud University, Riyadh 12372, Saudi Arabia
- Correspondence: (M.A.); (I.A.K.)
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17
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Färkkilä M, Kautiainen H, Tenca A, Jokelainen K, Arola J. PNPLA3 allele frequency has no impact on biliary bile acid composition or disease course in patients with primary sclerosing cholangitis. PLoS One 2022; 17:e0277084. [PMID: 36454904 PMCID: PMC9714899 DOI: 10.1371/journal.pone.0277084] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2021] [Accepted: 10/19/2022] [Indexed: 12/02/2022] Open
Abstract
BACKGROUND AND AIMS Primary sclerosing cholangitis (PSC) is a chronic inflammatory disease that leads to bile duct strictures, cholestasis, and biliary cirrhosis. PNPLA3 (patatin-like phospholipase domain containing 3), regulates cellular lipid synthesis by converting lysophosphatidic acid into phosphatidic acid. Isoleucine mutation to methionine at position 148 (I148M) causes a loss of this function. Only two studies, with contradictory results, have evaluated the role of PNPLA3 in PSC. The rs738409(G) variant of PNPLA3 has been associated with an increased risk for transplantation in male patients with dominant strictures (DS). The study aimed to evaluate the PNPLA3 allele frequency effect on the clinical outcomes, progression, and prognosis of PSC. Furthermore, we analyzed the impact of PNPLA3 on phospholipid and bile acid composition to evaluate the effect of the PNPLA3 status on UDCA response. PATIENTS AND METHODS We recruited 560 patients prospectively and collected clinical and laboratory data as well as liver histology and imaging findings. PNPLA3 (CC, CG, GG) alleles were analyzed with TaqManTM. We also analyzed bile acids (BA), cholesterol and phospholipids and individual BA from a sample aspirated during endoscopic retrograde cholangiography (ERC). RESULTS Among the recruited patients, 58.4%, 35.7% and 5.9% had the wild (CC), heterozygous (CG) and homozygous (GG) alleles, respectively. The PNPLA3 haplotype did not impact bile composition or individual BA. In addition, we found no differences in age at diagnosis, disease progression, liver fibrosis or survival between the cohorts. CONCLUSIONS The PNPLA3 I148M variant had no significant impact on on bile composition, including UDCA content, clinical outcomes, progression of liver fibrosis, hepatobiliary cancer risk, liver transplantation, or overall survival.
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Affiliation(s)
- Martti Färkkilä
- Department of Gastroenterology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
- * E-mail:
| | - Hannu Kautiainen
- Folkhälsan Research Center, Helsinki, Finland
- Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland
| | - Andrea Tenca
- Department of Gastroenterology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Kalle Jokelainen
- Department of Gastroenterology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Johanna Arola
- Department of Pathology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
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Ivashkin VT, Maevskaya MV, Zharkova MS, Kotovskaya YV, Tkacheva ON, Troshina EA, Shestakova MV, Maev IV, Breder VV, Gheivandova NI, Doshchitsin VL, Dudinskaya EN, Ershova EV, Kodzoeva KB, Komshilova KA, Korochanskaya NV, Mayorov AY, Mishina EE, Nadinskaya MY, Nikitin IG, Pogosova NV, Tarzimanova AI, Shamkhalova MS. Clinical Practice Guidelines of the Russian Scientific Liver Society, Russian Gastroenterological Association, Russian Association of Endocrinologists, Russian Association of Gerontologists and Geriatricians and National Society for Preventive Cardiology on Diagnosis and Treatment of Non-Alcoholic Liver Disease. RUSSIAN JOURNAL OF GASTROENTEROLOGY, HEPATOLOGY, COLOPROCTOLOGY 2022; 32:104-140. [DOI: 10.22416/1382-4376-2022-32-4-104-140] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
Abstract
Aim:present clinical guidelines, aimed at general practitioners, gastroenterologists, cardiologists, endocrinologists, comprise up-to-date methods of diagnosis and treatment of non-alcoholic fatty liver disease.Key points.Nonalcoholic fatty liver disease, the most wide-spread chronic liver disease, is characterized by accumulation of fat by more than 5 % of hepatocytes and presented by two histological forms: steatosis and nonalcoholic steatohepatitis. Clinical guidelines provide current views on pathogenesis of nonalcoholic fatty liver disease as a multisystem disease, methods of invasive and noninvasive diagnosis of steatosis and liver fibrosis, principles of nondrug treatment and pharmacotherapy of nonalcoholic fatty liver disease and associated conditions. Complications of nonalcoholic fatty liver disease include aggravation of cardiometabolic risks, development of hepatocellular cancer, progression of liver fibrosis to cirrhotic stage.Conclusion.Progression of liver disease can be avoided, cardiometabolic risks can be reduced and patients' prognosis — improved by the timely recognition of diagnosis of nonalcoholic fatty liver disease and associated comorbidities and competent multidisciplinary management of these patients.
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Affiliation(s)
| | | | | | - Yu. V. Kotovskaya
- Russian Gerontology Research and Clinical Centre, Pirogov Russian National Research Medical University
| | - O. N. Tkacheva
- Russian Gerontology Research and Clinical Centre, Pirogov Russian National Research Medical University
| | | | | | - I. V. Maev
- Yevdokimov Moscow State University of Medicine and Dentistry
| | - V. V. Breder
- Blokhin National Medical Research Center of Oncology
| | | | | | - E. N. Dudinskaya
- Russian Gerontology Research and Clinical Centre, Pirogov Russian National Research Medical University
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19
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Velázquez AM, Bentanachs R, Sala-Vila A, Lázaro I, Rodríguez-Morató J, Sánchez RM, Laguna JC, Roglans N, Alegret M. KHK, PNPLA3 and PPAR as Novel Targets for the Anti-Steatotic Action of Bempedoic Acid. Biomedicines 2022; 10:biomedicines10071517. [PMID: 35884822 PMCID: PMC9312949 DOI: 10.3390/biomedicines10071517] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2022] [Revised: 06/21/2022] [Accepted: 06/22/2022] [Indexed: 12/12/2022] Open
Abstract
Bempedoic acid (BemA) is an ATP-citrate lyase (ACLY) inhibitor used to treat hypercholesterolemia. We studied the anti-steatotic effect of BemA, and the mechanisms involved, in a model of fatty liver in female rats obtained through the administration of a high-fat diet supplemented with liquid fructose (HFHFr) for three months. In the third month, a group of rats was treated with BemA (30 mg/kg/day) by gavage. Plasma analytes, liver histology, adiposity, and the expression of key genes controlling fatty acid metabolism were determined, and PPAR agonism was explored by using luciferase reporter assays. Our results showed that, compared to HFHFr, BemA-treated rats exhibited lower body weight, higher liver/body weight, and reduced hepatic steatosis. In addition to ACLY inhibition, we found three novel mechanisms that could account for the anti-steatotic effect: (1) reduction of liver ketohexokinase, leading to lower fructose intake and reduced de novo lipogenesis; (2) increased expression of patatin-like phospholipase domain-containing protein 3, a protein related to the export of liver triglycerides to blood; and (3) PPARα agonist activity, leading to increased hepatic fatty acid β-oxidation. In conclusion, BemA may represent a novel approach to treat hepatic steatosis, and therefore to avoid progression to advanced stages of non-alcoholic fatty liver disease.
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Affiliation(s)
- Ana Magdalena Velázquez
- Department of Pharmacology, Toxicology and Therapeutic Chemistry, School of Pharmacy and Food Science, University of Barcelona, Av. Joan XXIII 27–31, 08028 Barcelona, Spain; (A.M.V.); (R.B.); (R.M.S.); (J.C.L.)
| | - Roger Bentanachs
- Department of Pharmacology, Toxicology and Therapeutic Chemistry, School of Pharmacy and Food Science, University of Barcelona, Av. Joan XXIII 27–31, 08028 Barcelona, Spain; (A.M.V.); (R.B.); (R.M.S.); (J.C.L.)
| | - Aleix Sala-Vila
- Cardiovascular Risk and Nutrition, Hospital del Mar Medical Research Institute (IMIM), 08003 Barcelona, Spain; (A.S.-V.); (I.L.)
| | - Iolanda Lázaro
- Cardiovascular Risk and Nutrition, Hospital del Mar Medical Research Institute (IMIM), 08003 Barcelona, Spain; (A.S.-V.); (I.L.)
| | - Jose Rodríguez-Morató
- Integrative Pharmacology and Systems Neuroscience Research Group, Hospital del Mar Medical Research Institute (IMIM), Dr. Aiguader 88, 08003 Barcelona, Spain;
- Department of Medicine and Life Sciences, Universitat Pompeu Fabra, Dr. Aiguader 88, 08003 Barcelona, Spain
- Spanish Biomedical Research Centre in Physiopathology of Obesity and Nutrition (CIBEROBN), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain
| | - Rosa María Sánchez
- Department of Pharmacology, Toxicology and Therapeutic Chemistry, School of Pharmacy and Food Science, University of Barcelona, Av. Joan XXIII 27–31, 08028 Barcelona, Spain; (A.M.V.); (R.B.); (R.M.S.); (J.C.L.)
- Spanish Biomedical Research Centre in Physiopathology of Obesity and Nutrition (CIBEROBN), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain
- Institute of Biomedicine, University of Barcelona, 08028 Barcelona, Spain
| | - Juan Carlos Laguna
- Department of Pharmacology, Toxicology and Therapeutic Chemistry, School of Pharmacy and Food Science, University of Barcelona, Av. Joan XXIII 27–31, 08028 Barcelona, Spain; (A.M.V.); (R.B.); (R.M.S.); (J.C.L.)
- Spanish Biomedical Research Centre in Physiopathology of Obesity and Nutrition (CIBEROBN), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain
- Institute of Biomedicine, University of Barcelona, 08028 Barcelona, Spain
| | - Núria Roglans
- Department of Pharmacology, Toxicology and Therapeutic Chemistry, School of Pharmacy and Food Science, University of Barcelona, Av. Joan XXIII 27–31, 08028 Barcelona, Spain; (A.M.V.); (R.B.); (R.M.S.); (J.C.L.)
- Spanish Biomedical Research Centre in Physiopathology of Obesity and Nutrition (CIBEROBN), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain
- Institute of Biomedicine, University of Barcelona, 08028 Barcelona, Spain
- Correspondence: (N.R.); (M.A.)
| | - Marta Alegret
- Department of Pharmacology, Toxicology and Therapeutic Chemistry, School of Pharmacy and Food Science, University of Barcelona, Av. Joan XXIII 27–31, 08028 Barcelona, Spain; (A.M.V.); (R.B.); (R.M.S.); (J.C.L.)
- Spanish Biomedical Research Centre in Physiopathology of Obesity and Nutrition (CIBEROBN), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain
- Institute of Biomedicine, University of Barcelona, 08028 Barcelona, Spain
- Correspondence: (N.R.); (M.A.)
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20
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Maevskaya M, Kotovskaya Y, Ivashkin V, Tkacheva O, Troshina E, Shestakova M, Breder V, Geyvandova N, Doschitsin V, Dudinskaya E, Ershova E, Kodzoeva K, Komshilova K, Korochanskaya N, Mayorov A, Mishina E, Nadinskaya M, Nikitin I, Pogosova N, Tarzimanova A, Shamkhalova M. The National Consensus statement on the management of adult patients with non-alcoholic fatty liver disease and main comorbidities. TERAPEVT ARKH 2022; 94:216-253. [PMID: 36286746 DOI: 10.26442/00403660.2022.02.201363] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Indexed: 12/15/2022]
Abstract
The National Consensus was prepared with the participation of the National Medical Association for the Study of the Multimorbidity, Russian Scientific Liver Society, Russian Association of Endocrinologists, Russian Association of Gerontologists and Geriatricians, National Society for Preventive Cardiology, Professional Foundation for the Promotion of Medicine Fund PROFMEDFORUM.
The aim of the multidisciplinary consensus is a detailed analysis of the course of non-alcoholic fatty liver disease (NAFLD) and the main associated conditions. The definition of NAFLD is given, its prevalence is described, methods for diagnosing its components such as steatosis, inflammation and fibrosis are described.
The association of NAFLD with a number of cardio-metabolic diseases (arterial hypertension, atherosclerosis, thrombotic complications, type 2 diabetes mellitus (T2DM), obesity, dyslipidemia, etc.), chronic kidney disease (CKD) and the risk of developing hepatocellular cancer (HCC) were analyzed. The review of non-drug methods of treatment of NAFLD and modern opportunities of pharmacotherapy are presented.
The possibilities of new molecules in the treatment of NAFLD are considered: agonists of nuclear receptors, antagonists of pro-inflammatory molecules, etc. The positive properties and disadvantages of currently used drugs (vitamin E, thiazolidinediones, etc.) are described. Special attention is paid to the multi-target ursodeoxycholic acid (UDCA) molecule in the complex treatment of NAFLD as a multifactorial disease. Its anti-inflammatory, anti-oxidant and cytoprotective properties, the ability to reduce steatosis an independent risk factor for the development of cardiovascular pathology, reduce inflammation and hepatic fibrosis through the modulation of autophagy are considered.
The ability of UDCA to influence glucose and lipid homeostasis and to have an anticarcinogenic effect has been demonstrated. The Consensus statement has advanced provisions for practitioners to optimize the diagnosis and treatment of NAFLD and related common pathogenetic links of cardio-metabolic diseases.
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21
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van Kleef LA, Ayada I, Alferink LJM, Pan Q, de Knegt RJ. Metabolic dysfunction-associated fatty liver disease improves detection of high liver stiffness: The Rotterdam Study. Hepatology 2022; 75:419-429. [PMID: 34453359 PMCID: PMC9299928 DOI: 10.1002/hep.32131] [Citation(s) in RCA: 70] [Impact Index Per Article: 23.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Revised: 07/22/2021] [Accepted: 08/24/2021] [Indexed: 12/11/2022]
Abstract
BACKGROUND AND AIMS Recently metabolic dysfunction-associated fatty liver disease (MAFLD) has been introduced and was defined as hepatic steatosis with either overweight, diabetes, and/or a combination of other metabolic risk factors. We investigated the application of the MAFLD criteria as compared with NAFLD. APPROACH AND RESULTS We performed a cross-sectional analysis within the Rotterdam Study, a large prospective population-based cohort. Participants who attended the liver ultrasound and transient elastography program between 2009 and 2014 were eligible for inclusion. Subsequently, individuals with viral hepatitis, alcohol intake >60 g/day, missing alcohol data, and/or missing body mass index were excluded. According to their NAFLD and MAFLD status based on metadata and ultrasound, participants were allocated in overlap fatty liver disease (FLD), NAFLD-only, MAFLD-only, or no FLD. Fibrosis was defined as liver stiffness ≥8.0 kPa. In our analysis, 5445 participants were included: 1866 (34.3%) had MAFLD and 1604 (29.5%) [Correction added on December 27, 2021 after first online publication: The preceding fragment was changed from "1623 (29.8%)"] had NAFLD. This resulted in 1547 (28.4%) [Correction added on December 27, 2021 after first online publication: The preceding fragment was changed from "1566 (28.8%)"] individuals with overlap FLD, 319 (5.9%) [Correction added on December 27, 2021 after first online publication: The preceding fragment was changed from "300 (5.5%)"] with MAFLD-only, 57 (1.0%) with NAFLD-only, and 3522 (64.7%) with no FLD. The MAFLD-only group was strongly associated with fibrosis (adjusted OR 5.30 [Correction added on December 27, 2021 after first online publication: The preceding fragment was changed from "OR 5.27"], p < 0.001) and log-transformed liver stiffness (adjusted beta 0.116, p < 0.001), as opposed to the NAFLD-only group, in which no cases of fibrosis were identified and no association with liver stiffness (adjusted beta 0.006, p = 0.90) was found. CONCLUSIONS FLD is highly prevalent in the general population. However, not the NAFLD-only, but the MAFLD-only group was associated with fibrosis and higher liver stiffness-independent of demographic and lifestyle factors. We believe that using the MAFLD criteria will help improve the identification and treatment of patients with FLD at risk for fibrosis.
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Affiliation(s)
- Laurens A van Kleef
- Departments of Gastroenterology and HepatologyErasmus MC University Medical CenterRotterdamthe Netherlands
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22
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Correlations between PNPLA3 Gene Polymorphisms and NAFLD in Type 2 Diabetic Patients. MEDICINA (KAUNAS, LITHUANIA) 2021; 57:medicina57111249. [PMID: 34833467 PMCID: PMC8620174 DOI: 10.3390/medicina57111249] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Revised: 11/03/2021] [Accepted: 11/12/2021] [Indexed: 12/20/2022]
Abstract
Background and Objectives: Non-alcoholic fatty liver disease is a worldwide significant public health problem, particularly in patients with type 2 diabetes mellitus. Identifying possible risk factors for the disease is mandatory for a better understandingand management of this condition. Patatin-like phospholipase domain-containing protein 3 (PNPLA3) has been linked to the development and evolution of fatty liver but not to insulin resistance. The aim of this study isto evaluate the relationships between PNPLA3 and fatty liver, metabolic syndrome and subclinical atherosclerosis. Materials and Methods: The study group consisted of patients with type 2 diabetes mellitus without insulin treatment. The degree of liver fat loading was assessed by ultrasonography, and subclinical atherosclerosis was assessed using carotid intima-media thickness (CIMT). PNPLA3 rs738409 genotype determination was performed by high-resolution melting analysis that allowed three standard genotypes: CC, CG, and GG. Results: Among the 92 patients, more than 90% showed various degrees of hepatic steatosis, almost 62% presented values over the normal limit for the CIMT. The majority of the included subjects met the criteria for metabolic syndrome. Genotyping of PNPLA3 in 68 patients showed that the difference between subjects without steatosis and subjects with hepatic steatosis was due to the higher frequency of genotype GG. The CC genotype was the most common in the group we studied and was significantly more frequent in the group of subjects with severe steatosis; the GG genotype was significantly more frequent in subjects with moderate steatosis; the frequency of the CG genotype was not significantly different among the groups.When we divided the group of subjects into two groups: those with no or mild steatosis and those with moderate or severe steatosis it was shown that the frequency of the GG genotype was significantly higher in the group of subjects with moderate or severe steatosis. PNPLA3 genotypes were not associated with metabolic syndrome, subclinical atherosclerosis, or insulin resistance. Conclusions: Our results suggest that PNPLA3 does not independently influence cardiovascular risk in patients with type 2 diabetes mellitus. The hypothesis that PNPLA3 may have a cardioprotective effect requires future confirmation.
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Roe JD, Garcia LA, Klimentidis YC, Coletta DK. Association of PNPLA3 I148M with Liver Disease Biomarkers in Latinos. Hum Hered 2021; 86:21-27. [PMID: 34749354 DOI: 10.1159/000520734] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2021] [Accepted: 11/03/2021] [Indexed: 11/19/2022] Open
Abstract
INTRODUCTION Liver disease accounts for approximately 2 million deaths per year worldwide. The majority of liver diseases are due to complications of cirrhosis, viral hepatitis, and hepatocellular carcinoma. Increased levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) may indicate liver disease. Moreover, there are additional noninvasive liver fibrosis indices that help to estimate liver damage, including AST-to-ALT ratio, AST-to-platelet ratio index (APRI), fibrosis-4 (FIB-4) score, and nonalcoholic fatty liver disease (NAFLD) fibrosis score. The aims of the present study were to (1) perform an association analysis of the patatin-like phospholipase domain containing 3 (PNPLA3) I148M (rs738409) variant with ALT, AST, and various liver fibrosis indices, and (2) determine whether there are gender-related differences in these associations. METHODS We obtained demographic, anthropometric, and metabolic phenotypes from Latino adult participants (n = 503, 64% female, 36.4 ± 0.5 years) from the Arizona Insulin Resistance (AIR) registry. SNP genotyping of I148M was performed using the TaqMan allelic discrimination assay. We used linear regression for the association analyses of the genotypes with ALT, AST, and the various liver fibrosis indices. We included genotype, age, body mass index, and alcohol status in the linear regression model. RESULTS The variant I148M was in Hardy-Weinberg equilibrium, with genotype distribution: non-risk CC 118, heterozygous CG 246, and risk GG 139. The G allele was significantly associated with increased ALT and AST levels (p = 7.8 × 10-7 and p = 9.7 × 10-6, respectively). Moreover, we showed that the G allele was significantly associated with higher APRI (p = 3.7 × 10-7) and FIB-4 score (p = 4.1 × 10-3). When we analyzed the data by gender, we observed similar significant trends for ALT, AST, and APRI (all, p < 0.01). In females, the G allele was significantly associated with increased FIB-4 score (p = 6.9 × 10-3), which was not observed in the males (p > 0.05). There was no association of the I148M variant with AST/ALT ratio nor NAFLD risk score, whether analyzed in all adults or by gender. DISCUSSION/CONCLUSION Our findings provide additional evidence of an association of PNPLA3 I148M with several liver disease biomarkers in male and female Latinos residing in the Southwest of the United States.
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Affiliation(s)
- Jonathan D Roe
- Department of Physiology, College of Medicine, University of Arizona, Tucson, Arizona, USA
| | - Luis A Garcia
- Department of Medicine, Division of Endocrinology, College of Medicine, University of Arizona, Tucson, Arizona, USA.,Center for Disparities in Diabetes Obesity, and Metabolism, University of Arizona, Tucson, Arizona, USA
| | - Yann C Klimentidis
- Department of Epidemiology and Biostatistics, Mel and Enid Zuckerman College of Public Health, University of Arizona, Tucson, Arizona, USA
| | - Dawn K Coletta
- Department of Physiology, College of Medicine, University of Arizona, Tucson, Arizona, USA.,Department of Medicine, Division of Endocrinology, College of Medicine, University of Arizona, Tucson, Arizona, USA.,Center for Disparities in Diabetes Obesity, and Metabolism, University of Arizona, Tucson, Arizona, USA
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24
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Belbin GM, Rutledge S, Dodatko T, Cullina S, Turchin MC, Kohli S, Torre D, Yee MC, Gignoux CR, Abul-Husn NS, Houten SM, Kenny EE. Leveraging health systems data to characterize a large effect variant conferring risk for liver disease in Puerto Ricans. Am J Hum Genet 2021; 108:2099-2111. [PMID: 34678161 PMCID: PMC8595966 DOI: 10.1016/j.ajhg.2021.09.016] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Accepted: 09/28/2021] [Indexed: 12/22/2022] Open
Abstract
The integration of genomic data into health systems offers opportunities to identify genomic factors underlying the continuum of rare and common disease. We applied a population-scale haplotype association approach based on identity-by-descent (IBD) in a large multi-ethnic biobank to a spectrum of disease outcomes derived from electronic health records (EHRs) and uncovered a risk locus for liver disease. We used genome sequencing and in silico approaches to fine-map the signal to a non-coding variant (c.2784-12T>C) in the gene ABCB4. In vitro analysis confirmed the variant disrupted splicing of the ABCB4 pre-mRNA. Four of five homozygotes had evidence of advanced liver disease, and there was a significant association with liver disease among heterozygotes, suggesting the variant is linked to increased risk of liver disease in an allele dose-dependent manner. Population-level screening revealed the variant to be at a carrier rate of 1.95% in Puerto Rican individuals, likely as the result of a Puerto Rican founder effect. This work demonstrates that integrating EHR and genomic data at a population scale can facilitate strategies for understanding the continuum of genomic risk for common diseases, particularly in populations underrepresented in genomic medicine.
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Affiliation(s)
- Gillian M Belbin
- Institute for Genomic Health, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
| | - Stephanie Rutledge
- Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Tetyana Dodatko
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Sinead Cullina
- Institute for Genomic Health, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Michael C Turchin
- Institute for Genomic Health, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Sumita Kohli
- Institute for Genomic Health, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Denis Torre
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Muh-Ching Yee
- Stanford Functional Genomics Facility, Stanford University, Stanford, CA 94305, USA
| | - Christopher R Gignoux
- Colorado Center for Personalized Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Noura S Abul-Husn
- Institute for Genomic Health, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Sander M Houten
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Eimear E Kenny
- Institute for Genomic Health, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
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25
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Xiang H, Wu Z, Wang J, Wu T. Research progress, challenges and perspectives on PNPLA3 and its variants in Liver Diseases. J Cancer 2021; 12:5929-5937. [PMID: 34476007 PMCID: PMC8408107 DOI: 10.7150/jca.57951] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2021] [Accepted: 07/26/2021] [Indexed: 12/02/2022] Open
Abstract
The human patatin-like phospholipase domain-containing 3 gene (PNPLA3) is highly expressed in liver and adipose tissue and encodes a transmembrane polypeptide chain containing 481 amino acids. The I148M variant of PNPLA3 is a single nucleotide polymorphism, which is related to a variety of liver and cardiovascular diseases and their complications (such as non-alcoholic fatty liver disease, liver fibrosis, coronary artery disease). This review mainly describes the pathophysiological effects of PNPLA3 and its variants, and their roles in the progression of liver disease and its complications.
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Affiliation(s)
- Hongjiao Xiang
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Zecheng Wu
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Junmin Wang
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Tao Wu
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
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26
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Li P, Xia Z, Kong W, Wang Q, Zhao Z, Arnold A, Xu Q, Xu J. Exogenous L-carnitine ameliorates burn-induced cellular and mitochondrial injury of hepatocytes by restoring CPT1 activity. Nutr Metab (Lond) 2021; 18:65. [PMID: 34167568 PMCID: PMC8223334 DOI: 10.1186/s12986-021-00592-x] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2021] [Accepted: 06/12/2021] [Indexed: 12/24/2022] Open
Abstract
Background Impaired hepatic fatty acid metabolism and persistent mitochondrial dysfunction are phenomena commonly associated with liver failure. Decreased serum levels of L-carnitine, a amino acid derivative involved in fatty-acid and energy metabolism, have been reported in severe burn patients. The current study aimed to evaluate the effects of L-carnitine supplementation on mitochondrial damage and other hepatocyte injuries following severe burns and the related mechanisms. Methods Serum carnitine and other indicators of hepatocytic injury, including AST, ALT, LDH, TG, and OCT, were analyzed in severe burn patients and healthy controls. A burn model was established on the back skin of rats; thereafter, carnitine was administered, and serum levels of the above indicators were evaluated along with Oil Red O and TUNEL staining, transmission electron microscopy, and assessment of mitochondrial membrane potential and carnitine palmitoyltransferase 1 (CPT1) activity and expression levels in the liver. HepG2 cells pretreated with the CPT1 inhibitor etomoxir were treated with or without carnitine for 24 h. Next, the above indicators were examined, and apoptotic cells were analyzed via flow cytometry. High-throughput sequencing of rat liver tissues identified several differentially expressed genes (Fabp4, Acacb, Acsm5, and Pnpla3) were confirmed using RT-qPCR. Results Substantially decreased serum levels of carnitine and increased levels of AST, ALT, LDH, and OCT were detected in severe burn patients and the burn model rats. Accumulation of TG, evident mitochondrial shrinkage, altered mitochondrial membrane potential, decreased ketogenesis, and reduced CPT1 activity were detected in the liver tissue of the burned rats. Carnitine administration recovered CPT1 activity and improved all indicators related to cellular and fatty acid metabolism and mitochondrial injury. Inhibition of CPT1 activity with etomoxir induced hepatocyte injuries similar to those in burn patients and burned rats; carnitine supplementation restored CPT1 activity and ameliorated these injuries. The expression levels of the differentially expressed genes Fabp4, Acacb, Acsm5, and Pnpla3 in the liver tissue from burned rats and etomoxir-treated hepatocytes were also restored by treatment with exogenous carnitine. Conclusion Exogenous carnitine exerts protective effects against severe burn-induced cellular, fatty-acid metabolism, and mitochondrial dysfunction of hepatocytes by restoring CPT1 activity. Supplementary Information The online version contains supplementary material available at 10.1186/s12986-021-00592-x.
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Affiliation(s)
- Pengtao Li
- Department of Burns, The First Affiliated Hospital of Anhui Medical University, No. 218 Jixi Road, Hefei, 230022, Anhui, China.,Department of Immunology, School of Basic Medical Sciences of Anhui Medical University, No. 81 Meishan Road, Hefei, 230032, Anhui, China
| | - Zhengguo Xia
- Department of Wound Repair and Plastic and Aesthetic Surgery, The Fourth Affiliated Hospital of Anhui Medical University, No. 100 Huaihai Road, Xinzhan District, China
| | - Weichang Kong
- Department of Burns, The First Affiliated Hospital of Anhui Medical University, No. 218 Jixi Road, Hefei, 230022, Anhui, China
| | - Qiong Wang
- Department of Immunology, School of Basic Medical Sciences of Anhui Medical University, No. 81 Meishan Road, Hefei, 230032, Anhui, China
| | - Ziyue Zhao
- Department of Immunology, School of Basic Medical Sciences of Anhui Medical University, No. 81 Meishan Road, Hefei, 230032, Anhui, China
| | - Ashley Arnold
- International College of Anhui Medical University, No. 81 Meishan road, Hefei, 230032, Anhui, China
| | - Qinglian Xu
- Department of Burns, The First Affiliated Hospital of Anhui Medical University, No. 218 Jixi Road, Hefei, 230022, Anhui, China.
| | - Jiegou Xu
- Department of Immunology, School of Basic Medical Sciences of Anhui Medical University, No. 81 Meishan Road, Hefei, 230032, Anhui, China.
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27
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Scapaticci S, D’Adamo E, Mohn A, Chiarelli F, Giannini C. Non-Alcoholic Fatty Liver Disease in Obese Youth With Insulin Resistance and Type 2 Diabetes. Front Endocrinol (Lausanne) 2021; 12:639548. [PMID: 33889132 PMCID: PMC8056131 DOI: 10.3389/fendo.2021.639548] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2020] [Accepted: 01/28/2021] [Indexed: 02/06/2023] Open
Abstract
Currently, Non-Alcoholic Fatty Liver Disease (NAFLD) is the most prevalent form of chronic liver disease in children and adolescents worldwide. Simultaneously to the epidemic spreading of childhood obesity, the rate of affected young has dramatically increased in the last decades with an estimated prevalence of NAFLD of 3%-10% in pediatric subjects in the world. The continuous improvement in NAFLD knowledge has significantly defined several risk factors associated to the natural history of this complex liver alteration. Among them, Insulin Resistance (IR) is certainly one of the main features. As well, not surprisingly, abnormal glucose tolerance (prediabetes and diabetes) is highly prevalent among children/adolescents with biopsy-proven NAFLD. In addition, other factors such as genetic, ethnicity, gender, age, puberty and lifestyle might affect the development and progression of hepatic alterations. However, available data are still lacking to confirm whether IR is a risk factor or a consequence of hepatic steatosis. There is also evidence that NAFLD is the hepatic manifestation of Metabolic Syndrome (MetS). In fact, NAFLD often coexist with central obesity, impaired glucose tolerance, dyslipidemia, and hypertension, which represent the main features of MetS. In this Review, main aspects of the natural history and risk factors of the disease are summarized in children and adolescents. In addition, the most relevant scientific evidence about the association between NAFLD and metabolic dysregulation, focusing on clinical, pathogenetic, and histological implication will be provided with some focuses on the main treatment options.
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Affiliation(s)
| | | | | | | | - Cosimo Giannini
- Department of Pediatrics, University of Chieti, Chieti, Italy
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28
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LaBranche TP, Kopec AK, Mantena SR, Hollingshead BD, Harrington AW, Stewart ZS, Zhan Y, Hayes KD, Whiteley LO, Burdick AD, Davis JW. Zucker Lean Rats With Hepatic Steatosis Recapitulate Asymptomatic Metabolic Syndrome and Exhibit Greater Sensitivity to Drug-Induced Liver Injury Compared With Standard Nonclinical Sprague-Dawley Rat Model. Toxicol Pathol 2020; 48:994-1007. [PMID: 33252024 DOI: 10.1177/0192623320968716] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Fatty liver disease is a potential risk factor for drug-induced liver injury (DILI). Despite advances in nonclinical in vitro and in vivo models to assess liver injury during drug development, the pharmaceutical industry is still plagued by idiosyncratic DILI. Here, we tested the hypothesis that certain features of asymptomatic metabolic syndrome (namely hepatic steatosis) increase the risk for DILI in certain phenotypes of the human population. Comparison of the Zucker Lean (ZL) and Zucker Fatty rats fed a high fat diet (HFD) revealed that HFD-fed ZL rats developed mild hepatic steatosis with compensatory hyperinsulinemia without increases in liver enzymes. We then challenged steatotic HFD-fed ZL rats and Sprague-Dawley (SD) rats fed normal chow, a nonclinical model widely used in the pharmaceutical industry, with acetaminophen overdose to induce liver injury. Observations in HFD-fed ZL rats included increased liver injury enzymes and greater incidence and severity of hepatic necrosis compared with similarly treated SD rats. The HFD-fed ZL rats also had disproportionately higher hepatic drug accumulation, which was linked with abnormal hepatocellular efflux transporter distribution. Here, we identify ZL rats with HFD-induced hepatic steatosis as a more sensitive nonclinical in vivo test system for modeling DILI compared with SD rats fed normal chow.
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Affiliation(s)
- Timothy P LaBranche
- 376392Pfizer Inc, Cambridge, MA, USA.,Blueprint Medicines, Cambridge, MA, USA.,*Timothy P. LaBranche and Anna K. Kopec contributed equally
| | - Anna K Kopec
- 2253Pfizer Inc, Groton, CT, USA.,*Timothy P. LaBranche and Anna K. Kopec contributed equally
| | | | | | - Andrew W Harrington
- 2253Pfizer Inc, Chesterfield, MO, USA.,Department of Ophthalmology & Visual Sciences, Washington University School of Medicine, St Louis, MO, USA
| | - Zachary S Stewart
- 2253Pfizer Inc, Andover, MA, USA.,Hooke Laboratories, Lawrence, MA, USA
| | | | - Kyle D Hayes
- 2253Pfizer Inc, Andover, MA, USA.,Mallinckrodt Pharmaceuticals, Hazelwood, MO, USA
| | | | | | - John W Davis
- 376392Pfizer Inc, Cambridge, MA, USA.,Dyne Therapeutics, Waltham, MA, USA
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29
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Hu DS, Zhu SH, Liu WY, Pan XY, Zhu PW, Li YY, Zheng KI, Ma HL, You J, Targher G, Byrne CD, Chen YP, Zheng MH. PNPLA3 polymorphism influences the association between high-normal TSH level and NASH in euthyroid adults with biopsy-proven NAFLD. DIABETES & METABOLISM 2020; 46:496-503. [PMID: 32035968 DOI: 10.1016/j.diabet.2020.02.001] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/12/2019] [Revised: 01/15/2020] [Accepted: 02/02/2020] [Indexed: 12/30/2022]
Abstract
AIM We aimed to evaluate the association between serum thyroid stimulating hormone (TSH) levels, within the reference range, and the histological severity of nonalcoholic fatty liver disease (NAFLD), and whether this association was modulated by the patatin-like phospholipase domain-containing 3 (PNPLA3) rs738409 polymorphism. MATERIALS AND METHODS We enrolled 327 euthyroid individuals with biopsy-proven NAFLD, who were subdivided into two groups, i.e., a 'strict-normal' TSH group (TSH level 0.4 to 2.5mIU/L; n=283) and a 'high-normal' TSH group (TSH level 2.5 to 5.3mIU/L with normal thyroid hormones; n=44). Logistic regression analyses were performed to assess the association between TSH status and presence of nonalcoholic steatohepatitis (NASH) after stratifying subjects by PNPLA3 genotypes. RESULTS Compared to strict-normal TSH group, patients with high-normal TSH levels were younger and had a greater prevalence of NASH and higher histologic NAFLD activity score. After stratifying by PNPLA3 genotypes, the significant association between high-normal TSH levels and presence of NASH was restricted only to carriers of the PNPLA3 G risk allele and remained significant even after adjustment for potential confounding factors (adjusted-odds ratio: 3.279; 95% CI: 1.298-8.284; P=0.012). CONCLUSION In euthyroid individuals with biopsy-proven NAFLD, we found a significant association between high-normal TSH levels and NASH. After stratifying by PNPLA3 rs738409 genotypes, this association was observed only among carriers of the PNPLA3 G risk allele.
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Affiliation(s)
- D-S Hu
- Department of Gastroenterology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - S-H Zhu
- Department of Gastroenterology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - W-Y Liu
- Department of Endocrinology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - X-Y Pan
- Department of Endocrinology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - P-W Zhu
- Department of Clinical Laboratory, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Y-Y Li
- Department of Pathology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - K I Zheng
- NAFLD Research Centre, Department of Hepatology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - H-L Ma
- NAFLD Research Centre, Department of Hepatology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - J You
- Department of Thyroid and Breast Surgery, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - G Targher
- Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, University and Azienda Ospedaliera Universitaria Integrata of Verona, Verona, Italy
| | - C D Byrne
- Southampton National Institute for Health Research Biomedical Research Centre, University Hospital Southampton, Southampton General Hospital, Southampton, UK
| | - Y-P Chen
- NAFLD Research Centre, Department of Hepatology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China; Institute of Hepatology, Wenzhou Medical University, Wenzhou, China; Key Laboratory of Diagnosis and Treatment for The Development of Chronic Liver Disease in Zhejiang Province, Wenzhou, China
| | - M-H Zheng
- NAFLD Research Centre, Department of Hepatology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China; Institute of Hepatology, Wenzhou Medical University, Wenzhou, China; Key Laboratory of Diagnosis and Treatment for The Development of Chronic Liver Disease in Zhejiang Province, Wenzhou, China.
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30
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Tavaglione F, Targher G, Valenti L, Romeo S. Human and molecular genetics shed lights on fatty liver disease and diabetes conundrum. Endocrinol Diabetes Metab 2020; 3:e00179. [PMID: 33102799 PMCID: PMC7576307 DOI: 10.1002/edm2.179] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2020] [Revised: 07/28/2020] [Accepted: 08/01/2020] [Indexed: 12/13/2022] Open
Abstract
The causal role of abdominal overweight/obesity, insulin resistance and type 2 diabetes (T2D) on the risk of fatty liver disease (FLD) has robustly been proven. A consensus of experts has recently proposed the novel definition of 'metabolic dysfunction-associated fatty liver disease, MAFLD' instead of 'nonalcoholic fatty liver disease, NAFLD', emphasizing the central role of dysmetabolism in the disease pathogenesis. Conversely, a direct and independent contribution of FLD per se on risk of developing T2D is still a controversial topic. When dealing with FLD as a potential risk factor for T2D, it is straightforward to think of hepatic insulin resistance as the most relevant underlying mechanism. Emerging evidence supports genetic determinants of FLD (eg PNPLA3, TM6SF2, MBOAT7, GCKR, HSD17B13) as determinants of insulin resistance and T2D. However, recent studies highlighted that the key molecular mechanism of dysmetabolism is not fat accumulation per se but the degree of hepatic fibrosis (excess liver fat content-lipotoxicity), leading to reduced insulin clearance, insulin resistance and T2D. A consequence of these findings is that drugs that will ameliorate liver fat accumulation and fibrosis in principle may also exert a beneficial effect on insulin resistance and risk of T2D in individuals with FLD. Finally, initial findings show that these genetic factors might be directly implicated in modulating pancreatic beta-cell function, although future studies are needed to fully understand this relationship.
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Affiliation(s)
- Federica Tavaglione
- Clinical Medicine and Hepatology UnitDepartment of Internal Medicine and GeriatricsCampus Bio‐Medico UniversityRomeItaly
- Department of Molecular and Clinical MedicineSahlgrenska AcademyUniversity of GothenburgGothenburgSweden
| | - Giovanni Targher
- Section of Endocrinology, Diabetes and MetabolismDepartment of MedicineUniversity and Azienda Ospedaliera Universitaria Integrata of VeronaVeronaItaly
| | - Luca Valenti
- Department of Pathophysiology and TransplantationUniversità degli Studi di MilanoMilanoItaly
- Translational MedicineDepartment of Transfusion Medicine and HematologyFondazione IRCCS Ca’ Granda Ospedale Maggiore PoliclinicoMilanoItaly
| | - Stefano Romeo
- Department of Molecular and Clinical MedicineSahlgrenska AcademyUniversity of GothenburgGothenburgSweden
- Clinical Nutrition UnitDepartment of Medical and Surgical ScienceMagna Graecia UniversityCatanzaroItaly
- Department of CardiologySahlgrenska University HospitalGothenburgSweden
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31
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Perakakis N, Stefanakis K, Mantzoros CS. The role of omics in the pathophysiology, diagnosis and treatment of non-alcoholic fatty liver disease. Metabolism 2020; 111S:154320. [PMID: 32712221 PMCID: PMC7377759 DOI: 10.1016/j.metabol.2020.154320] [Citation(s) in RCA: 65] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2020] [Revised: 07/15/2020] [Accepted: 07/18/2020] [Indexed: 12/12/2022]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a multifaceted metabolic disorder, whose spectrum covers clinical, histological and pathophysiological developments ranging from simple steatosis to non-alcoholic steatohepatitis (NASH) and liver fibrosis, potentially evolving into cirrhosis, hepatocellular carcinoma and liver failure. Liver biopsy remains the gold standard for diagnosing NAFLD, while there are no specific treatments. An ever-increasing number of high-throughput Omics investigations on the molecular pathobiology of NAFLD at the cellular, tissue and system levels produce comprehensive biochemical patient snapshots. In the clinical setting, these applications are considerably enhancing our efforts towards obtaining a holistic insight on NAFLD pathophysiology. Omics are also generating non-invasive diagnostic modalities for the distinct stages of NAFLD, that remain though to be validated in multiple, large, heterogenous and independent cohorts, both cross-sectionally as well as prospectively. Finally, they aid in developing novel therapies. By tracing the flow of information from genomics to epigenomics, transcriptomics, proteomics, metabolomics, lipidomics and glycomics, the chief contributions of these techniques in understanding, diagnosing and treating NAFLD are summarized herein.
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Affiliation(s)
- Nikolaos Perakakis
- Department of Internal Medicine, Boston VA Healthcare system and Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA..
| | - Konstantinos Stefanakis
- Department of Internal Medicine, Boston VA Healthcare system and Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
| | - Christos S Mantzoros
- Department of Internal Medicine, Boston VA Healthcare system and Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
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32
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Khalifa O, Errafii K, Al-Akl NS, Arredouani A. Noncoding RNAs in Nonalcoholic Fatty Liver Disease: Potential Diagnosis and Prognosis Biomarkers. DISEASE MARKERS 2020; 2020:8822859. [PMID: 33133304 PMCID: PMC7593715 DOI: 10.1155/2020/8822859] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/05/2020] [Revised: 07/25/2020] [Accepted: 07/31/2020] [Indexed: 12/14/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is currently the most common chronic liver disease worldwide in part due to the concomitant obesity pandemic and insulin resistance (IR). It is increasingly becoming evident that NAFLD is a disease affecting numerous extrahepatic vital organs and regulatory pathways. The molecular mechanisms underlying the nonalcoholic steatosis formation are poorly understood, and little information is available on the pathways that are responsible for the progressive hepatocellular damage that follows lipid accumulation. Recently, much research has focused on the identification of the epigenetic modifications that contribute to NAFLD pathogenesis. Noncoding RNAs (ncRNAs) are one of such epigenetic factors that could be implicated in the NAFLD development and progression. In this review, we summarize the current knowledge of the genetic and epigenetic factors potentially underlying the disease. Particular emphasis will be put on the contribution of microRNAs (miRNAs), long noncoding RNAs (lncRNAs), and circular RNAs (circRNAs) to the pathophysiology of NAFLD as well as their potential use as therapeutic targets or as markers for the prediction and the progression of the disease.
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Affiliation(s)
- Olfa Khalifa
- Diabetes Research Center, Qatar Biomedical Research Institute, Hamad Bin Khalifa University, Qatar Foundation, Doha, Qatar
| | - Khaoula Errafii
- Diabetes Research Center, Qatar Biomedical Research Institute, Hamad Bin Khalifa University, Qatar Foundation, Doha, Qatar
- College of Health and Life Sciences, Hamad Bin Khalifa University, Qatar Foundation, Education City, Doha, Qatar
| | - Nayla S. Al-Akl
- Diabetes Research Center, Qatar Biomedical Research Institute, Hamad Bin Khalifa University, Qatar Foundation, Doha, Qatar
| | - Abdelilah Arredouani
- Diabetes Research Center, Qatar Biomedical Research Institute, Hamad Bin Khalifa University, Qatar Foundation, Doha, Qatar
- College of Health and Life Sciences, Hamad Bin Khalifa University, Qatar Foundation, Education City, Doha, Qatar
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33
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Ntandja Wandji LC, Gnemmi V, Mathurin P, Louvet A. Combined alcoholic and non-alcoholic steatohepatitis. JHEP Rep 2020; 2:100101. [PMID: 32514497 PMCID: PMC7267467 DOI: 10.1016/j.jhepr.2020.100101] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2019] [Revised: 02/18/2020] [Accepted: 03/10/2020] [Indexed: 02/06/2023] Open
Abstract
While metabolic syndrome and alcohol consumption are the two main causes of chronic liver disease, one of the two conditions is often predominant, with the other acting as a cofactor of morbimortality. It has been shown that obesity and alcohol act synergistically to increase the risk of fibrosis progression, hepatic carcinogenesis and mortality, while genetic polymorphisms can strongly influence disease progression. Based on common pathogenic pathways, there are several potential targets that could be used to treat both diseases; based on the prevalence and incidence of these diseases, new therapies and clinical trials are needed urgently.
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Key Words
- ACC, acetyl-CoA carboxylase
- ALD
- ALD, alcohol-related liver disease
- ASH
- ASH, alcohol-related steatohepatitis
- ASK-1, apoptosis signal-regulating kinase 1
- Alcohol
- BMI, body mass index
- CLD, chronic liver disease
- CPT, carnitine palmitoyltransferase
- DNL, de novo lipogenesis
- EASL, European Association for the Study of the Liver
- ER, endoplasmic reticulum
- FXR, farnesoid X receptor
- HCC, hepatocellular carcinoma
- HSD17B13, hydroxysteroid 17-beta dehydrogenase 13
- IL, interleukin
- LPS, lipopolysaccharide
- MBOAT7, membrane bound O-acyl transferase 7
- MELD, model for end-stage liver disease
- NAFLD
- NAFLD, non-alcoholic fatty liver disease
- NASH
- NASH, non-alcoholic steatohepatitis
- OR, odds ratio
- PAMP, pathogen-associated molecular pattern
- PI3K, phosphatidylinositol-3-kinase
- PIP3, phosphatidylinositol 3,4,5-triphosphate
- PNPLA3, palatin-like phospholipase domain-containing 3
- PRKCE, protein kinase C Epsilon
- ROS, reactive oxygen species
- SREBP-1c, sterol regulatory element binding protein-1c
- TLR, Toll-like receptor
- TM6SF2, transmembrane 6 superfamily member 2
- TNF-α, tumour necrosis factor-α
- WHO, World Health Organization
- diabetes
- metabolic syndrome
- obesity
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Affiliation(s)
- Line Carolle Ntandja Wandji
- Service des maladies de l'appareil digestif, Hôpital Huriez, Rue Polonowski, 59037 Lille Cedex, France
- Université Lille Nord de France, Lille, France
- Unité INSERM 995, Lille, France
| | | | - Philippe Mathurin
- Service des maladies de l'appareil digestif, Hôpital Huriez, Rue Polonowski, 59037 Lille Cedex, France
- Université Lille Nord de France, Lille, France
- Unité INSERM 995, Lille, France
| | - Alexandre Louvet
- Service des maladies de l'appareil digestif, Hôpital Huriez, Rue Polonowski, 59037 Lille Cedex, France
- Université Lille Nord de France, Lille, France
- Unité INSERM 995, Lille, France
- Corresponding author. Address: Service des maladies de l'appareil digestif, Hôpital Huriez, Rue Polonowski, 59037 Lille Cedex, France. Tel.: +33 320445597; fax: +33 320445564.
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34
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Krawczyk M, Liebe R, Lammert F. Toward Genetic Prediction of Nonalcoholic Fatty Liver Disease Trajectories: PNPLA3 and Beyond. Gastroenterology 2020; 158:1865-1880.e1. [PMID: 32068025 DOI: 10.1053/j.gastro.2020.01.053] [Citation(s) in RCA: 79] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2019] [Revised: 01/29/2020] [Accepted: 01/29/2020] [Indexed: 12/14/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is on the verge of becoming the leading cause of liver disease. NAFLD develops at the interface between environmental factors and inherited predisposition. Genome-wide association studies, followed by exome-wide analyses, led to identification of genetic risk variants (eg, PNPLA3, TM6SF2, and SERPINA1) and key pathways involved in fatty liver disease pathobiology. Functional studies improved our understanding of these genetic factors and the molecular mechanisms underlying the trajectories from fat accumulation to fibrosis, cirrhosis, and cancer over time. Here, we summarize key NAFLD risk genes and illustrate their interactions in a 3-dimensional "risk space." Although NAFLD genomics sometimes appears to be "lost in translation," we envision clinical utility in trial design, outcome prediction, and NAFLD surveillance.
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Affiliation(s)
- Marcin Krawczyk
- Department of Medicine II (Gastroenterology and Endocrinology), Saarland University Medical Center, Saarland University, Homburg; Laboratory of Metabolic Liver Diseases, Center for Preclinical Research, Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw, Poland
| | - Roman Liebe
- Department of Medicine II (Gastroenterology and Endocrinology), Saarland University Medical Center, Saarland University, Homburg; Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Heinrich Heine University, Düsseldorf, Germany
| | - Frank Lammert
- Department of Medicine II (Gastroenterology and Endocrinology), Saarland University Medical Center, Saarland University, Homburg.
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Luukkonen PK, Tukiainen T, Juuti A, Sammalkorpi H, Haridas PAN, Niemelä O, Arola J, Orho-Melander M, Hakkarainen A, Kovanen PT, Dwivedi O, Groop L, Hodson L, Gastaldelli A, Hyötyläinen T, Orešič M, Yki-Järvinen H. Hydroxysteroid 17-β dehydrogenase 13 variant increases phospholipids and protects against fibrosis in nonalcoholic fatty liver disease. JCI Insight 2020; 5:132158. [PMID: 32161197 DOI: 10.1172/jci.insight.132158] [Citation(s) in RCA: 75] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2019] [Accepted: 02/05/2020] [Indexed: 12/22/2022] Open
Abstract
Carriers of the hydroxysteroid 17-β dehydrogenase 13 (HSD17B13) gene variant (rs72613567:TA) have a reduced risk of NASH and cirrhosis but not steatosis. We determined its effect on liver histology, lipidome, and transcriptome using ultra performance liquid chromatography-mass spectrometry and RNA-seq. In carriers and noncarriers of the gene variant, we also measured pathways of hepatic fatty acids (de novo lipogenesis [DNL] and adipose tissue lipolysis [ATL] using 2H2O and 2H-glycerol) and insulin sensitivity using 3H-glucose and euglycemic-hyperinsulinemic clamp) and plasma cytokines. Carriers and noncarriers had similar age, sex and BMI. Fibrosis was significantly less frequent while phospholipids, but not other lipids, were enriched in the liver in carriers compared with noncarriers. Expression of 274 genes was altered in carriers compared with noncarriers, consisting predominantly of downregulated inflammation-related gene sets. Plasma IL-6 concentrations were lower, but DNL, ATL and hepatic insulin sensitivity were similar between the groups. In conclusion, carriers of the HSD17B13 variant have decreased fibrosis and expression of inflammation-related genes but increased phospholipids in the liver. These changes are not secondary to steatosis, DNL, ATL, or hepatic insulin sensitivity. The increase in phospholipids and decrease in fibrosis are opposite to features of choline-deficient models of liver disease and suggest HSD17B13 as an attractive therapeutic target.
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Affiliation(s)
- Panu K Luukkonen
- Department of Medicine, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.,Minerva Foundation Institute for Medical Research, Helsinki, Finland.,Yale School of Medicine, Yale University, New Haven, Connecticut, USA
| | - Taru Tukiainen
- Institute for Molecular Medicine Finland, Helsinki, Finland
| | - Anne Juuti
- Department of Surgery, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Henna Sammalkorpi
- Department of Surgery, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | | | - Onni Niemelä
- Department of Laboratory Medicine and Medical Research Unit, Seinäjoki Central Hospital and University of Tampere, Tampere, Finland
| | - Johanna Arola
- Department of Pathology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | | | - Antti Hakkarainen
- Department of Radiology, HUS Medical Imaging Center, Helsinki University Hospital and University of Helsinki, Helsinki, Finland.,Department of Neuroscience and Biomedical Engineering, Aalto University School of Science, Espoo, Finland
| | | | - Om Dwivedi
- Institute for Molecular Medicine Finland, Helsinki, Finland
| | - Leif Groop
- Institute for Molecular Medicine Finland, Helsinki, Finland.,Department of Clinical Sciences, Lund University, Malmö, Sweden
| | - Leanne Hodson
- Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, United Kingdom
| | - Amalia Gastaldelli
- Institute of Clinical Physiology, Consiglio Nazionale delle Ricerche, Pisa, Italy
| | | | - Matej Orešič
- Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku, Finland.,School of Medical Sciences, Örebro University, Örebro, Sweden
| | - Hannele Yki-Järvinen
- Department of Medicine, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.,Minerva Foundation Institute for Medical Research, Helsinki, Finland
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Delik A, Akkız H, Dinçer S. The effect of PNPLA3 polymorphism as gain in function mutation in the pathogenesis of non-alcoholic fatty liver disease. Indian J Gastroenterol 2020; 39:84-91. [PMID: 32333362 DOI: 10.1007/s12664-020-01026-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2019] [Accepted: 02/05/2020] [Indexed: 02/06/2023]
Abstract
BACKGROUND Non-alcoholic fatty liver disease (NAFLD) is often associated with metabolic syndrome (type 2 diabetes, hypertension, hypertriglyceridemia, insulin resistance, and obesity). NAFLD is multi-factorial in pathogenesis with some genetic predisposition. The variant patatin-like phospholipase domain-containing protein 3 (PNPLA3) is known to be an independent risk factor for hepatocellular cancer (HCC). The aim of this study was to investigate the role of PNPLA3 polymorphism as the risk factor for NAFLD. METHODOLOGY Patients had histological, ultrasonographic, biopsy evidence of NAFLD (n=248) and 81 controls were studied for PNPLA3 polymorphism. PNPLA3 genotyping was done from peripheral blood DNA by real-time polymerase chain reaction (RT-PCR). RESULTS PNPLA3 genotyping of the groups NAFLD (CC [n = 76], CG [n = 83], GG [n = 89]) and control (CC [n= 42], CG [n = 22], GG [n = 17]) was determined. In the patient group, the G allele was 261 (52.63%) and the C allele was 235 (47.37%), whereas in the control group, the G allele was 56 (34.54%) and the C allele was 106 (65.43%). In our study, 53 out of 174 women had GG allele and 54 out of 155 men had GG allele. CONCLUSION The findings suggest that there is a predominant relationship between men with PNPLA3 I148M variant with NAFLD in women. Patients with NAFLD carrying PNPLA3 rs738409 G>C variant are at higher risk of NAFLD.
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Affiliation(s)
- Anıl Delik
- Department of Gastroenterology, Faculty of Medicine, Çukurova University, 01330, Adana, Turkey. .,Department of Biology, Faculty of Natural and Applied Science, Çukurova University, 01330, Adana, Turkey.
| | - Hikmet Akkız
- Department of Gastroenterology, Faculty of Medicine, Çukurova University, 01330, Adana, Turkey
| | - Sadık Dinçer
- Department of Biology, Faculty of Natural and Applied Science, Çukurova University, 01330, Adana, Turkey
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Boeckmans J, Natale A, Rombaut M, Buyl K, Rogiers V, De Kock J, Vanhaecke T, Rodrigues RM. Anti-NASH Drug Development Hitches a Lift on PPAR Agonism. Cells 2019; 9:E37. [PMID: 31877771 PMCID: PMC7016963 DOI: 10.3390/cells9010037] [Citation(s) in RCA: 102] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2019] [Revised: 12/15/2019] [Accepted: 12/17/2019] [Indexed: 02/07/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) affects one-third of the population worldwide, of which a substantial number of patients suffer from non-alcoholic steatohepatitis (NASH). NASH is a severe condition characterized by steatosis and concomitant liver inflammation and fibrosis, for which no drug is yet available. NAFLD is also generally conceived as the hepatic manifestation of the metabolic syndrome. Consequently, well-established drugs that are indicated for the treatment of type 2 diabetes and hyperlipidemia are thought to exert effects that alleviate the pathological features of NASH. One class of these drugs targets peroxisome proliferator-activated receptors (PPARs), which are nuclear receptors that play a regulatory role in lipid metabolism and inflammation. Therefore, PPARs are now also being investigated as potential anti-NASH druggable targets. In this paper, we review the mechanisms of action and physiological functions of PPARs and discuss the position of the different PPAR agonists in the therapeutic landscape of NASH. We particularly focus on the PPAR agonists currently under evaluation in clinical phase II and III trials. Preclinical strategies and how refinement and optimization may improve PPAR-targeted anti-NASH drug testing are also discussed. Finally, potential caveats related to PPAR agonism in anti-NASH therapy are stipulated.
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Käräjämäki AJ, Hukkanen J, Kauma H, Kesäniemi YA, Ukkola O. Metabolic syndrome but not genetic polymorphisms known to induce NAFLD predicts increased total mortality in subjects with NAFLD (OPERA study). Scandinavian Journal of Clinical and Laboratory Investigation 2019; 80:106-113. [PMID: 31851849 DOI: 10.1080/00365513.2019.1700428] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Metabolic syndrome (MetS) and genetic polymorphisms PNPLA3 rs738409, TM6SF2 rs58542926 and MBOAT7 rs641738 are known inductors of non-alcoholic fatty liver disease (NAFLD). However, knowledge about how these affect the mortality of subjects with NAFLD is scarce. Therefore, we investigated the impact of MetS, PNPLA3 rs738409, TM6SF2 rs58542926 and MBOAT7 rs641738 on overall and cardiovascular disease (CVD) specific mortality among subjects with or without NAFLD. NAFLD diagnosis was based on liver ultrasound at the baseline. After this and other comprehensive examinations, 958 middle-aged Finns, 249 with NAFLD, were followed for 21 years. The mortality data was gathered from the National Death Registry. After multiple adjustments, the NAFLD individuals with MetS had increased risk of overall mortality as compared to the NAFLD subjects without MetS [2.054 (1.011-4.173, p = .046)]. However, PNPLA3 rs738409 [1.049 (0.650-1.692, p = .844)], TM6SF2 rs58542926 [0.721 (0.369-1.411, p = .340)] or MBOAT7 rs641738 [0.885 (0.543-1.439, p = .621)] did not affect the overall mortality. MetS was also a marker of increased risk of CVD mortality (15% vs. 2%, p = .013) while genetic polymorphisms did not affect CVD mortality. In conclusion, MetS, but not the gene polymorphisms studied, predicts increased overall and CVD-specific mortality among NAFLD subjects.
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Affiliation(s)
- Aki Juhani Käräjämäki
- Department of Gastroenterology, Vaasa Central Hospital, Vaasa, Finland.,Research Unit of Internal Medicine, Medical Research Center Oulu, Oulu University Hospital, University of Oulu, Oulu, Finland
| | - Janne Hukkanen
- Research Unit of Internal Medicine, Medical Research Center Oulu, Oulu University Hospital, University of Oulu, Oulu, Finland
| | - Heikki Kauma
- Research Unit of Internal Medicine, Medical Research Center Oulu, Oulu University Hospital, University of Oulu, Oulu, Finland
| | - Y Antero Kesäniemi
- Research Unit of Internal Medicine, Medical Research Center Oulu, Oulu University Hospital, University of Oulu, Oulu, Finland
| | - Olavi Ukkola
- Research Unit of Internal Medicine, Medical Research Center Oulu, Oulu University Hospital, University of Oulu, Oulu, Finland
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Abstract
Fatty liver disease (FLD) affects more than one-third of the population in the western world and an increasing number of children in the United States. It is a leading cause of obesity and liver transplantation. Mechanistic insights into the causes of FLD are urgently needed since no therapeutic intervention has proven to be effective. A sequence variation in patatin like phospholipase domain-containing protein 3 (PNPLA3), rs 738409, is strongly associated with the progression of fatty liver disease. The resulting mutant causes a substitution of isoleucine to methionine at position 148. The underlying mechanism of this disease remains unsolved although several studies have illuminated key insights into its pathogenesis. This review highlights the progress in our understanding of PNPLA3 function in lipid droplet dynamics and explores possible therapeutic interventions to ameliorate this human health hazard.
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Affiliation(s)
- Soumik Basu Ray
- Eugene McDermott Center for Human Growth and Development, Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX, USA
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Machado CM, Leite NC, França PH, Cardoso CR, Salles GF, Villela-Nogueira CA. PNPLA3 gene polymorphism in Brazilian patients with type 2 diabetes: A prognostic marker beyond liver disease? Nutr Metab Cardiovasc Dis 2019; 29:965-971. [PMID: 31377187 DOI: 10.1016/j.numecd.2019.06.002] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2019] [Revised: 06/06/2019] [Accepted: 06/06/2019] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Genetic factors may impact nonalcoholic fatty liver disease (NAFLD) severity. We aimed to assess the prevalence of patatin-like phospholipase domain-containing 3 protein (PNPLA3) gene rs738409 C > G polymorphism in Brazilian individuals with type 2 diabetes and to investigate its association with liver disease severity, diabetic chronic degenerative complications, and metabolic control. METHODS AND RESULTS PNPLA3 genotyping was performed and classified as CC, CG, and GG. Clinical and laboratory data were obtained, including chronic degenerative diabetes complications. Liver stiffness and steatosis were evaluated by transient hepatic elastography with CAP using FibroScan®. Multiple logistic regression was performed to investigate the association of PNPLA3 G allele with clinical and laboratory variables and with hepatic fibrosis/steatosis. Three hundred three patients were included (118 male, mean age 59 ± 9.5 years). The G allele frequency was 32.5% (CC 47%, CG 41%, and GG 12%). Significant liver fibrosis and severe steatosis were diagnosed in 26% and 43% of patients, respectively. The variables independently associated with the G allele were coronary artery disease (OR: 2.25; 95% CI: 1.03-4.88; p = 0.04), better glycemic control (OR for having an HbA1c ≥ 8% [64 mmol/mol]: 0.53; 95% CI: 0.31-0.89; p = 0.01), and significant liver fibrosis (OR: 1.82; 95% CI: 1.04-3.17; p = 0.03). CONCLUSION In individuals with diabetes and NAFLD, PNPLA3 gene rs738409 C > G polymorphism is a marker for the risk of significant liver fibrosis and cardiovascular disease and may be associated with better glycemic control.
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Affiliation(s)
- Carolina M Machado
- School of Medicine, Internal Medicine Department and Clementino Fraga Filho University Hospital, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
| | - Nathalie C Leite
- School of Medicine, Internal Medicine Department and Clementino Fraga Filho University Hospital, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Paulo H França
- University of Joinville, UNIVILLE, Joinville, Santa Catarina, Brazil
| | - Claudia R Cardoso
- School of Medicine, Internal Medicine Department and Clementino Fraga Filho University Hospital, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Gil F Salles
- School of Medicine, Internal Medicine Department and Clementino Fraga Filho University Hospital, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Cristiane A Villela-Nogueira
- School of Medicine, Internal Medicine Department and Clementino Fraga Filho University Hospital, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
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41
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El Saeed KM, Ahmed OA, Khalifa MO, Fahmy EM. Detection of patatin-like phospholipase domain-containing protein 3 in nonalcoholic fatty liver disease among egyptian patients. THE EGYPTIAN JOURNAL OF INTERNAL MEDICINE 2019; 31:273-280. [DOI: 10.4103/ejim.ejim_43_18] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2018] [Accepted: 07/04/2018] [Indexed: 11/04/2022] Open
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Young KA, Palmer ND, Fingerlin TE, Langefeld CD, Norris JM, Wang N, Xiang AH, Guo X, Williams AH, Chen YDI, Taylor KD, Rotter JI, Raffel LJ, Goodarzi MO, Watanabe RM, Wagenknecht LE. Genome-Wide Association Study Identifies Loci for Liver Enzyme Concentrations in Mexican Americans: The GUARDIAN Consortium. Obesity (Silver Spring) 2019; 27:1331-1337. [PMID: 31219225 PMCID: PMC6656610 DOI: 10.1002/oby.22527] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2019] [Accepted: 04/18/2019] [Indexed: 12/18/2022]
Abstract
OBJECTIVE Populations of Mexican American ancestry are at an increased risk for nonalcoholic fatty liver disease. The objective of this study was to determine whether loci in known and novel genes were associated with variation in aspartate aminotransferase (AST) (n = 3,644), alanine aminotransferase (ALT) (n = 3,595), and gamma-glutamyl transferase (GGT) (n = 1,577) levels by conducting the first genome-wide association study (GWAS) of liver enzymes, which commonly measure liver function, in individuals of Mexican American ancestry. METHODS Levels of AST, ALT, and GGT were determined by enzymatic colorimetric assays. A multi-cohort GWAS of individuals of Mexican American ancestry was performed. Single-nucleotide polymorphisms (SNP) were tested for association with liver outcomes by multivariable linear regression using an additive genetic model. Association analyses were conducted separately in each cohort, followed by a nonparametric meta-analysis. RESULTS In the PNPLA3 gene, rs4823173 (P = 3.44 × 10-10 ), rs2896019 (P = 7.29 × 10-9 ), and rs2281135 (P = 8.73 × 10-9 ) were significantly associated with AST levels. Although not genome-wide significant, these same SNPs were the top hits for ALT (P = 7.12 × 10-8 , P = 1.98 × 10-7 , and P = 1.81 × 10-7 , respectively). The strong correlation (r2 = 1.0) for these SNPs indicated a single hit in the PNPLA3 gene. No genome-wide significant associations were found for GGT. CONCLUSIONS PNPLA3, a locus previously identified with ALT, AST, and nonalcoholic fatty liver disease in European and Japanese GWAS, is also associated with liver enzymes in populations of Mexican American ancestry.
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Affiliation(s)
- Kendra A Young
- Department of Epidemiology, Colorado School of Public Health, University of Colorado Denver, Aurora, Colorado, USA
| | - Nicholette D Palmer
- Department of Biochemistry, School of Medicine, Wake Forest University, Winston-Salem, North Carolina, USA
| | - Tasha E Fingerlin
- Department of Epidemiology, Colorado School of Public Health, University of Colorado Denver, Aurora, Colorado, USA
- Center for Genes, Environment, and Health, National Jewish Health, Denver, Colorado, USA
| | - Carl D Langefeld
- Department of Biostatistical Sciences, School of Medicine, Wake Forest University, Winston-Salem, North Carolina, USA
| | - Jill M Norris
- Department of Epidemiology, Colorado School of Public Health, University of Colorado Denver, Aurora, Colorado, USA
| | - Nan Wang
- Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
| | - Anny H Xiang
- Research and Evaluation Branch, Kaiser Permanente of Southern California, Pasadena, California, USA
| | - Xiuqing Guo
- Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute, Harbor-UCLA Medical Center, Torrance, California, USA
| | - Adrienne H Williams
- Department of Biostatistical Sciences, School of Medicine, Wake Forest University, Winston-Salem, North Carolina, USA
| | - Yii-Der I Chen
- Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute, Harbor-UCLA Medical Center, Torrance, California, USA
- Department of Pediatrics, Los Angeles Biomedical Research Institute, Harbor-UCLA Medical Center, Torrance, California, USA
| | - Kent D Taylor
- Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute, Harbor-UCLA Medical Center, Torrance, California, USA
- Department of Pediatrics, Los Angeles Biomedical Research Institute, Harbor-UCLA Medical Center, Torrance, California, USA
| | - Jerome I Rotter
- Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute, Harbor-UCLA Medical Center, Torrance, California, USA
- Department of Pediatrics, Los Angeles Biomedical Research Institute, Harbor-UCLA Medical Center, Torrance, California, USA
| | - Leslie J Raffel
- Medical Genetics Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Mark O Goodarzi
- Medical Genetics Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
- Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Richard M Watanabe
- Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
| | - Lynne E Wagenknecht
- Division of Public Health Sciences, School of Medicine, Wake Forest University, Winston-Salem, North Carolina, USA
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Lutz SZ, Hennige AM, Peter A, Kovarova M, Totsikas C, Machann J, Kröber SM, Sperl B, Schleicher E, Schick F, Heni M, Ullrich A, Häring HU, Stefan N. The Gly385(388)Arg Polymorphism of the FGFR4 Receptor Regulates Hepatic Lipogenesis Under Healthy Diet. J Clin Endocrinol Metab 2019; 104:2041-2053. [PMID: 30541128 DOI: 10.1210/jc.2018-01573] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/20/2018] [Accepted: 12/07/2018] [Indexed: 12/12/2022]
Abstract
CONTEXT The effect of a lifestyle intervention to reduce liver fat content in nonalcoholic fatty liver disease in humans is influenced by genetics. We hypothesized that the amino acid exchange in human Gly388Arg (mouse homolog: Gly385Arg) in fibroblast growth factor receptor 4 (FGFR4), which regulates bile acid, lipid, and glucose metabolism, could determine hepatic lipid accumulation and insulin sensitivity. Mechanisms of this substitution were studied in mice under normal chow and high-fat diets. DESIGN In humans, the Gly388Arg polymorphism was studied for its relationship with changes in liver fat content and insulin sensitivity during 9 months of a lifestyle intervention. We also studied a knock-in mouse strain with an Arg385 allele introduced into the murine FGFR4 gene under normal chow and high-fat diets. RESULTS In humans, the FGFR4 Arg388 allele was not associated with liver fat content or insulin sensitivity in subjects who were overweight and obese before lifestyle intervention. However, it was associated with less decrease in liver fat content and less increase in insulin sensitivity during the intervention. In mice receiving normal chow, the FGFR4 Arg385 allele was associated with elevated hepatic triglyceride content, altered hepatic lipid composition, and increased hepatic expression of genes inducing de novo lipogenesis and glycolysis. Body fat mass and distribution, glucose tolerance, and insulin sensitivity were unaltered. The FGFR4 Arg385 allele had no effect on glucose or lipid metabolism under the high-fat diet. CONCLUSION Our data indicate that the FGFR4 Arg388(385) allele affects hepatic lipid and glucose metabolism specifically during healthy caloric intake.
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Affiliation(s)
- Stefan Z Lutz
- Department of Internal Medicine, Division of Endocrinology, Diabetology, Vascular Disease, Nephrology and Clinical Chemistry, University of Tübingen, Tübingen, Germany
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany
- German Center for Diabetes Research, Munich-Neuherberg, Germany
| | - Anita M Hennige
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany
- German Center for Diabetes Research, Munich-Neuherberg, Germany
| | - Andreas Peter
- Department of Internal Medicine, Division of Endocrinology, Diabetology, Vascular Disease, Nephrology and Clinical Chemistry, University of Tübingen, Tübingen, Germany
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany
- German Center for Diabetes Research, Munich-Neuherberg, Germany
| | - Marketa Kovarova
- Department of Internal Medicine, Division of Endocrinology, Diabetology, Vascular Disease, Nephrology and Clinical Chemistry, University of Tübingen, Tübingen, Germany
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany
- German Center for Diabetes Research, Munich-Neuherberg, Germany
| | - Charisis Totsikas
- Department of Internal Medicine, Division of Endocrinology, Diabetology, Vascular Disease, Nephrology and Clinical Chemistry, University of Tübingen, Tübingen, Germany
| | - Jürgen Machann
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany
- German Center for Diabetes Research, Munich-Neuherberg, Germany
- Section on Experimental Radiology, Department of Diagnostic and Interventional Radiology, University of Tübingen, Tübingen, Germany
| | - Stefan M Kröber
- Institute of Pathology, University of Tübingen, Tübingen, Germany
| | - Bianca Sperl
- Department of Molecular Biology, Max-Planck-Institute of Biochemistry, Martinsried, Germany
| | - Erwin Schleicher
- Department of Internal Medicine, Division of Endocrinology, Diabetology, Vascular Disease, Nephrology and Clinical Chemistry, University of Tübingen, Tübingen, Germany
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany
- German Center for Diabetes Research, Munich-Neuherberg, Germany
| | - Fritz Schick
- Section on Experimental Radiology, Department of Diagnostic and Interventional Radiology, University of Tübingen, Tübingen, Germany
| | - Martin Heni
- Department of Internal Medicine, Division of Endocrinology, Diabetology, Vascular Disease, Nephrology and Clinical Chemistry, University of Tübingen, Tübingen, Germany
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany
- German Center for Diabetes Research, Munich-Neuherberg, Germany
| | - Axel Ullrich
- Department of Molecular Biology, Max-Planck-Institute of Biochemistry, Martinsried, Germany
| | - Hans-Ulrich Häring
- Department of Internal Medicine, Division of Endocrinology, Diabetology, Vascular Disease, Nephrology and Clinical Chemistry, University of Tübingen, Tübingen, Germany
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany
- German Center for Diabetes Research, Munich-Neuherberg, Germany
| | - Norbert Stefan
- Department of Internal Medicine, Division of Endocrinology, Diabetology, Vascular Disease, Nephrology and Clinical Chemistry, University of Tübingen, Tübingen, Germany
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany
- German Center for Diabetes Research, Munich-Neuherberg, Germany
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Zhou JH, Cai JJ, She ZG, Li HL. Noninvasive evaluation of nonalcoholic fatty liver disease: Current evidence and practice. World J Gastroenterol 2019; 25:1307-1326. [PMID: 30918425 PMCID: PMC6429343 DOI: 10.3748/wjg.v25.i11.1307] [Citation(s) in RCA: 157] [Impact Index Per Article: 26.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2019] [Revised: 02/20/2019] [Accepted: 02/22/2019] [Indexed: 02/06/2023] Open
Abstract
With the increasing number of individuals with diabetes and obesity, nonalcoholic fatty liver disease (NAFLD) is becoming increasingly prevalent, affecting one-quarter of adults worldwide. The spectrum of NAFLD ranges from simple steatosis or nonalcoholic fatty liver (NAFL) to nonalcoholic steatohepatitis (NASH). NAFLD, especially NASH, may progress to fibrosis, leading to cirrhosis and hepatocellular carcinoma. NAFLD can impose a severe economic burden, and patients with NAFLD-related terminal or deteriorative liver diseases have become one of the main groups receiving liver transplantation. The increasing prevalence of NAFLD and the severe outcomes of NASH make it necessary to use effective methods to identify NAFLD. Although recognized as the gold standard, biopsy is limited by its sampling bias, poor acceptability, and severe complications, such as mortality, bleeding, and pain. Therefore, noninvasive methods are urgently needed to avoid biopsy for diagnosing NAFLD. This review discusses the current noninvasive methods for assessing NAFLD, including steatosis, NASH, and NAFLD-related fibrosis, and explores the advantages and disadvantages of measurement tools. In addition, we analyze potential noninvasive biomarkers for tracking disease processes and monitoring treatment effects, and explore effective algorithms consisting of imaging and nonimaging biomarkers for diagnosing advanced fibrosis and reducing unnecessary biopsies in clinical practice.
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Affiliation(s)
- Jiang-Hua Zhou
- Department of Cardiology, Renmin Hospital of Wuhan University, Institute of Model Animal of Wuhan University, Wuhan 430071, Hubei Province, China
| | - Jing-Jing Cai
- Department of Cardiology, The 3rd Xiangya Hospital of Central South University, Changsha 410013, Hunan Province, China
| | - Zhi-Gang She
- Department of Cardiology, Renmin Hospital of Wuhan University, Institute of Model Animal of Wuhan University, Wuhan 430071, Hubei Province, China
| | - Hong-Liang Li
- Department of Cardiology, Renmin Hospital of Wuhan University, Institute of Model Animal of Wuhan University, Wuhan 430071, Hubei Province, China
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Younossi ZM. Non-alcoholic fatty liver disease - A global public health perspective. J Hepatol 2019; 70:531-544. [PMID: 30414863 DOI: 10.1016/j.jhep.2018.10.033] [Citation(s) in RCA: 1426] [Impact Index Per Article: 237.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2018] [Revised: 10/24/2018] [Accepted: 10/30/2018] [Indexed: 12/04/2022]
Abstract
As the epidemics of obesity and type 2 diabetes mellitus increase worldwide, the prevalence of non-alcoholic fatty liver disease (NAFLD) is increasing proportionately. The subtype of NAFLD which can be characterised as non-alcoholic steatohepatitis (NASH) is a potentially progressive liver disease that can lead to cirrhosis, hepatocellular carcinoma, liver transplantation, and death. NAFLD is also associated with extrahepatic manifestations such as chronic kidney disease, cardiovascular disease and sleep apnoea. NAFLD and NASH carry a large economic burden and create poor health-related quality of life. Despite this important burden, we are only beginning to understand its mechanisms of pathogenesis and the contribution of environmental and genetic factors to the risk of developing a progressive course of disease. Research is underway to identify appropriate non-invasive diagnostic methods and effective treatments. Although the risk of liver-related mortality is increased in patients with NAFLD and liver fibrosis stages F3 or F4, the leading cause of death is cardiovascular disease. Given the rapidly growing global burden of NAFLD and NASH, efforts must continue to find accurate non-invasive diagnostic and prognostic biomarkers, to develop effective treatments for individuals with advanced NASH and prevention methods for individuals at high risk of NAFLD and progressive liver disease.
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Affiliation(s)
- Zobair M Younossi
- Center for Liver Diseases, Department of Medicine, Inova Fairfax Hospital, Falls Church, VA, USA; Betty and Guy Beatty Center for Integrated Research, Inova Health System, Falls Church, VA, USA.
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Mancina RM, Ferri F, Farcomeni A, Molinaro A, Maffongelli A, Mischitelli M, Poli E, Parlati L, Burza MA, De Santis A, Attilia F, Rotondo C, Rando MM, Attilia ML, Ceccanti M, Ginanni Corradini S. A two gene-based risk score predicts alcoholic cirrhosis development in males with at-risk alcohol consumption. APPLICATION OF CLINICAL GENETICS 2019; 12:1-10. [PMID: 30666147 PMCID: PMC6330982 DOI: 10.2147/tacg.s187922] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Background Alcoholic cirrhosis represents 1% of all cause-of-deaths worldwide. Its incidence is higher in males and results from the combination of environmental and genetic factors. Among all the genetic determinants of alcoholic cirrhosis, the patatin-like phospholipase domain protein 3 (PNPLA3) rs738409 represents the most widely validated determinant. Recent cross-sectional studies on alcohol abusers identified transmembrane-6 superfamily member 2 (TM6SF2) rs58542926, membrane bound O-acyltransferase domain containing 7 (MBOAT7) rs641738, and cluster of differentiation 14 (CD14) rs2569190 as new genetic risk factors for alcoholic cirrhosis. We aimed to develop a gene-based risk score to predict the incidence of alcoholic cirrhosis in males with at-risk alcohol consumption. Materials and methods A total of 416 male at-risk alcohol drinkers were retrospectively examined. The association between alcoholic cirrhosis incidence and PNPLA3, CD14, TM6SF2, and MBOAT7 variants was tested. Age at onset of at-risk alcohol consumption, age, and body mass index (BMI) were included as covariates to determine the prediction score for alcoholic cirrhosis incidence by evaluating time-dependent receiver operating characteristic curves. Results We found that PNPLA3, CD14, and TM6SF2 were associated with alcoholic cirrhosis prevalence. PNPLA3 and CD14 were also associated with its incidence. The best predictive score formula was (age at onset of at-risk alcohol consumption × 0.1) + (number of CD14 allele T) + (number of PNPLA3 allele M) + (BMI × 0.1). A threshold of 7.27 was identified as cutoff for the predictive risk of alcoholic cirrhosis development in 36 years from the onset of at-risk alcohol consumption with 70.1% sensitivity and 78.7% specificity. Conclusion We developed the first score for alcoholic cirrhosis prediction that combines clinical and genetic factors.
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Affiliation(s)
- Rosellina Margherita Mancina
- Department of Molecular and Clinical Medicine, The Sahlgrenska Academy at the University of Gothenburg, Wallenberg Laboratory, Göteborg, Sweden,
| | - Flaminia Ferri
- Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy,
| | - Alessio Farcomeni
- Department of Public Health and Infectious Diseases, Sapienza University of Rome, Rome, Italy
| | - Antonio Molinaro
- Department of Molecular and Clinical Medicine, The Sahlgrenska Academy at the University of Gothenburg, Wallenberg Laboratory, Göteborg, Sweden,
| | - Angela Maffongelli
- Department of General Surgery, Urgency and Organ Transplantation, University Hospital "Paolo Giaccone", University of Palermo, Palermo, Italy
| | - Monica Mischitelli
- Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy,
| | - Edoardo Poli
- Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy,
| | - Lucia Parlati
- Hepatology Department, Université Paris Descartes, Cochin Hospital, APHP, Paris, France
| | - Maria Antonella Burza
- Department of Medicine, Division of Gastroenterology and Hepatology, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Adriano De Santis
- Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy,
| | - Fabio Attilia
- Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy,
| | - Claudia Rotondo
- Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy,
| | - Maria Margherita Rando
- Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy,
| | - Maria Luisa Attilia
- Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy,
| | - Mauro Ceccanti
- Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy,
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Jensen T, Wieland A, Cree-Green M, Nadeau K, Sullivan S. Clinical workup of fatty liver for the primary care provider. Postgrad Med 2018; 131:19-30. [PMID: 30496690 DOI: 10.1080/00325481.2019.1546532] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is quickly emerging as a global epidemic in parallel with the rise in obesity and the Metabolic Syndrome. NAFLD, once seen simply as a passive consequence of the Metabolic Syndrome (MetS), has been found to interact with other features of MetS to exacerbate insulin resistance, diabetes, and cardiovascular disease. NAFLD is also becoming the top indication for liver transplant and an important risk factor for hepatocellular carcinoma. Treatment of this disorder is limited mainly to lifestyle modifications to promote weight loss along with consideration for off-label use of certain medications, but recent progression in clinical trials means more effective treatments are on the horizon. Therefore, the primary care provider must be prepared to recognize and determine the severity of this disorder in order to optimize management. In this review, we will discuss risk factors for NAFLD, workup and differential, and finally, offer recommendations on screening.
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Affiliation(s)
- Thomas Jensen
- a Department of Endocrinology , University of Colorado School of Medicine , Aurora , CO , USA
| | - Amanda Wieland
- b Department of Hepatology , University of Colorado School of Medicine , Aurora , CO , USA
| | - Melanie Cree-Green
- c Department of Pediatric Endocrinology , University of Colorado School of Medicine , Aurora , CO , USA
| | - Kristen Nadeau
- c Department of Pediatric Endocrinology , University of Colorado School of Medicine , Aurora , CO , USA
| | - Shelby Sullivan
- d Department of Gastroenterology , University of Colorado Denver , Aurora , CO , USA
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Panera N, Barbaro B, Della Corte C, Mosca A, Nobili V, Alisi A. A review of the pathogenic and therapeutic role of nutrition in pediatric nonalcoholic fatty liver disease. Nutr Res 2018; 58:1-16. [DOI: 10.1016/j.nutres.2018.05.002] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2018] [Revised: 04/30/2018] [Accepted: 05/08/2018] [Indexed: 02/06/2023]
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Luo JJ, Cao HX, Yang RX, Zhang RN, Pan Q. PNPLA3 rs139051 is associated with phospholipid metabolite profile and hepatic inflammation in nonalcoholic fatty liver disease. World J Clin Cases 2018; 6:355-364. [PMID: 30283798 PMCID: PMC6163133 DOI: 10.12998/wjcc.v6.i10.355] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2018] [Revised: 07/27/2018] [Accepted: 08/04/2018] [Indexed: 02/05/2023] Open
Abstract
AIM To investigate the effect of PNPLA3 polymorphisms on serum lipidomics and pathological characteristics in nonalcoholic fatty liver disease (NAFLD).
METHODS Thirty-four biopsy-proven NAFLD patients from Northern, Central, and Southern China were subjected to stratification by genotyping their single nucleotide polymorphisms (SNPs) in PNPLA3. Ultra performance liquid chromatographytandem mass spectrometry was then employed to characterize the effects of PNPLA3 SNPs on serum lipidomics. In succession, correlation analysis revealed the association of PNPLA3-related lipid profile and hepatic pathological characteristics on a basis of steatosis, activity, and fibrosis assessment. The variant-based scoring of hepatocyte steatosis, ballooning, lobular inflammation, and liver fibrosis was finally performed so as to uncover the actions of lipidomics-affecting PNPLA3 SNPs in NAFLD-specific pathological alterations.
RESULTS PNPLA3 SNPs (rs139051, rs738408, rs738409, rs 2072906, rs2294918, rs2294919, and rs4823173) demonstrated extensive association with the serum lipidomics, especially phospholipid metabolites [lysophosphatidylcholine (LPC), lysophosphatidylcholine plasmalogen (LPCO), lysophosphatdylethanolamine (LPE), phosphatidylcholine (PC), choline plasmalogen (PCO), phosphatidylethanolamine (PE), ethanolamine plasmalogen (PEO)], of NAFLD patients. PNPLA3 rs139051 (A/A genotype) and rs2294918 (G/G genotype) dominated the up-regulatory effect on phospholipids of LPCs (LPC 17:0, LPC 18:0, LPC 20:0, LPC 20:1, LPC 20:2) and LPCOs (LPC O-16:1, LPC O-18:1). Moreover, subjects with high-level LPCs/LPCOs were predisposed to low-grade lobular inflammation of NAFLD (rho: -0.407 to -0.585, P < 0.05-0.001). The significant correlation of PNPLA3 rs139051 and inflammation grading [A/A vs A/G + G/G: 0.50 (0.00, 1.75) vs 1.50 (1.00, 2.00), P < 0.05] further demonstrated its pathological role based on the modulation of phospholipid metabolite profile.
CONCLUSION The A/A genotype at PNPLA3 rs139051 exerts an up-regulatory effect on serum phospholipids of LPCs and LPCOs, which are associated with low-grade lobular inflammation of NAFLD.
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Affiliation(s)
- Ji-Jun Luo
- Department of Gastroenterology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, China
| | - Hai-Xia Cao
- Department of Gastroenterology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, China
| | - Rui-Xu Yang
- Department of Gastroenterology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, China
| | - Rui-Nan Zhang
- Department of Gastroenterology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, China
| | - Qin Pan
- Department of Gastroenterology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, China
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Liang J, Liu Y, Liu J, Li Z, Fan Q, Jiang Z, Yan F, Wang Z, Huang P, Feng N. Chitosan-functionalized lipid-polymer hybrid nanoparticles for oral delivery of silymarin and enhanced lipid-lowering effect in NAFLD. J Nanobiotechnology 2018; 16:64. [PMID: 30176941 PMCID: PMC6122632 DOI: 10.1186/s12951-018-0391-9] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2018] [Accepted: 08/25/2018] [Indexed: 12/15/2022] Open
Abstract
Background Non-alcoholic fatty liver disease (NAFLD) is a chronic disease that causes excessive hepatic lipid accumulation. Reducing hepatic lipid deposition is a key issue in treatment and inhibition of NAFLD evolution. Silymarin is a potent hepatoprotective agent; however, it has low oral bioavailability due to its poor aqueous solubility and low membrane permeability. Unfortunately, few studies have addressed the development of convenient oral nanocarriers that can efficiently deliver silymarin to the liver and enhance its lipid-lowering effect. We designed silymarin-loaded lipid polymer hybrid nanoparticles containing chitosan (CS-LPNs) to improve silymarin bioavailability and evaluated their lipid-lowering effect in adiponutrin/patatin-like phospholipase-3 I148M transgenic mice, an NAFLD model. Results Compared to chitosan-free nanoparticles, CS-LPNs showed 1.92-fold higher uptake by fatty liver cells. Additionally, CS-LPNs significantly reduced TG levels in fatty liver cells in an in vitro lipid deposition assay, suggesting their potential lipid-lowering effects. The oral bioavailability of silymarin from CS-LPNs was 14.38-fold higher than that from suspensions in rats. Moreover, compared with chitosan-free nanoparticles, CS-LPNs effectively reduced blood lipid levels (TG), improved liver function (AST and ALT), and reduced lipid accumulation in the livers of mice in vivo. Reduced macrovesicular steatosis in pathological tissue after CS-LPN treatment indicated their protective effect against liver steatosis in NAFLD. Conclusions CS-LPNs enhanced oral delivery of silymarin and exhibited a desirable lipid-lowering effect in a mouse model. These findings suggest that CS-LPNs may be a promising oral nanocarrier for NAFLD therapeutics. Electronic supplementary material The online version of this article (10.1186/s12951-018-0391-9) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Jun Liang
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Ying Liu
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Jinguang Liu
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Zhe Li
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Qiangyuan Fan
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Zifei Jiang
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Fei Yan
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Zhi Wang
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Peiwen Huang
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Nianping Feng
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
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