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Bril F, Elbert A. Metabolic dysfunction-associated steatotic liver disease and urinary system cancers: Mere coincidence or reason for concern? Metabolism 2025; 162:156066. [PMID: 39551388 DOI: 10.1016/j.metabol.2024.156066] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/03/2024] [Revised: 11/06/2024] [Accepted: 11/07/2024] [Indexed: 11/19/2024]
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a systemic disease characterized by insulin resistance and lipotoxicity. Its association with type 2 diabetes, cardiovascular disease, liver cirrhosis, and hepatocellular carcinoma are well described. However, the association of MASLD and extra-hepatic cancers has received significantly less attention. This narrative review will summarize the conflicting evidence regarding the association between MASLD and cancers of the urinary system, including renal cell carcinoma, urothelial carcinoma, and prostate adenocarcinoma. It will explore potential mechanisms that could be responsible for a higher risk of urinary system cancers in patients with MASLD. We hope that our comprehensive assessment of the literature will help the readers to better interpret the available evidence.
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Affiliation(s)
- Fernando Bril
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Alabama at Birmingham, Birmingham (UAB), AL, USA; UAB Comprehensive Diabetes Center, University of Alabama at Birmingham, Birmingham, AL, USA.
| | - Alicia Elbert
- Centro de Enfermedades Renales e Hipertension Arterial (CEREHA), Buenos Aires, Argentina
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Pérez-Mingan GC, Sierra-Merlano RM, Yepes I, Vergara MJP, Ortiz M, Peña B, Cano-Pérez E, Gómez-Camargo D. Relationship of Interleukin 6 with Hepatic Steatosis and Liver Fibrosis in Rheumatoid Arthritis at a Rheumatology Care Center in Cartagena, Colombia. Genes (Basel) 2024; 15:1639. [PMID: 39766906 PMCID: PMC11675702 DOI: 10.3390/genes15121639] [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: 11/22/2024] [Revised: 12/16/2024] [Accepted: 12/18/2024] [Indexed: 01/03/2025] Open
Abstract
BACKGROUND/OBJECTIVES This study aimed to investigate the association of IL-6 with steatotic liver disease (SLD) and liver fibrosis (LF) in rheumatoid arthritis (RA) patients at a rheumatology center in Cartagena de Indias, Colombia. METHODS This was a cross-sectional study that included RA and non-RA cases. The level of cellular expression of interleukin 6 (IL-6) was evaluated by flow cytometry in peripheral blood leukocytes, and the presence of SLD and LF was detected by elastosonography. The main outcome was to establish the association between the levels of cellular expression of IL-6 and the development of SLD and LF. RESULTS This study included 47 cases of RA and 34 cases on-RA, with a mean age of 54 and 55 years, respectively. The frequency of SLD was 55.3% in RA and 38.2% in non-RA. The frequency of LF was 12.8% in RA and 14.7% in non-RA, with no statistical difference. The levels of cellular expression of IL-6 were significantly higher in RA compared to non-RA. Cellular expression of IL-6 was associated with the presence of SLD (54% vs. 30.3%; p = 0.002). This association was not maintained in RA cases (49.5% vs. 47.6%; p = 0.571). No association was found between cellular expression of IL-6 and LF in the total population (43.8% vs. 42.7%; p = 0.813) nor in RA cases (59.41% vs. 48.3%; p = 0.526). CONCLUSIONS IL-6 levels were related to SLD in the evaluated sample, and RA was not a risk factor for SLD or LF. The prognostic role of IL-6 for SLD in patients with RA requires further studies.
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Affiliation(s)
- Gloria Caterine Pérez-Mingan
- Departamento de Medicina Interna, Facultad de Medicina, Universidad de Cartagena, Cartagena 130001, Colombia; (G.C.P.-M.); (R.M.S.-M.); (I.Y.)
| | - Rita Magola Sierra-Merlano
- Departamento de Medicina Interna, Facultad de Medicina, Universidad de Cartagena, Cartagena 130001, Colombia; (G.C.P.-M.); (R.M.S.-M.); (I.Y.)
| | - Ismael Yepes
- Departamento de Medicina Interna, Facultad de Medicina, Universidad de Cartagena, Cartagena 130001, Colombia; (G.C.P.-M.); (R.M.S.-M.); (I.Y.)
| | | | - Miguel Ortiz
- Programa de Medicina, Facultad de Ciencias de la Salud, Universidad del Sinú, Cartagena 130001, Colombia;
| | - Breiner Peña
- Programa de Medicina, Facultad de Ciencias de la Salud, Universidad del Magdalena, Santa Marta 470001, Colombia;
| | - Eder Cano-Pérez
- Grupo de Investigación UNIMOL, Facultad de Medicina, Universidad de Cartagena, Cartagena 130001, Colombia;
- Doctorado en Medicina Tropical, Facultad de Medicina, Universidad de Cartagena, Cartagena 130001, Colombia
| | - Doris Gómez-Camargo
- Grupo de Investigación UNIMOL, Facultad de Medicina, Universidad de Cartagena, Cartagena 130001, Colombia;
- Doctorado en Medicina Tropical, Facultad de Medicina, Universidad de Cartagena, Cartagena 130001, Colombia
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Arisaka O, Koyama S, Imataka G, Naganuma J, Arisaka T, Akatsuka S. The Unexpected Detection of Esophageal Varices Caused by Liver Cirrhosis in a 47-Year-Old Man Treated with a Growth Hormone in Childhood. Diseases 2024; 12:251. [PMID: 39452494 PMCID: PMC11507581 DOI: 10.3390/diseases12100251] [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: 09/09/2024] [Revised: 10/06/2024] [Accepted: 10/07/2024] [Indexed: 10/26/2024] Open
Abstract
Background: We report a rare case highlighting the progression of liver disease in a male patient with idiopathic childhood-onset growth hormone (GH) deficiency. Case presentation: The patient was diagnosed with hypopituitarism at six years old and was treated with thyroxine therapy and GH for his short stature, with testosterone added at the age of 15. GH therapy was discontinued when the patient was 18 years old, but thyroid and testosterone treatments continued. The patient had been taking medication for hyperlipidemia until the age of 30 and was noted to have impaired glucose tolerance at the age of 40, but HbA1c levels remained normal. At the age of 47, esophageal varices were incidentally discovered via endoscopy, revealing liver cirrhosis. Laboratory tests showed liver dysfunction and abnormal lipid levels, and hepatitis viral markers were absent. The patient had no history of drinking alcohol or smoking, and no family history of diabetes. Results: Ultimately, this case demonstrates that metabolic dysfunction-associated steatotic liver disease (MASLD/metabolic dysfunction-associated steatohepatitis (MASH)) is under-recognized in GH deficiency cases and can progress to liver cirrhosis. Conclusions: Therefore, careful evaluation of MASLD/MASH in childhood-onset GH deficiency is necessary, and GH replacement therapy should continue into adulthood, if possible.
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Affiliation(s)
- Osamu Arisaka
- Department of Pediatrics, Dokkyo Medical University, Tochigi 321-0293, Japan; (S.K.); (G.I.); (J.N.)
| | - Satomi Koyama
- Department of Pediatrics, Dokkyo Medical University, Tochigi 321-0293, Japan; (S.K.); (G.I.); (J.N.)
| | - George Imataka
- Department of Pediatrics, Dokkyo Medical University, Tochigi 321-0293, Japan; (S.K.); (G.I.); (J.N.)
| | - Junko Naganuma
- Department of Pediatrics, Dokkyo Medical University, Tochigi 321-0293, Japan; (S.K.); (G.I.); (J.N.)
| | - Takahiro Arisaka
- Department of Gastroenterology, Dokkyo Medical University, Tochigi 321-0293, Japan;
| | - Sei Akatsuka
- Department of Pediatrics, Koto Hospital, Tokyo 136-0072, Japan
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Mladenić K, Lenartić M, Marinović S, Polić B, Wensveen FM. The "Domino effect" in MASLD: The inflammatory cascade of steatohepatitis. Eur J Immunol 2024; 54:e2149641. [PMID: 38314819 DOI: 10.1002/eji.202149641] [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: 08/24/2023] [Revised: 01/17/2024] [Accepted: 01/17/2024] [Indexed: 02/07/2024]
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) is an increasingly common complication of obesity, affecting over a quarter of the global adult population. A key event in the pathophysiology of MASLD is the development of metabolic-associated steatohepatitis (MASH), which greatly increases the chances of developing cirrhosis and hepatocellular carcinoma. The underlying cause of MASH is multifactorial, but accumulating evidence indicates that the inflammatory process in the hepatic microenvironment typically follows a pattern that can be roughly divided into three stages: (1) Detection of hepatocyte stress by tissue-resident immune cells including γδ T cells and CD4-CD8- double-negative T cells, followed by their secretion of pro-inflammatory mediators, most notably IL-17A. (2) Recruitment of pro-inflammatory cells, mostly of the myeloid lineage, and initiation of inflammation through secretion of effector-type cytokines such as TNF, TGF-β, and IL-1β. (3) Escalation of the inflammatory response by recruitment of lymphocytes including Th17, CD8 T, and B cells leading to chronic inflammation, hepatic stellate cell activation, and fibrosis. Here we will discuss these three stages and how they are consecutively linked like falling domino tiles to the pathophysiology of MASH. Moreover, we will highlight the clinical potential of inflammation as a biomarker and therapeutic target for the treatment of MASLD.
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Affiliation(s)
- Karlo Mladenić
- Department of Histology and Embryology, Faculty of Medicine, University of Rijeka, Rijeka, Croatia
| | - Maja Lenartić
- Department of Histology and Embryology, Faculty of Medicine, University of Rijeka, Rijeka, Croatia
| | - Sonja Marinović
- Department of Histology and Embryology, Faculty of Medicine, University of Rijeka, Rijeka, Croatia
- Division of Molecular Medicine, Laboratory for Personalized Medicine, Ruđer Bošković Institute, Zagreb, Croatia
| | - Bojan Polić
- Department of Histology and Embryology, Faculty of Medicine, University of Rijeka, Rijeka, Croatia
| | - Felix M Wensveen
- Department of Histology and Embryology, Faculty of Medicine, University of Rijeka, Rijeka, Croatia
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Majeed M, Nagabhushanam K, Noureddin M, Paulose S, Barik C, Saklecha S, Mundkur L. A scientifically validated combination of garcinol, curcuminoids, and piperine for mild to moderate nonalcoholic steatohepatitis patients-results from a randomized, double-blind, placebo-controlled study. Front Nutr 2023; 10:1201186. [PMID: 38170037 PMCID: PMC10760641 DOI: 10.3389/fnut.2023.1201186] [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: 04/06/2023] [Accepted: 11/30/2023] [Indexed: 01/05/2024] Open
Abstract
Background Garcinol is a naturally occurring compound from the fruit rind of the Garcinia indica, with antioxidant, anti-inflammatory, and anticancer properties. Curcuminoids are the active molecule from the rhizome of Curcuma longa, studied extensively for its health benefits as an anti-inflammatory and antioxidant activities. Non-alcoholic steatohepatitis (NASH) is the progressive form of nonalcoholic steatohepatitis characterized by liver fat and inflammation. Objective To evaluate the clinical efficacy and safety of Garcinol, Curcuminoids and piperine (GCP) combination in patients with mild to moderate NASH in a randomized, double-blind, placebo-controlled study. Methods The patients received one tablet (450 mg) of GCP containing garcinol-50 mg, curcuminoids -250 mg and piperine 5 mg or a placebo (450 mg of microcrystalline cellulose) twice daily for 90 days. Changes in circulating aspartate aminotransferase (AST), alanine transaminase (ALT) levels, liver stiffness measurement (LSM), and controlled attenuation parameter (CAP) using Fibroscan were compared from baseline to day 90. Anthropometric parameters, serum levels of lipids, Interleukin (IL-6), hsCRP, and adiponectin were estimated. Safety was evaluated by laboratory parameters and by monitoring adverse events. Results Seventy-two patients were randomized and 63 (GCP = 32, Placebo = 31) completed the study. The mean age of the patients was 48.3 ± 8.7 years (36 males and 27 females). The mean reduction in AST (U/L) was 9.53 in GCP and 3.16 in placebo (p < 0.001) and that of ALT (U/L) was 13.47 in GCP and 7.43 in Placebo (p = 0.002). The liver stiffness and CAP scores showed a better reduction in GCP (0.56 kPa and 12.38 db/m) compared to placebo (0.064 kPa and 10.42 db/m) p < 0.05. Consequently, the noninvasive Fibroscan-AST (FAST) score reduction was also found to be significant in GCP compared to placebo. Additionally, body weight, lipid levels, hsCRP, and IL-6 in serum decreased, while adiponectin levels increased in GCP-supplemented participants compared to placebo. The combination of garcinol and curcuminoids was well tolerated with no significant changes in hematological and clinical laboratory parameters during the 90-day supplementation. Conclusion Our results suggest that GCP could be a possible supplement for the management of NASH.Clinical trial registration: https://clinicaltrials.gov/, identifier CTRI/2019/11/022147.
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Affiliation(s)
- Muhammed Majeed
- Sami-Sabinsa Group Limited, Bangalore, Karnataka, India
- Sabinsa Corporation, East Windsor, NJ, United States
| | | | - Mazen Noureddin
- Houston Liver Institute, Houston Research Institute, Houston, TX, United States
| | - Shaji Paulose
- Sami-Sabinsa Group Limited, Bangalore, Karnataka, India
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Infante-Menéndez J, López-Pastor AR, González-Illanes T, González-López P, Huertas-Lárez R, Rey E, González-Rodríguez Á, García-Monzón C, Patil NP, de Céniga MV, Baker AB, Gómez-Hernández A, Escribano O. Increased let-7d-5p in non-alcoholic fatty liver promotes insulin resistance and is a potential blood biomarker for diagnosis. Liver Int 2023; 43:1714-1728. [PMID: 37057737 PMCID: PMC10523911 DOI: 10.1111/liv.15581] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2022] [Revised: 02/15/2023] [Accepted: 03/26/2023] [Indexed: 04/15/2023]
Abstract
BACKGROUND AND AIMS The molecular mechanisms driving non-alcoholic fatty liver disease (NAFLD) are poorly understood; however, microRNAs might play a key role in these processes. We hypothesize that let-7d-5p could contribute to the pathophysiology of NAFLD and serve as a potential diagnostic biomarker. METHODS We evaluated let-7d-5p levels and its targets in liver biopsies from a cross-sectional study including patients with NAFLD and healthy donors, and from a mouse model of NAFLD. Moreover, the induction of let-7d-5p expression by fatty acids was evaluated in vitro. Further, we overexpressed let-7d-5p in vitro to corroborate the results observed in vivo. Circulating let-7d-5p and its potential as a NAFLD biomarker was determined in isolated extracellular vesicles from human plasma by RT-qPCR. RESULTS Our results demonstrate that hepatic let-7d-5p was significantly up-regulated in patients with steatosis, and this increase correlated with obesity and a decreased expression of AKT serine/threonine kinase (AKT), insulin-like growth factor 1 (IGF1), IGF-I receptor (IGF1R) and insulin receptor (INSR). These alterations were corroborated in a NAFLD mouse model. In vitro, fatty acids increased let-7d-5p expression, and its overexpression decreased AKT, IGF-IR and IR protein expression. Furthermore, let-7d-5p hindered AKT phosphorylation in vitro after insulin stimulation. Finally, circulating let-7d-5p significantly decreased in steatosis patients and receiver operating characteristic (ROC) analyses confirmed its utility as a diagnostic biomarker. CONCLUSIONS Our results highlight the emerging role of let-7d-5p as a potential therapeutic target for NAFLD since its overexpression impairs hepatic insulin signalling, and also, as a novel non-invasive biomarker for NAFLD diagnosis.
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Affiliation(s)
- Jorge Infante-Menéndez
- Laboratory of Hepatic and Cardiovascular Diseases, Biochemistry and Molecular Biology Department, School of Pharmacy, Complutense University of Madrid. Madrid, Spain
| | - Andrea R. López-Pastor
- Laboratory of Hepatic and Cardiovascular Diseases, Biochemistry and Molecular Biology Department, School of Pharmacy, Complutense University of Madrid. Madrid, Spain
| | - Tamara González-Illanes
- Laboratory of Hepatic and Cardiovascular Diseases, Biochemistry and Molecular Biology Department, School of Pharmacy, Complutense University of Madrid. Madrid, Spain
| | - Paula González-López
- Laboratory of Hepatic and Cardiovascular Diseases, Biochemistry and Molecular Biology Department, School of Pharmacy, Complutense University of Madrid. Madrid, Spain
| | - Raquel Huertas-Lárez
- Laboratory of Hepatic and Cardiovascular Diseases, Biochemistry and Molecular Biology Department, School of Pharmacy, Complutense University of Madrid. Madrid, Spain
| | - Esther Rey
- Liver Research Unit, Hospital Universitario Santa Cristina, Instituto de Investigación Sanitaria Princesa. Madrid, Spain
| | - Águeda González-Rodríguez
- Liver Research Unit, Hospital Universitario Santa Cristina, Instituto de Investigación Sanitaria Princesa. Madrid, Spain
- CIBER de Diabetes y Enfermedades Metabólicas Asociadas, Madrid, Spain
| | - Carmelo García-Monzón
- Liver Research Unit, Hospital Universitario Santa Cristina, Instituto de Investigación Sanitaria Princesa. Madrid, Spain
- CIBER de Enfermedades Hepáticas y Digestivas, Madrid, Spain
| | - Nikita P. Patil
- Department of Biomedical Engineering, University of Texas at Austin, Austin, TX, USA
| | - Melina Vega de Céniga
- Department of Angiology and Vascular Surgery, Hospital de Galdakao-Usansolo, Galdakao, Bizkaia, Spain
- Biocruces Bizkaia Health Research Institute, Barakaldo, Bizkaia, Spain
| | - Aaron B. Baker
- Department of Biomedical Engineering, University of Texas at Austin, Austin, TX, USA
| | - Almudena Gómez-Hernández
- Laboratory of Hepatic and Cardiovascular Diseases, Biochemistry and Molecular Biology Department, School of Pharmacy, Complutense University of Madrid. Madrid, Spain
| | - Oscar Escribano
- Laboratory of Hepatic and Cardiovascular Diseases, Biochemistry and Molecular Biology Department, School of Pharmacy, Complutense University of Madrid. Madrid, Spain
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Stiglund N, Hagström H, Stål P, Cornillet M, Björkström NK. Dysregulated peripheral proteome reveals NASH-specific signatures identifying patient subgroups with distinct liver biology. Front Immunol 2023; 14:1186097. [PMID: 37342340 PMCID: PMC10277514 DOI: 10.3389/fimmu.2023.1186097] [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: 03/14/2023] [Accepted: 05/22/2023] [Indexed: 06/22/2023] Open
Abstract
Background and aims Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease. The prognosis may vary from simple steatosis to more severe outcomes such as nonalcoholic steatohepatitis (NASH), liver cirrhosis, and hepatocellular carcinoma. The understanding of the biological processes leading to NASH is limited and non-invasive diagnostic tools are lacking. Methods The peripheral immunoproteome in biopsy-proven NAFL (n=35) and NASH patients (n=35) compared to matched, normal-weight healthy controls (n=15) was studied using a proximity extension assay, combined with spatial and single cell hepatic transcriptome analysis. Results We identified 13 inflammatory serum proteins that, independent of comorbidities and fibrosis stage, distinguished NASH from NAFL. Analysis of co-expression patterns and biological networks further revealed NASH-specific biological perturbations indicative of temporal dysregulation of IL-4/-13, -10, -18, and non-canonical NF-kβ signaling. Of the identified inflammatory serum proteins, IL-18 and EN-RAGE as well as ST1A1 mapped to hepatic macrophages and periportal hepatocytes, respectively, at the single cell level. The signature of inflammatory serum proteins further permitted identification of biologically distinct subgroups of NASH patients. Conclusion NASH patients have a distinct inflammatory serum protein signature, which can be mapped to the liver parenchyma, disease pathogenesis, and identifies subgroups of NASH patients with altered liver biology.
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Affiliation(s)
- Natalie Stiglund
- Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Hannes Hagström
- Department of Upper GI, Karolinska University Hospital, Stockholm, Sweden
- Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden
| | - Per Stål
- Department of Upper GI, Karolinska University Hospital, Stockholm, Sweden
- Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden
| | - Martin Cornillet
- Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Niklas K. Björkström
- Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
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The Role of Growth Hormone and Insulin Growth Factor 1 in the Development of Non-Alcoholic Steato-Hepatitis: A Systematic Review. Cells 2023; 12:cells12040517. [PMID: 36831184 PMCID: PMC9954460 DOI: 10.3390/cells12040517] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2023] [Revised: 01/30/2023] [Accepted: 02/02/2023] [Indexed: 02/08/2023] Open
Abstract
Diabetic and obese patients have a high prevalence of non-alcoholic fatty liver disease (NAFLD). This condition groups a spectrum of conditions varying from simple steatosis to non-alcoholic steatohepatitis (NASH), with or without fibrosis. Multiple factors are involved in the development of NAFLD. However, details about its pathogenesis and factors that promote the progression to NASH are still missing. Growth hormone (GH) and insulin-like growth factor 1 (IGF-1) regulate metabolic, immune, and hepatic stellate cell functions. Increasing evidence suggests they may have roles in the progression from NAFLD to NASH. Following the PRISMA reporting guidelines, we conducted a systematic review to evaluate all clinical and experimental studies published in the literature correlating GH and IGF-1 to inflammation and fibrosis in NAFLD and NASH. Our results showed that GH and IGF-1 have a fundamental role in the pathogenesis of NASH, acting in slightly different ways to produce a synergic effect. Indeed, GH may mediate its protective effect in the pathogenesis of NASH by regulating lipogenesis pathways, while IGF-1 has the same effect by regulating cholesterol transport. Therefore, they could be used as therapeutic strategies in preventing NAFLD progression to NASH.
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Ohkubo R, Mu WC, Wang CL, Song Z, Barthez M, Wang Y, Mitchener N, Abdullayev R, Lee YR, Ma Y, Curtin M, Srinivasan S, Zhang X, Yang F, Sudmant PH, Pisco AO, Neff N, Haynes CM, Chen D. The hepatic integrated stress response suppresses the somatotroph axis to control liver damage in nonalcoholic fatty liver disease. Cell Rep 2022; 41:111803. [PMID: 36516757 PMCID: PMC9825120 DOI: 10.1016/j.celrep.2022.111803] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2022] [Revised: 10/14/2022] [Accepted: 11/18/2022] [Indexed: 12/15/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) can be ameliorated by calorie restriction, which leads to the suppressed somatotroph axis. Paradoxically, the suppressed somatotroph axis is associated with patients with NAFLD and is correlated with the severity of fibrosis. How the somatotroph axis becomes dysregulated and whether the repressed somatotroph axis impacts liver damage during the progression of NAFLD are unclear. Here, we identify a regulatory branch of the hepatic integrated stress response (ISR), which represses the somatotroph axis in hepatocytes through ATF3, resulting in enhanced cell survival and reduced cell proliferation. In mouse models of NAFLD, the ISR represses the somatotroph axis, leading to reduced apoptosis and inflammation but decreased hepatocyte proliferation and exacerbated fibrosis in the liver. NAD+ repletion reduces the ISR, rescues the dysregulated somatotroph axis, and alleviates NAFLD. These results establish that the hepatic ISR suppresses the somatotroph axis to control cell fate decisions and liver damage in NAFLD.
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Affiliation(s)
- Rika Ohkubo
- Metabolic Biology Graduate Program, University of California, Berkeley, Berkeley, CA 94720, USA; Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA
| | - Wei-Chieh Mu
- Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA; Endocrinology Graduate Program, University of California, Berkeley, Berkeley, CA 94720, USA
| | - Chih-Ling Wang
- Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA
| | - Zehan Song
- Metabolic Biology Graduate Program, University of California, Berkeley, Berkeley, CA 94720, USA; Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA
| | - Marine Barthez
- Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA
| | - Yifei Wang
- Metabolic Biology Graduate Program, University of California, Berkeley, Berkeley, CA 94720, USA; Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA
| | - Nathaniel Mitchener
- Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA
| | - Rasul Abdullayev
- Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA
| | - Yeong Rim Lee
- Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA; Endocrinology Graduate Program, University of California, Berkeley, Berkeley, CA 94720, USA
| | - Yuze Ma
- Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA
| | - Megan Curtin
- Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA
| | - Suraj Srinivasan
- Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA
| | - Xingjia Zhang
- Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA
| | - Fanghan Yang
- Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA; Endocrinology Graduate Program, University of California, Berkeley, Berkeley, CA 94720, USA
| | - Peter H Sudmant
- Department of Integrative Biology, University of California, Berkeley, Berkeley, CA 94720, USA; Center for Computational Biology, University of California, Berkeley, Berkeley, CA 94720, USA
| | | | - Norma Neff
- Chan Zuckerberg Biohub, San Francisco, CA, USA
| | - Cole M Haynes
- Department of Molecular, Cell and Cancer Biology, UMass-Chan Medical School, Worcester, MA 01605, USA
| | - Danica Chen
- Metabolic Biology Graduate Program, University of California, Berkeley, Berkeley, CA 94720, USA; Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA; Endocrinology Graduate Program, University of California, Berkeley, Berkeley, CA 94720, USA.
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Ikewaki N, Levy GA, Kurosawa G, Iwasaki M, Dedeepiya VD, Vaddi S, Senthilkumar R, Preethy S, Abraham SJ. Hepatoprotective Effects of Aureobasidium pullulans Derived β 1,3-1,6 Glucans in a Murine Model of Non-alcoholic Steatohepatitis. J Clin Exp Hepatol 2022; 12:1428-1437. [PMID: 36340302 PMCID: PMC9630018 DOI: 10.1016/j.jceh.2022.06.008] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Accepted: 06/21/2022] [Indexed: 12/12/2022] Open
Abstract
Background Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are highly prevalent conditions characterized by inflammation and fibrosis of the liver, which can progress to cirrhosis and hepatocellular carcinoma if left untreated. Conventional modalities are mainly symptomatic, with no definite solution. Beta-glucan-based biological response modifiers are a potential strategy in lieu of their beneficial metabolic effects. Aureobasidium pullulans strains AFO-202 and N-163 beta-glucans were evaluated for anti-fibrotic and anti-inflammatory hepatoprotective potentials in a NASH animal model in this study. Methods In the STAM™ murine model of NASH, five groups were studied for 8 weeks: (1) vehicle (RO water), (2) AFO-202 beta-glucan; (3) N-163 beta-glucan, (4) AFO-202+N-163 beta-glucan, and (5) telmisartan (standard pharmacological intervention). Evaluation of biochemical parameters in plasma and hepatic histology including Sirius red staining and F4/80 immunostaining were performed. Results AFO-202 beta-glucan significantly decreased inflammation-associated hepatic cell ballooning and steatosis. N-163 beta-glucan decreased fibrosis and inflammation significantly (P value < 0.05). The combination of AFO-202 with N-163 significantly decreased the NAFLD Activity Score (NAS) compared with other groups. Conclusion This preclinical study supports the potential of N-163 and AFO-202 beta-glucans alone or in combination as potential preventive and therapeutic agent(s), for NASH.
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Key Words
- ALT, Alanine aminotransferase
- ARRIVE, Animal Research: Reporting of In Vivo Experiments
- IL, Interleukin
- MCP-1, Monocyte chemoattractant protein-1
- NAFLD, Non-alcoholic fatty liver disease
- NAS, NAFLD Activity Score
- NASH, Non-alcoholic steatohepatitis
- PPAR, Peroxisome proliferator-activated receptor
- STAM, Stelic Animal Model
- TGF-β, Transforming growth factor beta
- TIMPs, Tissue inhibitors of matrix metalloproteinases
- TNF-α, Tumor necrosis factor alpha
- anti-fibrotic
- anti-inflammatory
- beta-glucans
- hepatoprotective
- non-alcoholic fatty liver disease (NAFLD)
- non-alcoholic steatohepatitis (NASH)
- telmisartan
- αSMA, Smooth muscle alpha-actin
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Affiliation(s)
- Nobunao Ikewaki
- Department of Medical Life Science, Kyushu University of Health and Welfare, Japan
- Institute of Immunology, Junsei Educational Institute, Nobeoka, Miyazaki, Japan
| | - Gary A. Levy
- Medicine and Immunology, University of Toronto, Ontario, Canada
| | - Gene Kurosawa
- Department of Academic Research Support Promotion Facility, Center for Research Promotion and Support, Fujita Health University, Aichi, Japan
- MabGenesis KK, Nagoya, Japan
| | - Masaru Iwasaki
- Centre for Advancing Clinical Research (CACR), University of Yamanashi - School of Medicine, Chuo, Japan
| | - Vidyasagar D. Dedeepiya
- Mary-Yoshio Translational Hexagon (MYTH), Nichi-In Centre for Regenerative Medicine (NCRM), Chennai, India
| | | | - Rajappa Senthilkumar
- Fujio-Eiji Academic Terrain (FEAT), Nichi-In Centre for Regenerative Medicine (NCRM), Chennai, India
| | - Senthilkumar Preethy
- Fujio-Eiji Academic Terrain (FEAT), Nichi-In Centre for Regenerative Medicine (NCRM), Chennai, India
| | - Samuel J.K. Abraham
- Centre for Advancing Clinical Research (CACR), University of Yamanashi - School of Medicine, Chuo, Japan
- Mary-Yoshio Translational Hexagon (MYTH), Nichi-In Centre for Regenerative Medicine (NCRM), Chennai, India
- Antony- Xavier Interdisciplinary Scholastics (AXIS), GN Corporation Co. Ltd., Kofu, Japan
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11
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Turgut S, Acarer D, Seyit H, Pamuk N, Piskinpasa H, Bozkur E, Karabulut M, Cakir I. Insulin-Like Growth Factor-I Might be a Predictor for Severe Non-Alcoholic Fatty Liver Disease in Morbidly Obese Patients. Horm Metab Res 2022; 54:696-703. [PMID: 35588737 DOI: 10.1055/a-1856-7014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
The aim of the study was to compare the IGF-1 levels, metabolic and clinical parameters among the ultrasonographically classified non-alcoholic fatty liver disease (NAFLD) groups and determine the factors that may predict the NAFLD severity in patients with morbid obesity. This study was conducted on 316 morbidly obese patients (250 F/66 M). The data of patients before and 1st-year after bariatric surgery were recorded. According to the ultrasonographically NAFLD screening, patients with normal hepatic features were classified as Group 1(n=57), with mild and moderate NAFLD were classified as Group 2(n=219), and with severe NAFLD were classified as Group 3(n=40). IGF-1 standard deviation scores (SDSIGF1) were calculated according to age and gender. Parameters that could predict the presence and severity of NAFLD were evaluated. IGF-1 levels were significantly associated with Group 3 than Group 1(p=0.037), and the significance remained between the same groups when IGF-1 levels were standardized as SDSIGF1(p=0.036). Decreased levels of SDSIGF1 explained 5% of severe NAFLD than the normal group (p=0.036). Liver Diameter, FPG, ALT, AST, and GGT were also found as significant predictors for severe NAFLD. There were significant differences between pre-and postop values in all groups (p<0.001). This study showed that IGF-1 might be considered a sgnificant predictor of severe NAFLD in morbidly obese patients. It is crucial in clinical practice to determine predictive factors of NAFLD that could support the diagnosis accompanied by non-invasive imaging methods.
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Affiliation(s)
- Seda Turgut
- Endocrinology and Metabolism, University of Health Science Bakırköy Dr. Sadi Konuk Training and Research Hospital, İstanbul, Turkey
| | - Didem Acarer
- Endocrinology and Metabolism, University of Health Science Bakırköy Dr. Sadi Konuk Training and Research Hospital, İstanbul, Turkey
| | - Hakan Seyit
- General Surgery, University of Health Science Bakirkoy Dr. Sadi Konuk Trainig and Research Hospital, İstanbul, Turkey
| | - Naim Pamuk
- Endocrinology and Metabolism, University of Health Science Bakırköy Dr. Sadi Konuk Training and Research Hospital, İstanbul, Turkey
| | - Hamide Piskinpasa
- Endocrinology and Metabolism, University of Health Science Bakırköy Dr. Sadi Konuk Training and Research Hospital, İstanbul, Turkey
| | - Evin Bozkur
- Endocrinology and Metabolism, University of Health Science Bakırköy Dr. Sadi Konuk Training and Research Hospital, İstanbul, Turkey
| | - Mehmet Karabulut
- General Surgery, University of Health Science Bakirkoy Dr. Sadi Konuk Trainig and Research Hospital, İstanbul, Turkey
| | - Ilkay Cakir
- Endocrinology and Metabolism, University of Health Science Bakırköy Dr. Sadi Konuk Training and Research Hospital, İstanbul, Turkey
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12
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Dichtel LE, Corey KE, Haines MS, Chicote ML, Kimball A, Colling C, Simon TG, Long MT, Husseini J, Bredella MA, Miller KK. The GH/IGF-1 Axis Is Associated With Intrahepatic Lipid Content and Hepatocellular Damage in Overweight/Obesity. J Clin Endocrinol Metab 2022; 107:e3624-e3632. [PMID: 35779256 PMCID: PMC9387707 DOI: 10.1210/clinem/dgac405] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2022] [Indexed: 01/25/2023]
Abstract
CONTEXT Obesity is a state of relative growth hormone (GH) deficiency, and GH has been identified as a candidate disease-modifying target in nonalcoholic fatty liver disease (NAFLD) because of its lipolytic and anti-inflammatory properties. However, the GH/IGF-1 axis has not been well characterized in NAFLD. OBJECTIVE We aimed to investigate serum GH and IGF-1 levels in relation to intrahepatic lipid content (IHL) and markers of hepatocellular damage and fibrosis in NAFLD. METHODS This cross-sectional study included 102 adults (43% women; age 19-67; BMI ≥ 25 kg/m2) without type 2 diabetes. IHL was measured by magnetic resonance spectroscopy; NAFLD was defined by ≥ 5% IHL. Peak-stimulated GH in response to GH releasing hormone and arginine was assessed as was serum IGF-1 (LC/MS). RESULTS There was no difference in mean age, BMI, or sex distribution in NAFLD vs controls. Mean (± SD) IHL was higher in NAFLD vs controls (21.8 ± 13.3% vs 2.9 ± 1.1%, P < 0.0001). Mean peak-stimulated GH was lower in NAFLD vs controls (9.0 ± 6.3 vs 15.4 ± 11.2 ng/mL, P = 0.003), including after controlling for age, sex, visceral adipose tissue, and fasting glucose. In a stepwise model, peak-stimulated GH predicted 14.6% of the variability in IHL (P = 0.004). Higher peak-stimulated GH was also associated with lower ALT. Higher serum IGF-1 levels were associated with lower risk of liver fibrosis by Fibrosis-4 scores. CONCLUSION Individuals with NAFLD have lower peak-stimulated GH levels but similar IGF-1 levels as compared to controls. Higher peak-stimulated GH levels are associated with lower IHL and less hepatocellular damage. Higher IGF-1 levels are associated with more favorable fibrosis risk scores. These data implicate GH and IGF-1 as potential disease modifiers in the development and progression of NAFLD.
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Affiliation(s)
- Laura E Dichtel
- Correspondence: Laura Dichtel, MD, Neuroendocrine Unit, Massachusetts General Hospital, 55 Fruit Street, BUL457, Boston, MA 02114, USA.
| | - Kathleen E Corey
- Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA
| | - Melanie S Haines
- Neuroendocrine Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA
| | - Mark L Chicote
- Neuroendocrine Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA
| | - Allison Kimball
- Neuroendocrine Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA
| | - Caitlin Colling
- Neuroendocrine Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA
| | - Tracey G Simon
- Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA
| | - Michelle T Long
- Section of Gastroenterology, Boston Medical Center, Boston University School of Medicine, Boston, MA, USA
| | - Jad Husseini
- Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, 02114, USA
| | - Miriam A Bredella
- Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, 02114, USA
| | - Karen K Miller
- Neuroendocrine Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA
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13
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Dichtel LE, Cordoba-Chacon J, Kineman RD. Growth Hormone and Insulin-Like Growth Factor 1 Regulation of Nonalcoholic Fatty Liver Disease. J Clin Endocrinol Metab 2022; 107:1812-1824. [PMID: 35172328 PMCID: PMC9202731 DOI: 10.1210/clinem/dgac088] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Indexed: 11/19/2022]
Abstract
Patients with obesity have a high prevalence of nonalcoholic fatty liver disease (NAFLD), representing a spectrum of simple steatosis to nonalcoholic steatohepatitis (NASH), without and with fibrosis. Understanding the etiology of NAFLD is clinically relevant since NAFLD is an independent risk factor for diabetes and cardiovascular disease. In addition, NASH predisposes patients to the development of cirrhosis and hepatocellular carcinoma, and NASH cirrhosis represents the fastest growing indication for liver transplantation in the United States. It is appreciated that multiple factors are involved in the development and progression of NAFLD. Growth hormone (GH) and insulin-like growth factor 1 (IGF1) regulate metabolic, immune, and hepatic stellate cell function, and alterations in the production and function of GH is associated with obesity and NAFLD/NASH. Therefore, this review will focus on the potential role of GH and IGF1 in the regulation of hepatic steatosis, inflammation, and fibrosis.
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Affiliation(s)
- Laura E Dichtel
- Neuroendocrine Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Jose Cordoba-Chacon
- Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Illinois at Chicago, Chicago, IL, USA
| | - Rhonda D Kineman
- Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Illinois at Chicago, Chicago, IL, USA
- Jesse Brown VA Medical Center, Research and Development Division, Chicago, IL, USA
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14
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Duan Y, Pan X, Luo J, Xiao X, Li J, Bestman PL, Luo M. Association of Inflammatory Cytokines With Non-Alcoholic Fatty Liver Disease. Front Immunol 2022; 13:880298. [PMID: 35603224 PMCID: PMC9122097 DOI: 10.3389/fimmu.2022.880298] [Citation(s) in RCA: 153] [Impact Index Per Article: 51.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2022] [Accepted: 04/11/2022] [Indexed: 01/30/2023] Open
Abstract
Background Inflammatory cytokines have been considered to be significant factors contributing to the development and progression of non-alcoholic fatty liver disease (NAFLD). However, the role of inflammatory cytokines in NAFLD remains inconclusive. Objective This study aimed to evaluate the association between inflammatory cytokines and NAFLD. Methods PubMed, Web of Science, the Cochrane Library, and EMBASE databases were searched until 31 December 2021 to identify eligible studies that reported the association of inflammatory cytokine with NAFLD and its subtypes. We pooled odds ratios (ORs) and hazard risk (HRs) with 95% confidence intervals (CIs) and conducted heterogeneity tests. Sensitivity analysis and analysis for publication bias were also carried out. Results The search in the databases identified 51 relevant studies that investigated the association between 19 different inflammatory cytokines and NAFLD based on 36,074 patients and 47,052 controls. The results of the meta-analysis showed significant associations for C-reactive protein (CRP), interleukin-1β (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and intercellular adhesion molecule-1 (ICAM-1) with NAFLD (ORs of 1.41, 1.08, 1.50, 1.15 and 2.17, respectively). In contrast, we observed non-significant associations for interferon-γ (IFN-γ), insulin-like growth factor (IGF-II), interleukin-2 (IL-2), interleukin-4 (IL-4), interleukin-5 (IL-5), interleukin-7 (IL-7), interleukin-8 (IL-8), interleukin-10 (IL-10), interleukin-12 (IL-12), monocyte chemoattractant protein-1(MCP-1), and transforming growth factor-β (TGF-β) with NAFLD. Our results also showed that CRP, IL-1β, and TNF-α were significantly associated with non-alcoholic steatohepatitis (NASH) and hepatic fibrosis. Conclusions Our results indicated that increased CRP, IL‐1β, IL-6, TNF‐α, and ICAM-1 concentrations were significantly associated with increased risks of NAFLD. These inflammatory mediators may serve as biomarkers for NAFLD subjects and expect to provide new insights into the aetiology of NAFLD as well as early diagnosis and intervention.
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Affiliation(s)
- Yamei Duan
- Department of Maternal and Child Health, Xiangya School of Public Health, Central South University, Changsha, China
| | - Xiongfeng Pan
- Department of Maternal and Child Health, Xiangya School of Public Health, Central South University, Changsha, China
| | - Jiayou Luo
- Department of Maternal and Child Health, Xiangya School of Public Health, Central South University, Changsha, China
| | - Xiang Xiao
- Department of Maternal and Child Health, Xiangya School of Public Health, Central South University, Changsha, China
| | - Jingya Li
- Department of Maternal and Child Health, Xiangya School of Public Health, Central South University, Changsha, China
| | - Prince L. Bestman
- Department of Maternal and Child Health, Xiangya School of Public Health, Central South University, Changsha, China
| | - Miyang Luo
- Department of Epidemiology and Health Statistics, Xiangya School of Public Health, Central South University, Changsha, China
- *Correspondence: Miyang Luo,
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15
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McNeilly AD, Yianakas A, Gallagher JG, Tarlton J, Ashford ML, McCrimmon RJ. Central deficiency of IL-6Ra in mice impairs glucose-stimulated insulin secretion. Mol Metab 2022; 61:101488. [PMID: 35470093 PMCID: PMC9065900 DOI: 10.1016/j.molmet.2022.101488] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Revised: 03/16/2022] [Accepted: 03/28/2022] [Indexed: 11/16/2022] Open
Affiliation(s)
- Alison D McNeilly
- Division of Systems Medicine, School of Medicine, University of Dundee, Ninewells Hospital and Medical School, Dundee, DD1 9SY, UK.
| | - Adonis Yianakas
- Division of Systems Medicine, School of Medicine, University of Dundee, Ninewells Hospital and Medical School, Dundee, DD1 9SY, UK
| | - Jennifer G Gallagher
- Division of Systems Medicine, School of Medicine, University of Dundee, Ninewells Hospital and Medical School, Dundee, DD1 9SY, UK
| | - Jamie Tarlton
- Division of Systems Medicine, School of Medicine, University of Dundee, Ninewells Hospital and Medical School, Dundee, DD1 9SY, UK
| | - Michael Lj Ashford
- Division of Systems Medicine, School of Medicine, University of Dundee, Ninewells Hospital and Medical School, Dundee, DD1 9SY, UK
| | - Rory J McCrimmon
- Division of Systems Medicine, School of Medicine, University of Dundee, Ninewells Hospital and Medical School, Dundee, DD1 9SY, UK
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16
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Ding Y, Liu X, Yuan Y, Sheng Y, Li D, Ojha SC, Sun C, Deng C. THRSP identified as a potential hepatocellular carcinoma marker by integrated bioinformatics analysis and experimental validation. Aging (Albany NY) 2022; 14:1743-1766. [PMID: 35196258 PMCID: PMC8908915 DOI: 10.18632/aging.203900] [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: 01/30/2021] [Accepted: 01/17/2022] [Indexed: 11/25/2022]
Abstract
Hepatocellular carcinoma (HCC) is the most common malignant liver tumor with high mortality and poor prognosis worldwide. This study aimed to identify hub genes and investigate the underlying molecular mechanisms in HCC progression by integrated bioinformatics analysis and experimental validation. Based on the Gene Expression Omnibus (GEO) databases and The Cancer Genome Atlas (TCGA), 12 critical differential co-expression genes were identified between tumor and normal tissues. Via survival analysis, we found higher expression of LCAT, ACSM3, IGF1, SRD5A2, THRSP and ACADS was associated with better prognoses in HCC patients. Among which, THRSP was selected for the next investigations. We found that THRSP mRNA expression was negatively correlated with its methylation and closely associated with clinical characteristics in HCC patients. Moreover, THRSP expression had a negative correlation with the infiltration levels of several immune cells (e.g., B cells and CD4+ T cells). qRT-PCR verified that THRSP was lower expressed in HCC tissues and cell lines compared with control. Silencing of THRSP promoted the migration, invasion, proliferation, and inhibited cell apoptosis of HCCLM and Huh7 cell lines. Decreased expression of THRSP promoted HCC progression by NF-κB, ERK1/2, and p38 MAPK signaling pathways. In conclusion, THRSP might serve as a novel biomarker and therapeutic target of HCC.
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Affiliation(s)
- Yuxi Ding
- The Department of Infectious Diseases, The Affiliated Hospital of Southwest Medical University, Luzhou 646000, China.,The Department of Tuberculosis, The Affiliated Hospital of Southwest Medical University, Luzhou 646000, China.,Laboratory of Infection and Immunity, The Affiliated Hospital of Southwest Medical University, Luzhou 646000, China
| | - Xiaoling Liu
- The Department of Infectious Diseases, The Affiliated Hospital of Southwest Medical University, Luzhou 646000, China.,The Department of Tuberculosis, The Affiliated Hospital of Southwest Medical University, Luzhou 646000, China.,Laboratory of Infection and Immunity, The Affiliated Hospital of Southwest Medical University, Luzhou 646000, China
| | - Yue Yuan
- The Department of Infectious Diseases, The Affiliated Hospital of Southwest Medical University, Luzhou 646000, China.,The Department of Tuberculosis, The Affiliated Hospital of Southwest Medical University, Luzhou 646000, China.,Laboratory of Infection and Immunity, The Affiliated Hospital of Southwest Medical University, Luzhou 646000, China
| | - Yunjian Sheng
- The Department of Infectious Diseases, The Affiliated Hospital of Southwest Medical University, Luzhou 646000, China.,The Department of Tuberculosis, The Affiliated Hospital of Southwest Medical University, Luzhou 646000, China.,Laboratory of Infection and Immunity, The Affiliated Hospital of Southwest Medical University, Luzhou 646000, China
| | - Decheng Li
- The Department of Infectious Diseases, The Affiliated Hospital of Southwest Medical University, Luzhou 646000, China.,The Department of Tuberculosis, The Affiliated Hospital of Southwest Medical University, Luzhou 646000, China.,Laboratory of Infection and Immunity, The Affiliated Hospital of Southwest Medical University, Luzhou 646000, China
| | - Suvash Chandra Ojha
- The Department of Infectious Diseases, The Affiliated Hospital of Southwest Medical University, Luzhou 646000, China.,The Department of Tuberculosis, The Affiliated Hospital of Southwest Medical University, Luzhou 646000, China.,Laboratory of Infection and Immunity, The Affiliated Hospital of Southwest Medical University, Luzhou 646000, China
| | - Changfeng Sun
- The Department of Infectious Diseases, The Affiliated Hospital of Southwest Medical University, Luzhou 646000, China.,The Department of Tuberculosis, The Affiliated Hospital of Southwest Medical University, Luzhou 646000, China.,Laboratory of Infection and Immunity, The Affiliated Hospital of Southwest Medical University, Luzhou 646000, China
| | - Cunliang Deng
- The Department of Infectious Diseases, The Affiliated Hospital of Southwest Medical University, Luzhou 646000, China.,The Department of Tuberculosis, The Affiliated Hospital of Southwest Medical University, Luzhou 646000, China.,Laboratory of Infection and Immunity, The Affiliated Hospital of Southwest Medical University, Luzhou 646000, China
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17
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Towards Understanding the Direct and Indirect Actions of Growth Hormone in Controlling Hepatocyte Carbohydrate and Lipid Metabolism. Cells 2021; 10:cells10102532. [PMID: 34685512 PMCID: PMC8533955 DOI: 10.3390/cells10102532] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2021] [Revised: 09/20/2021] [Accepted: 09/23/2021] [Indexed: 02/06/2023] Open
Abstract
Growth hormone (GH) is critical for achieving normal structural growth. In addition, GH plays an important role in regulating metabolic function. GH acts through its GH receptor (GHR) to modulate the production and function of insulin-like growth factor 1 (IGF1) and insulin. GH, IGF1, and insulin act on multiple tissues to coordinate metabolic control in a context-specific manner. This review will specifically focus on our current understanding of the direct and indirect actions of GH to control liver (hepatocyte) carbohydrate and lipid metabolism in the context of normal fasting (sleep) and feeding (wake) cycles and in response to prolonged nutrient deprivation and excess. Caveats and challenges related to the model systems used and areas that require further investigation towards a clearer understanding of the role GH plays in metabolic health and disease are discussed.
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18
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Marques V, Afonso MB, Bierig N, Duarte-Ramos F, Santos-Laso Á, Jimenez-Agüero R, Eizaguirre E, Bujanda L, Pareja MJ, Luís R, Costa A, Machado MV, Alonso C, Arretxe E, Alustiza JM, Krawczyk M, Lammert F, Tiniakos DG, Flehmig B, Cortez-Pinto H, Banales JM, Castro RE, Normann A, Rodrigues CMP. Adiponectin, Leptin, and IGF-1 Are Useful Diagnostic and Stratification Biomarkers of NAFLD. Front Med (Lausanne) 2021; 8:683250. [PMID: 34249975 PMCID: PMC8260936 DOI: 10.3389/fmed.2021.683250] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2021] [Accepted: 05/10/2021] [Indexed: 12/15/2022] Open
Abstract
Background: Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease where liver biopsy remains the gold standard for diagnosis. Here we aimed to evaluate the role of circulating adiponectin, leptin, and insulin-like growth factor 1 (IGF-1) levels as non-invasive NAFLD biomarkers and assess their correlation with the metabolome. Materials and Methods: Leptin, adiponectin, and IGF-1 serum levels were measured by ELISA in two independent cohorts of biopsy-proven obese NAFLD patients and healthy-liver controls (discovery: 38 NAFLD, 13 controls; validation: 194 NAFLD, 31 controls) and correlated with clinical data, histology, genetic parameters, and serum metabolomics. Results: In both cohorts, leptin increased in NAFLD vs. controls (discovery: AUROC 0.88; validation: AUROC 0.83; p < 0.0001). The leptin levels were similar between obese and non-obese healthy controls, suggesting that obesity is not a confounding factor. In the discovery cohort, adiponectin was lower in non-alcoholic steatohepatitis (NASH) vs. non-alcoholic fatty liver (AUROC 0.87; p < 0.0001). For the validation cohort, significance was attained for homozygous for PNPLA3 allele c.444C (AUROC 0.63; p < 0.05). Combining adiponectin with specific serum lipids improved the assay performance (AUROC 0.80; p < 0.0001). For the validation cohort, IGF-1 was lower with advanced fibrosis (AUROC 0.67, p < 0.05), but combination with international normalized ratio (INR) and ferritin increased the assay performance (AUROC 0.81; p < 0.01). Conclusion: Serum leptin discriminates NAFLD, and adiponectin combined with specific lipids stratifies NASH. IGF-1, INR, and ferritin distinguish advanced fibrosis.
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Affiliation(s)
- Vanda Marques
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
| | - Marta B Afonso
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
| | | | - Filipa Duarte-Ramos
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal.,EPIUnit-Instituto de Saúde Pública, Universidade do Porto, Oporto, Portugal
| | - Álvaro Santos-Laso
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain
| | - Raul Jimenez-Agüero
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain
| | - Emma Eizaguirre
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain
| | - Luis Bujanda
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain.,National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, Instituto de Salud Carlos III), Madrid, Spain
| | | | - Rita Luís
- Department of Pathological Anatomy, Hospital de Santa Maria, Centro Hospitalar Universitário Lisboa Norte, Lisbon, Portugal
| | - Adília Costa
- Department of Pathological Anatomy, Hospital de Santa Maria, Centro Hospitalar Universitário Lisboa Norte, Lisbon, Portugal
| | - Mariana V Machado
- Faculdade de Medicina, Clinica Universitária de Gastrenterologia, Universidade de Lisboa, Lisbon, Portugal.,Department of Gastroenterology, Hospital de Santa Maria, Centro Hospitalar Universitário Lisboa Norte, Lisbon, Portugal
| | | | - Enara Arretxe
- OWL Metabolomics, Bizkaia Technology Park, Derio, Spain
| | - José M Alustiza
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain.,Radiology Service, Osatek, Donostia, Spain
| | - Marcin Krawczyk
- Department of Medicine II, Saarland University Medical Center, Homburg, Germany.,Laboratory of Metabolic Liver Diseases, Department of General, Transplant and Liver Surgery, Centre for Preclinical Research, Medical University of Warsaw, Warsaw, Poland
| | - Frank Lammert
- Department of Medicine II, Saarland University Medical Center, Homburg, Germany
| | - Dina G Tiniakos
- Faculty of Medical Sciences, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom.,Department of Pathology, Aretaieio Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | | | - Helena Cortez-Pinto
- Faculdade de Medicina, Clinica Universitária de Gastrenterologia, Universidade de Lisboa, Lisbon, Portugal.,Department of Gastroenterology, Hospital de Santa Maria, Centro Hospitalar Universitário Lisboa Norte, Lisbon, Portugal
| | - Jesus M Banales
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain.,National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, Instituto de Salud Carlos III), Madrid, Spain.,IKERBASQUE, Basque Foundation for Science, Bilbao, Spain
| | - Rui E Castro
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
| | | | - Cecília M P Rodrigues
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
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19
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Olivero-Verbel J, Harkema JR, Roth RA, Ganey PE. Fenofibrate, a peroxisome proliferator-activated receptor-alpha agonist, blocks steatosis and alters the inflammatory response in a mouse model of inflammation-dioxin interaction. Chem Biol Interact 2021; 345:109521. [PMID: 34052195 DOI: 10.1016/j.cbi.2021.109521] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2020] [Revised: 04/07/2021] [Accepted: 05/14/2021] [Indexed: 12/01/2022]
Abstract
2,3,7,8-Tetrachlorodibenzo-p-dioxin (dioxin; TCDD) is an environmental contaminant that elicits a variety of toxic effects, many of which are mediated through activation of the aryl hydrocarbon receptor (AhR). Interaction between AhR and the peroxisome proliferator-activated receptor-alpha (PPAR-α), which regulates fatty acid metabolism, has been suggested. Furthermore, with recognition of the prevalence of inflammatory conditions, there is current interest in the potential for inflammatory stress to modulate the response to environmental agents. The aim of this work was to assess the interaction of TCDD with hepatic inflammation modulated by fenofibrate, a PPAR-α agonist. Female, C57BL/6 mice were treated orally with vehicle or fenofibrate (250 mg/kg) for 13 days, and then were given vehicle or 30 μg/kg TCDD. Four days later, the animals received an i.p. injection of lipopolysaccharide-galactosamine (LPS-GalN) (0.05x107 EU/kg and 500 mg/kg, respectively) to incite inflammation, or saline as vehicle control. After 4 h, the mice were euthanized, and blood and liver samples were collected for analysis. Livers of animals treated with TCDD with or without LPS-GalN had increased lipid deposition, and this effect was blocked by fenofibrate. In TCDD/LPS-GalN-treated mice, fenofibrate caused an increase in plasma activity of alanine aminotransferase, a marker of hepatocellular injury. TCDD reduced LPS-GalN-induced apoptosis, an effect that was prevented by fenofibrate pretreatment. LPS-GalN induced an increase in the concentration of interleukin-6 in plasma and accumulation of neutrophils in liver. TCDD exposure enhanced the former response and inhibited the latter one. These results suggest that fenofibrate counteracts the changes in lipid metabolism induced by TCDD but increases inflammation and liver injury in this model of inflammation-TCDD interaction.
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Affiliation(s)
- Jesus Olivero-Verbel
- Department of Pharmacology and Toxicology. Michigan State University, East Lansing, MI, USA; Environmental and Computational Chemistry Group, School of Pharmaceutical Sciences, University of Cartagena, Cartagena, 130014, Colombia
| | - Jack R Harkema
- Department of Pathobiology and Diagnostic Investigation, Institute for Integrative Toxicology, Michigan State University, USA
| | - Robert A Roth
- Department of Pharmacology and Toxicology. Michigan State University, East Lansing, MI, USA
| | - Patricia E Ganey
- Department of Pharmacology and Toxicology. Michigan State University, East Lansing, MI, USA.
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20
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Han S, Zhu F, Huang X, Yan P, Xu K, Shen F, Sun J, Yang Z, Jin G, Teng Y. Maternal obesity accelerated non-alcoholic fatty liver disease in offspring mice by reducing autophagy. Exp Ther Med 2021; 22:716. [PMID: 34007325 PMCID: PMC8120514 DOI: 10.3892/etm.2021.10148] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Accepted: 03/02/2021] [Indexed: 12/14/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disease characterized by an excessive accumulation of triacylglycerol in the liver. Autophagy is a lysosome-dependent degradation product recovery process, which widely occurs in eukaryotic cells, responsible for the vital maintenance of cellular energy balance. Previously published studies have demonstrated that autophagy is closely related to NAFLD occurrence and maternal obesity increases the susceptibility of offspring to non-alcoholic fatty liver disease, however, the underlying mechanism of this remains unclear. In the present study, NAFLD mouse models (offspring of an obese mother mouse via high-fat feeding) were generated, and the physiological indices of the liver were observed using total cholesterol, triglyceride, high-density lipoprotein and low-density lipoprotein serum assay kits. The morphological changes of the liver were also observed via HE, Masson and oil red O staining. Reverse transcription-quantitative-PCR and western blotting were performed to detect changes of autophagy-related genes in liver or fibrosis marker proteins (α-smooth muscle actin or TGF-β1). Changes in serum inflammatory cytokine IL-6 levels were determined via ELISA. The results of the present study demonstrated that the offspring of an obese mother were more likely to develop NALFD than the offspring of a chow-fed mother, due to their increased association with liver fibrosis. When feeding continued to 17 weeks, the worst cases of NAFLD were observed and the level of autophagy decreased significantly compared with the offspring of a normal weight mouse. In addition, after 17 weeks of feeding, compared with the offspring of a chow-fed mother, the offspring of an obese mouse mother had reduced adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) phosphorylation levels and increased mammalian target of rapamycin (mTOR) phosphorylation levels. These results suggested that a reduced level of AMPK/mTOR mediated autophagy may be of vital importance for the increased susceptibility of offspring to NAFLD caused by maternal obesity. In conclusion, the current study provided a new direction for the treatment of NAFLD in offspring caused by maternal obesity.
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Affiliation(s)
- Shuguang Han
- Graduate School, Bengbu Medical College, Bengbu, Anhui 233000, P.R. China.,Department of Endocrinology, The First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui 233000, P.R. China
| | - Feng Zhu
- Graduate School, Bengbu Medical College, Bengbu, Anhui 233000, P.R. China.,Department of Pediatrics, The Second Affiliated Hospital of Jiaxing University, Jiaxing Second Hospital, Jiaxing, Zhejiang 314000, P.R. China
| | - Xiaoxia Huang
- Department of Pediatrics, The Second Affiliated Hospital of Jiaxing University, Jiaxing Second Hospital, Jiaxing, Zhejiang 314000, P.R. China.,The Second Clinical Medical College of Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310000, P.R. China
| | - Panpan Yan
- Graduate School, Bengbu Medical College, Bengbu, Anhui 233000, P.R. China.,Department of Pediatrics, The Second Affiliated Hospital of Jiaxing University, Jiaxing Second Hospital, Jiaxing, Zhejiang 314000, P.R. China
| | - Ke Xu
- Department of Pediatrics, The Second Affiliated Hospital of Jiaxing University, Jiaxing Second Hospital, Jiaxing, Zhejiang 314000, P.R. China
| | - Fangfang Shen
- Department of Pediatrics, The Second Affiliated Hospital of Jiaxing University, Jiaxing Second Hospital, Jiaxing, Zhejiang 314000, P.R. China
| | - Jiawen Sun
- Graduate School, Bengbu Medical College, Bengbu, Anhui 233000, P.R. China
| | - Zeyu Yang
- Graduate School, Bengbu Medical College, Bengbu, Anhui 233000, P.R. China
| | - Guoxi Jin
- Graduate School, Bengbu Medical College, Bengbu, Anhui 233000, P.R. China.,Department of Endocrinology, The First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui 233000, P.R. China
| | - Yiqun Teng
- Graduate School, Bengbu Medical College, Bengbu, Anhui 233000, P.R. China.,Department of Pediatrics, The Second Affiliated Hospital of Jiaxing University, Jiaxing Second Hospital, Jiaxing, Zhejiang 314000, P.R. China
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21
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Sivasubramaniyam T, Yang J, Pollock E, Chon J, Schroer SA, Li YZ, Metherel AH, Dodington DW, Bazinet RP, Woo M. Hepatic Igf1-Deficiency Protects Against Atherosclerosis in Female Mice. Endocrinology 2021; 162:6153998. [PMID: 33647942 DOI: 10.1210/endocr/bqab040] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2020] [Indexed: 12/20/2022]
Abstract
Atherosclerosis is the leading cause of cardiovascular disease (CVD), with distinct sex-specific pathogenic mechanisms that are poorly understood. Aging, a major independent risk factor for atherosclerosis, correlates with a decline in circulating insulin-like growth factor-1 (IGF-1). However, the precise effects of Igf1 on atherosclerosis remain unclear. In the present study, we assessed the essential role of hepatic Igf1, the major source of circulating IGF-1, in atherogenesis. We generated hepatic Igf1-deficient atherosclerosis-prone apolipoprotein E (ApoE)-null mice (L-Igf1-/-ApoE-/-) using the Cre-loxP system driven by the Albumin promoter. Starting at 6 weeks of age, these mice and their littermate controls, separated into male and female groups, were placed on an atherogenic diet for 18 to 19 weeks. We show that hepatic Igf1-deficiency led to atheroprotection with reduced plaque macrophages in females, without significant effects in males. This protection from atherosclerosis in females was associated with increased subcutaneous adiposity and with impaired lipolysis. Moreover, this impaired lipid homeostasis was associated with disrupted adipokine secretion with reduced circulating interleukin-6 (IL-6) levels. Together, our data show that endogenous hepatic Igf1 plays a sex-specific regulatory role in atherogenesis, potentially through athero-promoting effects of adipose tissue-derived IL-6 secretion. These data provide potential novel sex-specific mechanisms in the pathogenesis of atherosclerosis.
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Affiliation(s)
- Tharini Sivasubramaniyam
- Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, M5G 2C4, Canada
| | - Jiaqi Yang
- Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, M5G 2C4, Canada
| | - Evan Pollock
- Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, M5G 2C4, Canada
| | - Joseph Chon
- Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, M5G 2C4, Canada
| | - Stephanie A Schroer
- Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, M5G 2C4, Canada
| | - Yu Zhe Li
- Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, M5G 2C4, Canada
- Institute of Medical Science, University of Toronto, Toronto, Ontario, M5G 2M9, Canada
| | - Adam H Metherel
- Department of Nutritional Sciences, University of Toronto, Toronto, Ontario, M5S 3E2, Canada
| | - David W Dodington
- Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, M5G 2C4, Canada
| | - Richard P Bazinet
- Department of Nutritional Sciences, University of Toronto, Toronto, Ontario, M5S 3E2, Canada
| | - Minna Woo
- Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, M5G 2C4, Canada
- Institute of Medical Science, University of Toronto, Toronto, Ontario, M5G 2M9, Canada
- Department of Immunology, University of Toronto, Toronto, Ontario, M5G 2M9, Canada
- Division of Endocrinology and Metabolism, Department of Medicine, University Health Network/ Sinai Health System, University of Toronto, Toronto, Ontario, M5G 2C4, Canada
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22
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Mohamed YI, Lee S, Xiao L, Hassan MM, Qayyum A, Hiatia R, Pestana RC, Haque A, George B, Rashid A, Duda DG, Elghazaly H, Wolff RA, Morris JS, Yao J, Amin HM, Kaseb AO. Insulin-like growth factor 1/Child-Turcotte-Pugh composite score as a predictor of treatment outcomes in patients with advanced hepatocellular carcinoma treated with sorafenib. Oncotarget 2021; 12:756-766. [PMID: 33889299 PMCID: PMC8057275 DOI: 10.18632/oncotarget.27924] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2020] [Accepted: 03/08/2021] [Indexed: 01/11/2023] Open
Abstract
Background: Sorafenib was the first systemic therapy approved for the treatment of Child-Turcotte-Pugh (CTP) class A patients with advanced hepatocellular carcinoma (HCC). However, there are no biomarkers to predict survival and treatment outcomes and guide HCC systemic therapy. Type 1 insulin-like growth factor (IGF-1)/CTP composite score has emerged as a potential hepatic reserve assessment tool. Our study investigated the association of the IGF/CTP score with overall survival (OS) and progression-free survival (PFS) of HCC patients treated with sorafenib. Materials and Methods: In this prospective study, patients with HCC were treated with sorafenib and followed up until progression/death. We calculated the IGF/CTP score and used the Kaplan-Meier method and log-rank test to estimate and compare the time-to-event outcomes between patient subgroups. Results: 171 patients were included, 116 of whom were CTP class A. Median PFS for IGF/CTP score AA and AB patients were 6.88 and 4.28 months, respectively (p = 0.1359). Median OS for IGF/CTP score AA and AB patients were 14.54 and 7.60 months, respectively (p = 0.1378). The PFS and OS was superior in AA patients, but the difference was not significant, likely due to the sample size. However, there was a significant difference in early OS and PFS curves between AA and AB (p = 0.0383 and p = 0.0099), respectively. Conclusions: In CTP class A patients, IGF/CTP score B was associated with shorter PFS and OS, however, study was underpowered to reach statistical significance. If validated in larger cohorts, IGF/CTP score may serve as stratification tool in clinical trials, a hepatic reserve assessment tool for HCC outcomes prediction and to assist in therapy decisions.
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Affiliation(s)
- Yehia I Mohamed
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Sunyoung Lee
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Lianchun Xiao
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Manal M Hassan
- Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Aliya Qayyum
- Department of Abdominal Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Rikita Hiatia
- Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Roberto Carmagnani Pestana
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Abedul Haque
- Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Bhawana George
- Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Asif Rashid
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Dan G Duda
- Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Hesham Elghazaly
- Department of Clinical Oncology, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Robert A Wolff
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Jeffrey S Morris
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - James Yao
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Hesham M Amin
- Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Ahmed O Kaseb
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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23
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Yen IC, Lin JC, Chen Y, Tu QW, Lee SY. Antrodia Cinnamomea Attenuates Non-Alcoholic Steatohepatitis by Suppressing NLRP3 Inflammasome Activation In Vitro and In Vivo. THE AMERICAN JOURNAL OF CHINESE MEDICINE 2020; 48:1859-1874. [PMID: 33308101 DOI: 10.1142/s0192415x20500937] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Blockade of the NOD-like receptor protein 3 (NLRP3) inflammasome has been shown to be effective in halting the progression of non-alcoholic steatohepatitis (NASH). Antrodia cinnamomea is a well-known indigenous medicine used by Taiwanese aboriginal tribes. However, its effect on NASH remains unclear. This study aimed to examine the mechanistic insight of Antrodia cinnamomea extract (ACE) in both in vitro and in vivo models of NASH. Murine RAW264.7 macrophages and human hepatocellular carcinoma HepG2 cells were treated with the indicated concentration of ACE 30 minutes prior to stimulation with lipopolysaccharide (LPS) for 24 h. Levels of inflammatory markers, NLRP3 inflammasome, components, and endoplasmic reticulum (ER) stress markers were analyzed by Western blotting. For the in vivo experiments, male C57BL/6 mice weighing 21-25 g were fed a methionine/choline deficient (MCD) diet along with vehicle or ACE (100 mg/kg) for 10 consecutive days. The serum glutamate pyruvate transaminase (SGPT) levels of the mice were measured. The liver tissues from the mice underwent histological analysis (hematoxylin and eosin staining), and the levels of inflammatory markers, NLRP3 inflammasome components, and autophagy-related proteins were evaluated. ACE significantly inhibited NLRP3 inflammasome activation in vitro and in vivo. In addition, ACE attenuated the severity of MCD-induced steatohepatitis, reduced the levels of oxidative stress markers, and ameliorated inflammatory responses, but restored autophagic flux. Based on these findings, Antrodia cinnamomea could be developed into an anti-non-alcoholic fatty liver disease/NASH agent.
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Affiliation(s)
- I-Chuan Yen
- School of Pharmacy, National Defense Medical Center, Taipei, Taiwan, ROC
| | - Jung-Chun Lin
- Division of Gastroenterology and Hepatology, Department of Internal Medicine Tri-Service General Hospital, Taipei City, Taiwan, ROC
| | - Yu Chen
- Graduate Institute of Aerospace and Undersea Medicine, National Defense Medical Center, Taipei, Taiwan, ROC
| | - Qian-Wen Tu
- Graduate Institute of Biochemistry, National Defense Medical Center, Taipei, Taiwan, ROC
| | - Shih-Yu Lee
- Graduate Institute of Aerospace and Undersea Medicine, National Defense Medical Center, Taipei, Taiwan, ROC
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24
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Chiou YL, Chyau CC, Li TJ, Kuo CF, Kang YY, Chen CC, Ko WS. Hepatoprotective Effect of Antrodia cinnamomea Mycelium in Patients with Nonalcoholic Steatohepatitis: A Randomized, Double-Blind, Placebo-Controlled Trial. J Am Coll Nutr 2020; 40:349-357. [PMID: 32657670 DOI: 10.1080/07315724.2020.1779850] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVE Nonalcoholic steatohepatitis (NASH) has become a prominent liver disease in contemporary society because of the changing dieting styles. Complicated syndromes often accompanied by obesity and diabetes makes no standard treatment for NASH. Therefore, we investigated the potential role of Antrodia cinnamomea mycelium (ACM) as nutraceutical supplementation in the treatment of NASH in this 6-month randomized, double-blind, placebo-controlled study. METHOD 28 Participants were treated with three capsules per day containing either 420 mg of ACM or 420 mg of starch as a placebo. The participants were required to follow a predetermined regular visit to hospital every three months during the intervention period (6 months). During each study visit, subjects underwent anthropometric measurements and blood testing for biochemical analysis, immune function assay, inflammatory cytokines assay, and FibroMax test. RESULTS The ACM supplemented group had a significant improvement in steatosis and decreased in the inflammatory marker of TNF-α after three and six months. NASH patients who received ACM showed a significant decrease in the SteatoTest mean value from 0.66 at baseline to 0.49 at 6 months (p < 0.029) and the ActiTest mean value decreased from 0.46 at baseline to 0.30 at 6 months (p < 0.029). CONCLUSION This is the first clinical investigation that explores the hepatoprotective effect of A. cinnamomea mycelium in patients with NASH. No participants experienced any adverse events during the study, which suggested that ACM is a safe alternative treatment for NASH.
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Affiliation(s)
- Ya-Ling Chiou
- Department of Nutrition, Master Program of Biomedical Nutrition, Hungkuang University, Taichung City, Taiwan
| | - Charng-Cherng Chyau
- Research Institute of Biotechnology, Hungkuang University, Taichung City, Taiwan
| | - Tsung-Ju Li
- Biotech Research Institute, Grape King Bio Ltd, Taoyuan City, Taiwan
| | - Chia-Feng Kuo
- Department of Food Science, Nutrition, and Nutraceutical Biotechnology, Shih Chien University, Taipei City, Taiwan
| | - Yu-Yling Kang
- Department of Nutrition, Master Program of Biomedical Nutrition, Hungkuang University, Taichung City, Taiwan
| | - Chin-Chu Chen
- Biotech Research Institute, Grape King Bio Ltd, Taoyuan City, Taiwan.,Department of Food Science, Nutrition, and Nutraceutical Biotechnology, Shih Chien University, Taipei City, Taiwan.,Institute of Food Science and Technology, National Taiwan University, Taipei City, Taiwan
| | - Wang-Sheng Ko
- Department of Nutrition, Master Program of Biomedical Nutrition, Hungkuang University, Taichung City, Taiwan.,Department of Internal Medicine, Kuang-Tien General Hospital, Taichung City, Taiwan
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25
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Katsarou A, Moustakas II, Pyrina I, Lembessis P, Koutsilieris M, Chatzigeorgiou A. Metabolic inflammation as an instigator of fibrosis during non-alcoholic fatty liver disease. World J Gastroenterol 2020; 26:1993-2011. [PMID: 32536770 PMCID: PMC7267690 DOI: 10.3748/wjg.v26.i17.1993] [Citation(s) in RCA: 67] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2020] [Revised: 04/09/2020] [Accepted: 04/20/2020] [Indexed: 02/06/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is characterized by excessive storage of fatty acids in the form of triglycerides in hepatocytes. It is most prevalent in western countries and includes a wide range of clinical and histopathological findings, namely from simple steatosis to steatohepatitis and fibrosis, which may lead to cirrhosis and hepatocellular cancer. The key event for the transition from steatosis to fibrosis is the activation of quiescent hepatic stellate cells (qHSC) and their differentiation to myofibroblasts. Pattern recognition receptors (PRRs), expressed by a plethora of immune cells, serve as essential components of the innate immune system whose function is to stimulate phagocytosis and mediate inflammation upon binding to them of various molecules released from damaged, apoptotic and necrotic cells. The activation of PRRs on hepatocytes, Kupffer cells, the resident macrophages of the liver, and other immune cells results in the production of proinflammatory cytokines and chemokines, as well as profibrotic factors in the liver microenvironment leading to qHSC activation and subsequent fibrogenesis. Thus, elucidation of the inflammatory pathways associated with the pathogenesis and progression of NAFLD may lead to a better understanding of its pathophysiology and new therapeutic approaches.
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Affiliation(s)
- Angeliki Katsarou
- Department of Physiology, Medical School, National and Kapodistrian University of Athens, Athens 11527, Greece
- 251 Hellenic Airforce General Hospital, Athens 11525, Greece
| | - Ioannis I Moustakas
- Department of Physiology, Medical School, National and Kapodistrian University of Athens, Athens 11527, Greece
| | - Iryna Pyrina
- Institute for Clinical Chemistry and Laboratory Medicine, University Hospital and Faculty of Medicine Carl Gustav Carus of TU Dresden, Dresden 01307, Germany
| | - Panagiotis Lembessis
- Department of Physiology, Medical School, National and Kapodistrian University of Athens, Athens 11527, Greece
| | - Michael Koutsilieris
- Department of Physiology, Medical School, National and Kapodistrian University of Athens, Athens 11527, Greece
| | - Antonios Chatzigeorgiou
- Department of Physiology, Medical School, National and Kapodistrian University of Athens, Athens 11527, Greece
- Institute for Clinical Chemistry and Laboratory Medicine, University Hospital and Faculty of Medicine Carl Gustav Carus of TU Dresden, Dresden 01307, Germany.
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26
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Polyzos SA, Perakakis N, Boutari C, Kountouras J, Ghaly W, Anastasilakis AD, Karagiannis A, Mantzoros CS. Targeted Analysis of Three Hormonal Systems Identifies Molecules Associated with the Presence and Severity of NAFLD. J Clin Endocrinol Metab 2020; 105:5613670. [PMID: 31690932 PMCID: PMC7112980 DOI: 10.1210/clinem/dgz172] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2019] [Accepted: 11/05/2019] [Indexed: 01/22/2023]
Abstract
AIMS To investigate circulating levels and liver gene expression of 3 hormonal pathways associated with obesity, insulin resistance, and inflammation to identify leads towards potential diagnostic markers and therapeutic targets in patients with nonalcoholic fatty liver disease (NAFLD). METHODS We compared circulating levels of (1) proglucagon-derived hormones (glucagon-like peptide [GLP]-1, GLP-2, glicentin, oxyntomodulin, glucagon, major proglucagon fragment [MPGF]), (2) follistatins-activins (follistatin-like [FSTL]3, activin B), (3) IGF axis (insulin-like growth factor [IGF]-1, total and intact IGF binding protein [IGFBP]-3 and IGFBP-4, and pregnancy-associated plasma protein [PAPP]-A) in 2 studies: (1) 18 individuals with early stage NAFLD versus 14 controls (study 1; early NAFLD study) and in (2) 31 individuals with biopsy proven NAFLD (15 with simple steatosis [SS] and 16 with nonalcoholic steatohepatitis [NASH]), vs 50 controls (24 lean and 26 obese) (study 2). Liver gene expression was assessed in 22 subjects (12 controls, 5 NASH, 5 NASH-related cirrhosis). RESULTS Patients in early stages of NAFLD demonstrate higher fasting MPGF and lower incremental increase of glicentin during oral glucose tolerance test than controls. In more advanced stages, FSTL3 levels are higher in NASH than simple steatosis and, within NAFLD patients, in those with more severe lobular and portal inflammation. The IGF-1/intact IGFBP-3 ratio is lower in patients with liver fibrosis. Genes encoding follistatin, activin A, activin B, and the IGF-1 receptor are higher in NASH. CONCLUSION MPGF and glicentin may be involved in early stages of NAFLD, whereas FSTL3 and IGF-1/intact IGFBP3 in the progression to NASH and liver fibrosis respectively, suggesting potential as diagnostic markers or therapeutic targets.
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Affiliation(s)
- Stergios A Polyzos
- First Department of Pharmacology, Faculty of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Nikolaos Perakakis
- Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Chrysoula Boutari
- Second Propaedeutic Department of Internal Medicine, Faculty of Medicine, Aristotle University of Thessaloniki, Ippokration Hospital, Thessaloniki Greece
| | - Jannis Kountouras
- Second Medical Clinic, Faculty of Medicine, Aristotle University of Thessaloniki, Ippokration Hospital, Thessaloniki, Greece
| | - Wael Ghaly
- Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
- Department of Physiology, Fayoum University, Fayoum, Egypt
| | | | - Asterios Karagiannis
- Second Propaedeutic Department of Internal Medicine, Faculty of Medicine, Aristotle University of Thessaloniki, Ippokration Hospital, Thessaloniki Greece
| | - Christos S Mantzoros
- Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
- Correspondence and Reprint Requests: Christos S. Mantzoros, 330 Brookline Avenue, East campus, Beth Israel Deaconess Medical Center, Stoneman Building, ST-820 Boston, MA 02215, USA. E-mail:
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Okamoto K, Koda M, Okamoto T, Onoyama T, Miyoshi K, Kishina M, Matono T, Kato J, Tokunaga S, Sugihara T, Hiramatsu A, Hyogo H, Tobita H, Sato S, Kawanaka M, Hara Y, Hino K, Chayama K, Murawaki Y, Isomoto H. Serum miR-379 expression is related to the development and progression of hypercholesterolemia in non-alcoholic fatty liver disease. PLoS One 2020; 15:e0219412. [PMID: 32106257 PMCID: PMC7046274 DOI: 10.1371/journal.pone.0219412] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2019] [Accepted: 02/10/2020] [Indexed: 12/15/2022] Open
Abstract
Introduction Non-alcoholic fatty liver disease (NAFLD) has a wide spectrum, eventually leading to cirrhosis and hepatic carcinogenesis. We previously reported that a series of microRNAs (miRNAs) mapped in the 14q32.2 maternally imprinted gene region (Dlk1-Dio3 mat) are related to NAFLD development and progression in a mouse model. We examined the suitability of miR-379, a circulating Dlk1-Dio3 mat miRNA, as a human NAFLD biomarker. Methods Eighty NAFLD patients were recruited for this study. miR-379 was selected from the putative Dlk1-Dio3 mat miRNA cluster because it exhibited the greatest expression difference between NAFLD and non-alcoholic steatohepatitis in our preliminary study. Real-time PCR was used to examine the expression levels of miR-379 and miR-16 as an internal control. One patient was excluded due to low RT-PCR signal. Results Compared to normal controls, serum miR-379 expression was significantly up-regulated in NAFLD patients. Receiver operating characteristic curve analysis suggested that miR-379 is a suitable marker for discriminating NAFLD patients from controls, with an area under the curve value of 0.72. Serum miR-379 exhibited positive correlations with alkaline phosphatase, total cholesterol, low-density-lipoprotein cholesterol and non-high-density-lipoprotein cholesterol levels in patients with early stage NAFLD (Brunt fibrosis stage 0 to 1). The correlation between serum miR-379 and cholesterol levels was lost in early stage NAFLD patients treated with statins. Software-based predictions indicated that various energy metabolism–related genes, including insulin-like growth factor-1 (IGF-1) and IGF-1 receptor, are potential targets of miR-379. Conclusions Serum miR-379 exhibits high potential as a biomarker for NAFLD. miR-379 appears to increase cholesterol lipotoxicity, leading to the development and progression of NAFLD, via interference with the expression of target genes, including those related to the IGF-1 signaling pathway. Our results could facilitate future research into the pathogenesis, diagnosis, and treatment of NAFLD.
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Affiliation(s)
- Kinya Okamoto
- Second Department of Internal Medicine, Tottori University School of Medicine, Yonago, Tottori, Japan
- * E-mail:
| | - Masahiko Koda
- Second Department of Internal Medicine, Tottori University School of Medicine, Yonago, Tottori, Japan
| | - Toshiaki Okamoto
- Second Department of Internal Medicine, Tottori University School of Medicine, Yonago, Tottori, Japan
| | - Takumi Onoyama
- Second Department of Internal Medicine, Tottori University School of Medicine, Yonago, Tottori, Japan
| | - Kenichi Miyoshi
- Second Department of Internal Medicine, Tottori University School of Medicine, Yonago, Tottori, Japan
| | - Manabu Kishina
- Second Department of Internal Medicine, Tottori University School of Medicine, Yonago, Tottori, Japan
| | - Tomomitsu Matono
- Second Department of Internal Medicine, Tottori University School of Medicine, Yonago, Tottori, Japan
| | - Jun Kato
- Second Department of Internal Medicine, Tottori University School of Medicine, Yonago, Tottori, Japan
| | - Shiho Tokunaga
- Second Department of Internal Medicine, Tottori University School of Medicine, Yonago, Tottori, Japan
| | - Takaaki Sugihara
- Second Department of Internal Medicine, Tottori University School of Medicine, Yonago, Tottori, Japan
| | - Akira Hiramatsu
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Hiroshima, Japan
| | - Hideyuki Hyogo
- Department of Gastroenterology and Hepatology, JA Hiroshima General Hospital, Hatsukaichi, Hiroshima, Japan
| | - Hiroshi Tobita
- Department of Gastroenterology and Hepatology, Shimane University School of Medicine, Izumo, Shimane, Japan
| | - Shuichi Sato
- Department of Gastroenterology and Hepatology, Shimane University School of Medicine, Izumo, Shimane, Japan
| | - Miwa Kawanaka
- Department of General Internal Medicine 2, General Medical Center, Kawasaki Medical School, Okayama, Okayama, Japan
| | - Yuichi Hara
- Department of Hepatology and Pancreatology, Kawasaki Medical School, Kurashiki, Okayama, Japan
| | - Keisuke Hino
- Department of Hepatology and Pancreatology, Kawasaki Medical School, Kurashiki, Okayama, Japan
| | - Kazuaki Chayama
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Hiroshima, Japan
| | - Yoshikazu Murawaki
- Second Department of Internal Medicine, Tottori University School of Medicine, Yonago, Tottori, Japan
| | - Hajime Isomoto
- Second Department of Internal Medicine, Tottori University School of Medicine, Yonago, Tottori, Japan
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Yao Y, Miao X, Zhu D, Li D, Zhang Y, Song C, Liu K. Insulin-like growth factor-1 and non-alcoholic fatty liver disease: a systemic review and meta-analysis. Endocrine 2019; 65:227-237. [PMID: 31243652 DOI: 10.1007/s12020-019-01982-1] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2019] [Accepted: 06/10/2019] [Indexed: 12/11/2022]
Abstract
AIM The prevalence of non-alcoholic fatty liver disease (NAFLD) is rapidly increasing worldwide. A number of researchers have studied the relationship between Insulin-like growth factor-1(IGF-1) and NAFLD. However, the results are controversial. This meta-analysis, aimed to systemically evaluate the correlation between IGF-1 and NAFLD. METHODS We searched for four online databases: PubMed, Web of Science, Embase and CNKI up to Feb 2018. We then applied a random-effects model to evaluate the overall effect sizes by calculating Standard mean difference (SMD) and its 95% confidence intervals (CIs). RESULTS Twelve articles were included in this meta-analysis. The pooled analysis showed that the level of IGF-1 in the control group was significantly higher than that in the NAFLD group. (SMD: 1.00, 95% CI: 0.54-1.46, P < 0.00001). However, significant heterogeneity was discovered among the included studies (P < 0.00001, I2 = 96%). Then a series of subgroup analyses were performed. Compared to the nonalcoholic steatohepatitis (NASH) group, the level of IGF-1 was significantly higher in the Non- or probable-NASH group (SMD: 1.42, 95% CI: 0.25-2.58, P = 0.02). The level of IGF-1 in patients with increased insulin resistance (SMD: 0.49; 95% CI: 0.36-0.63; P < 0.00001) and high Body Mass Index (SMD: 0.50; 95% CI: 0.22-0.79; P < 0.05) were significantly lower than healthy control. In addition, the same conclusion were found in studies carried out in Asia and Europe (Asia: SMD: 0.69, 95% CI: -0.29-1.66, P = 0.17; Europe: SMD: 0.89, 95% CI: 0.41-1.38, P < 0.05). CONCLUSION The level of IGF-1 is down-regulated in NAFLD patients compared to healthy controls, suggesting that IGF-1 might be used as a potential biomarker and therapeutic target for NAFLD.
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Affiliation(s)
- Yang Yao
- Department of Central Laboratory, the First Affiliated Hospital, Xi'an Medical University, Xi'an, Shaanxi, 710077, PR China
| | - Xiangxia Miao
- Clinical Medicine (three-year program) of Postgrade 2016, Xi'an Medical University, Xi'an, Shaanxi, 710021, PR China
| | - Donglie Zhu
- Department of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, 710032, PR China
| | - Dongmin Li
- Department of Biochemistry and Molecular Biology, School of Basic Medical Science, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, 710061, PR China
| | - Ying Zhang
- Clinical Medicine (three-year program) of Postgrade 2017, Xi'an Medical University, Xi'an, Shaanxi, 710021, PR China
| | - Chengyan Song
- Clinical Medicine (three-year program) of Postgrade 2017, Xi'an Medical University, Xi'an, Shaanxi, 710021, PR China
| | - Kaige Liu
- Department of Gastroenterology, the First Affiliated Hospital, Xi'an Medical University, Xi'an, Shaanxi, 710077, PR China.
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Miyauchi S, Miyake T, Miyazaki M, Eguchi T, Niiya T, Yamamoto S, Senba H, Furukawa S, Matsuura B, Hiasa Y. Insulin-like growth factor-1 is inversely associated with liver fibrotic markers in patients with type 2 diabetes mellitus. J Diabetes Investig 2019; 10:1083-1091. [PMID: 30592792 PMCID: PMC6626962 DOI: 10.1111/jdi.13000] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2018] [Revised: 12/21/2018] [Accepted: 12/26/2018] [Indexed: 02/06/2023] Open
Abstract
AIMS/INTRODUCTION Insulin-like growth factor-1 (IGF-1) regulates mitochondrial function, oxidative stress, inflammation, stellate cells and insulin sensitivity in the liver, and it might be associated with liver fibrosis from non-alcoholic steatohepatitis. In contrast, type 2 diabetes mellitus is closely associated with the progression from non-alcoholic fatty liver to non-alcoholic steatohepatitis and cirrhosis, so careful evaluation of liver fibrosis is required for patients with type 2 diabetes mellitus. Therefore, we examined the relationship between IGF-1 and liver fibrosis markers in type 2 diabetes patients without obvious alcoholic consumption and determined whether IGF-1 is associated with fibrosis of non-alcoholic fatty liver disease. MATERIALS AND METHODS We selected 415 patients with type 2 diabetes without obvious alcohol consumption, who were admitted to Uwajima City Hospital between May 2013 and December 2016. We collected and analyzed clinical data to determine correlations between IGF-1 or IGF-1 standard deviation score and fibrosis-4 index or 7S domain of type IV collagen. RESULTS Multiple linear regression analysis showed that the fibrosis-4 index was inversely correlated with IGF-1 and IGF-1 standard deviation score. Furthermore, the 7S domain of type IV collagen was also inversely correlated with IGF-1 and IGF-1 standard deviation score. CONCLUSIONS IGF-1 was inversely correlated with liver fibrosis markers in type 2 diabetes mellitus patients without obvious alcoholic consumption. Measuring serum IGF-1 levels might help clinicians to identify type 2 diabetes mellitus patients with advanced non-alcoholic steatohepatitis.
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Affiliation(s)
- Shozo Miyauchi
- Department of Internal MedicineUwajima City HospitalUwajimaEhimeJapan
| | - Teruki Miyake
- Department of Gastroenterology and MetabologyEhime University Graduate School of MedicineToonEhimeJapan
| | - Masumi Miyazaki
- Department of Internal MedicineUwajima City HospitalUwajimaEhimeJapan
| | - Toru Eguchi
- Aira Diabetes and Thyroid ClinicAiraKagoshimaJapan
| | - Tetsuji Niiya
- Department of Internal MedicineMatsuyama Shimin HospitalMatsuyamaEhimeJapan
| | - Shin Yamamoto
- Department of Lifestyle‐related MedicineEhime University Graduate School of MedicineToonEhimeJapan
| | - Hidenori Senba
- Department of Gastroenterology and MetabologyEhime University Graduate School of MedicineToonEhimeJapan
| | - Shinya Furukawa
- Department of Epidemiology and Preventive MedicineEhime University Graduate School of MedicineToonEhimeJapan
| | - Bunzo Matsuura
- Department of Lifestyle‐related MedicineEhime University Graduate School of MedicineToonEhimeJapan
| | - Yoichi Hiasa
- Department of Gastroenterology and MetabologyEhime University Graduate School of MedicineToonEhimeJapan
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Zhang YH, Ma DQ, Ding DP, Li J, Chen LL, Ao KJ, Tian YY. S100A4 Gene is Crucial for Methionine-Choline-Deficient Diet-Induced Non-Alcoholic Fatty Liver Disease in Mice. Yonsei Med J 2018; 59:1064-1071. [PMID: 30328321 PMCID: PMC6192886 DOI: 10.3349/ymj.2018.59.9.1064] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2018] [Revised: 08/06/2018] [Accepted: 08/24/2018] [Indexed: 12/17/2022] Open
Abstract
PURPOSE To explore the influence of S100 calcium binding protein A4 (S100A4) knockout (KO) on methionine-choline-deficient (MCD) diet-induced non-alcoholic fatty liver disease (NAFLD) in mice. MATERIALS AND METHODS S100A4 KO mice (n=20) and their wild-type (WT) counterparts (n=20) were randomly divided into KO/MCD, Ko/methionine-choline-sufficient (MCS), WT/MCD, and WT/MCS groups. After 8 weeks of feeding, blood lipid and liver function-related indexes were measured. HE, Oil Red O, and Masson stainings were used to observe the changes of liver histopathology. Additionally, expressions of S100A4 and proinflammatory and profibrogenic cytokines were detected by qRT-PCR and Western blot, while hepatocyte apoptosis was revealed by TUNEL staining. RESULTS Serum levels of aminotransferase, aspartate aminotransferase, triglyceride, and total cholesterol in mice were increased after 8-week MCD feeding, and hepatocytes performed varying balloon-like changes with increased inflammatory cell infiltration and collagen fibers; however, these effects were improved in mice of KO/MCD group. Meanwhile, total NAFLD activity scores and fibrosis were lower compared to WT+MCD group. Compared to WT/MCS group, S100A4 expression in liver tissue of WT/MCD group was enhanced. The expression of proinflammatory (TNF-α, IL-1β, IL-6) and profibrogenic cytokines (TGF-β1, COL1A1, α-SMA) in MCD-induced NAFLD mice were increased, as well as apoptotic index (AI). For MCD group, the expressions of proinflammatory and profibrogenic cytokines and AI in KO mice were lower than those of WT mice. CONCLUSION S100A4 was detected to be upregulated in NAFLD, while S100A4 KO alleviated liver fibrosis and inflammation, in addition to inhibiting hepatocyte apoptosis.
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Affiliation(s)
- Yin Hua Zhang
- Department of Infectious Diseases, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei, China
| | - De Qiang Ma
- Department of Infectious Diseases, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei, China
| | - De Ping Ding
- Department of Infectious Diseases, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei, China.
| | - Juan Li
- Maternal and Child Health-Care Hospital, Shiyan, Hubei, China
| | - Lin Li Chen
- Department of Infectious Diseases, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei, China
| | - Kang Jian Ao
- Department of Infectious Diseases, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei, China
| | - You You Tian
- Department of Infectious Diseases, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei, China
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BALTIERI L, CHAIM EA, CHAIM FDM, UTRINI MP, GESTIC MA, CAZZO E. CORRELATION BETWEEN NONALCOHOLIC FATTY LIVER DISEASE FEATURES AND LEVELS OF ADIPOKINES AND INFLAMMATORY CYTOKINES AMONG MORBIDLY OBESE INDIVIDUALS. ARQUIVOS DE GASTROENTEROLOGIA 2018; 55:247-251. [PMID: 30540086 DOI: 10.1590/s0004-2803.201800000-62] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/19/2018] [Accepted: 05/28/2018] [Indexed: 01/01/2023]
Abstract
ABSTRACT BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is the commonest hepatopathy worldwide. OBJECTIVE: To investigate the correlations between NAFLD histopathological features and the levels of adipokines (adiponectin, leptin, and resistin) and circulating inflammatory markers (interleukin-6 [IL-6], interleukin-8 [IL-8], tumor necrosis factor alpha [TNF-α], and C-reactive protein [CRP]). METHODS: This is an exploratory cross-sectional study, which enrolled 19 women with obesity who underwent bariatric surgery. Biochemical characteristics evaluated included the levels of adiponectin, leptin, resistin, IL-6, IL-8, TNF-α, and CRP. NAFLD was assessed through histological examination of liver biopsies carried out during the surgical procedures. RESULTS: The mean age of the study group was 37.3±8.2 years old; mean BMI was 36.2±2.5 kg/m2. Among individuals with liver fibrosis, the levels of IL-8 were significantly higher (24.4 ± 9.7 versus 12.7 ± 6.6; P=0.016726). The intensity of fibrosis presented a significant negative correlation with the levels of adiponectin (R= -0.49379; P=0.03166); i.e. the higher the levels of adiponectin, the lower the intensity of fibrosis. The intensity of steatohepatitis presented a significant negative correlation with the levels of adiponectin (R= -0.562321; P=0.01221); this means that the higher the levels of adiponectin, the lower the intensity of steatohepatitis. CONCLUSION: Adiponectin levels were inversely correlated with the severity of fibrosis and steatohepatitis, whereas IL-8 levels were higher in individuals with liver fibrosis among individuals with obesity and NAFLD undergoing bariatric surgery. The use of these markers to assess NAFLD may bring significant information within similar populations.
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Catalase and nonalcoholic fatty liver disease. Pflugers Arch 2018; 470:1721-1737. [PMID: 30120555 DOI: 10.1007/s00424-018-2195-z] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2018] [Revised: 08/01/2018] [Accepted: 08/06/2018] [Indexed: 02/06/2023]
Abstract
Obesity and insulin resistance are considered the main causes of nonalcoholic fatty liver disease (NAFLD), and oxidative stress accelerates the progression of NAFLD. Free fatty acids, which are elevated in the liver by obesity or insulin resistance, lead to incomplete oxidation in the mitochondria, peroxisomes, and microsomes, leading to the production of reactive oxygen species (ROS). Among the ROS generated, H2O2 is mainly produced in peroxisomes and decomposed by catalase. However, when the H2O2 concentration increases because of decreased expression or activity of catalase, it migrates to cytosol and other organelles, causing cell injury and participating in the Fenton reaction, resulting in serious oxidative stress. To date, numerous studies have been shown to inhibit the pathogenesis of NAFLD, but treatment for this disease mainly depends on weight loss and exercise. Various molecules such as vitamin E, metformin, liraglutide, and resveratrol have been proposed as therapeutic agents, but further verification of the dose setting, clinical application, and side effects is needed. Reducing oxidative stress may be a fundamental method for improving not only the progression of NAFLD but also obesity and insulin resistance. However, the relationship between NAFLD progression and antioxidants, particularly catalase, which is most commonly expressed in the liver, remains unclear. Therefore, this review summarizes the role of catalase, focusing on its potential therapeutic effects in NAFLD progression.
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Verhaegh P, Bavalia R, Winkens B, Masclee A, Jonkers D, Koek G. Noninvasive Tests Do Not Accurately Differentiate Nonalcoholic Steatohepatitis From Simple Steatosis: A Systematic Review and Meta-analysis. Clin Gastroenterol Hepatol 2018; 16:837-861. [PMID: 28838784 DOI: 10.1016/j.cgh.2017.08.024] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2017] [Revised: 08/15/2017] [Accepted: 08/16/2017] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Nonalcoholic fatty liver disease is a rapidly increasing health problem. Liver biopsy analysis is the most sensitive test to differentiate between nonalcoholic steatohepatitis (NASH) and simple steatosis (SS), but noninvasive methods are needed. We performed a systematic review and meta-analysis of noninvasive tests for differentiating NASH from SS, focusing on blood markers. METHODS We performed a systematic search of the PubMed, Medline and Embase (1990-2016) databases using defined keywords, limited to full-text papers in English and human adults, and identified 2608 articles. Two independent reviewers screened the articles and identified 122 eligible articles that used liver biopsy as reference standard. If at least 2 studies were available, pooled sensitivity (sensp) and specificity (specp) values were determined using the Meta-Analysis Package for R (metafor). RESULTS In the 122 studies analyzed, 219 different blood markers (107 single markers and 112 scoring systems) were identified to differentiate NASH from simple steatosis, and 22 other diagnostic tests were studied. Markers identified related to several pathophysiological mechanisms. The markers analyzed in the largest proportions of studies were alanine aminotransferase (sensp, 63.5% and specp, 74.4%) within routine biochemical tests, adiponectin (sensp, 72.0% and specp, 75.7%) within inflammatory markers, CK18-M30 (sensp, 68.4% and specp, 74.2%) within markers of cell death or proliferation and homeostatic model assessment of insulin resistance (sensp, 69.0% and specp, 72.7%) within the metabolic markers. Two scoring systems could also be pooled: the NASH test (differentiated NASH from borderline NASH plus simple steatosis with 22.9% sensp and 95.3% specp) and the GlycoNASH test (67.1% sensp and 63.8% specp). CONCLUSION In the meta-analysis, we found no test to differentiate NASH from SS with a high level of pooled sensitivity and specificity (≥80%). However, some blood markers, when included in scoring systems in single studies, identified patients with NASH with ≥80% sensitivity and specificity. Replication studies and more standardized study designs are urgently needed. At present, no marker or scoring system can be recommended for use in clinical practice to differentiate NASH from simple steatosis.
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Affiliation(s)
- Pauline Verhaegh
- Department of Internal Medicine, Division of Gastroenterology-Hepatology, Maastricht University Medical Centre, School of Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University, Maastricht, the Netherlands
| | - Roisin Bavalia
- Department of Internal Medicine, Division of Gastroenterology-Hepatology, Maastricht University Medical Centre, School of Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University, Maastricht, the Netherlands
| | - Bjorn Winkens
- Department of Methodology and Statistic, School for Public Health and Primary Care (CAPHRI), Maastricht University, Maastricht, the Netherlands
| | - Ad Masclee
- Department of Internal Medicine, Division of Gastroenterology-Hepatology, Maastricht University Medical Centre, School of Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University, Maastricht, the Netherlands
| | - Daisy Jonkers
- Department of Internal Medicine, Division of Gastroenterology-Hepatology, Maastricht University Medical Centre, School of Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University, Maastricht, the Netherlands
| | - Ger Koek
- Department of Internal Medicine, Division of Gastroenterology-Hepatology, Maastricht University Medical Centre, School of Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University, Maastricht, the Netherlands.
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Insulin-Like Growth Factor (IGF) System in Liver Diseases. Int J Mol Sci 2018; 19:ijms19051308. [PMID: 29702590 PMCID: PMC5983723 DOI: 10.3390/ijms19051308] [Citation(s) in RCA: 181] [Impact Index Per Article: 25.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2018] [Revised: 04/20/2018] [Accepted: 04/20/2018] [Indexed: 02/06/2023] Open
Abstract
Hepatocyte differentiation, proliferation, and apoptosis are affected by growth factors produced in liver. Insulin-like growth factor 1 and 2 (IGF1 and IGF2) act in response to growth hormone (GH). Other IGF family components include at least six binding proteins (IGFBP1 to 6), manifested by both IGFs develop due to interaction through the type 1 receptor (IGF1R). The data based on animal models and/or in vitro studies suggest the role of IGF system components in cellular aspects of hepatocarcinogenesis (cell cycle progression, uncontrolled proliferation, cell survival, migration, inhibition of apoptosis, protein synthesis and cell growth), and show that systemic IGF1 administration can reduce fibrosis and ameliorate general liver function. In epidemiologic and clinicopathological studies on chronic liver disease (CLD), lowered serum levels, decreased tissue expression of IGF1, elevated production of IGF1R and variable IGF2 expression has been noted, from the start of preneoplastic alterations up to the developed hepatocellular carcinoma (HCC) stage. These changes result in well-known clinical symptoms of IGF1 deficiency. This review summarized the current data of the complex role of IGF system components in the most common CLD (nonalcoholic fatty liver disease, cirrhosis, and hepatocellular carcinoma). Better recognition and understanding of this system can contribute to discovery of new and improved versions of current preventive and therapeutic actions in CLD.
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Aller R, Fernández-Rodríguez C, Lo Iacono O, Bañares R, Abad J, Carrión JA, García-Monzón C, Caballería J, Berenguer M, Rodríguez-Perálvarez M, Miranda JL, Vilar-Gómez E, Crespo J, García-Cortés M, Reig M, Navarro JM, Gallego R, Genescà J, Arias-Loste MT, Pareja MJ, Albillos A, Muntané J, Jorquera F, Solà E, Hernández-Guerra M, Rojo MÁ, Salmerón J, Caballería L, Diago M, Molina E, Bataller R, Romero-Gómez M. Consensus document. Management of non-alcoholic fatty liver disease (NAFLD). Clinical practice guideline. GASTROENTEROLOGIA Y HEPATOLOGIA 2018; 41:328-349. [PMID: 29631866 DOI: 10.1016/j.gastrohep.2017.12.003] [Citation(s) in RCA: 65] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/06/2017] [Revised: 09/11/2017] [Accepted: 12/01/2017] [Indexed: 02/07/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the main cause of liver diseases in Spain and the incidence is raising due to the outbreak of type 2 diabetes and obesity. This CPG suggests recommendation about diagnosis, mainly non-invasive biomarkers, and clinical management of this entity. Life-style modifications to achieve weight loss is the main target in the management of NAFLD. Low caloric Mediterranean diet and 200 minutes/week of aerobic exercise are encouraged. In non-responders patients with morbid obesity, bariatric surgery or metabolic endoscopy could be indicated. Pharmacological therapy is indicated in patients with NASH and fibrosis and non-responders to weight loss measures. NAFLD could influence liver transplantation, as a growing indication, the impact of steatosis in the graft viability, de novo NAFLD rate after OLT and a raised cardiovascular risk that modify the management of this entity. The current CPG was the result of the First Spanish NAFLD meeting in Seville.
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Affiliation(s)
- Rocío Aller
- Servicio de Gastroenterología, Hospital Clínico Universitario de Valladolid. Facultad de Medicina, Universidad de Valladolid. Centro de Investigación de Endocrinología y Nutrición, Facultad de Medicina, Universidad de Valladolid, Valladolid, España
| | - Conrado Fernández-Rodríguez
- Servicio de Gastroenterología, Hospital Universitario Fundación Alcorcón. Facultad de Medicina, Universidad Rey Juan Carlos, Alcorcón, Madrid, España
| | - Oreste Lo Iacono
- Servicio de Aparato Digestivo, Hospital del Tajo, Aranjuez, Madrid, España
| | - Rafael Bañares
- Servicio de Gastroenterología y Hepatología, Hospital Gregorio Marañón, Madrid, España
| | - Javier Abad
- Servicio de Gastroenterología y Hepatología, Hospital Puerta de Hierro, Madrid, España
| | | | | | - Joan Caballería
- Unidad de Hepatología, Hospital Clínic, IDIBAPS, CIBERehd, Barcelona, España
| | - Marina Berenguer
- Servicio de Medicina Digestiva, Hospital La Fe, Valencia, España
| | | | - José López Miranda
- Unidad de Trasplante Hepático, UGC de Aparato Digestivo, Hospital Reina Sofía, Córdoba, España
| | - Eduardo Vilar-Gómez
- UGC Aparato Digestivo, CIBERehd, Instituto de Biomedicina de Sevilla. Hospital Universitario Virgen del Rocío, Universidad de Sevilla, Sevilla, España
| | - Javier Crespo
- Servicio Aparato Digestivo, Hospital Universitario Marqués de Valdecilla, Universidad de Cantabria. CIBERehd. Instituto de Investigación Valdecilla (IDIVAL), Santander, España
| | | | - María Reig
- Unidad de Hepatología, Hospital Clínic, IDIBAPS, CIBERehd, Barcelona, España
| | - José María Navarro
- Unidad de Hepatología, Servicio de Digestivo, Hospital Costa del Sol, Marbella, Málaga, España
| | - Rocío Gallego
- UGC Aparato Digestivo, CIBERehd, Instituto de Biomedicina de Sevilla. Hospital Universitario Virgen del Rocío, Universidad de Sevilla, Sevilla, España
| | - Joan Genescà
- Servicio de Medicina Interna-Hepatología, Hospital Universitario Vall d'Hebron, Institut de Recerca Vall d'Hebron (VHIR), Universitat Autònoma de Barcelona, CIBERehd , Barcelona, España
| | - María Teresa Arias-Loste
- Servicio Aparato Digestivo, Hospital Universitario Marqués de Valdecilla, Universidad de Cantabria. CIBERehd. Instituto de Investigación Valdecilla (IDIVAL), Santander, España
| | | | - Agustín Albillos
- Servicio de Gastroenterología y Hepatología, Hospital Universitario Ramón y Cajal, Universidad de Alcalá, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS). CIBERehd, Madrid, España
| | - Jordi Muntané
- UGC de Cirugía General y Aparato Digestivo, Hospital Universitario Virgen del Rocío/Instituto de Biomedicina de Sevilla/CSIC/Universidad de Sevilla. CIBERehd, Sevilla, España
| | - Francisco Jorquera
- Servicio de Aparato Digestivo, Complejo Asistencial Universitario de León, IBIOMED y CIBERehd, León, España
| | - Elsa Solà
- Unidad de Hepatología, Hospital Clínic, IDIBAPS, CIBERehd, Barcelona, España
| | | | - Miguel Ángel Rojo
- Servicio de Gastroenterología, Hospital Clínico Universitario de Valladolid. Facultad de Medicina, Universidad de Valladolid. Centro de Investigación de Endocrinología y Nutrición, Facultad de Medicina, Universidad de Valladolid, Valladolid, España
| | - Javier Salmerón
- UGC de Aparato Digestivo, Hospital San Cecilio, Granada, España
| | - Llorenc Caballería
- Unidad de Apoyo a la Investigación de la Atención Primaria en la Metropolitana Norte, Barcelona, España
| | - Moisés Diago
- Servicio de Aparato Digestivo, Hospital General de Valencia, Valencia, España
| | - Esther Molina
- Unidad de Hepatología, Servicio de Aparato Digestivo, Hospital Clínico-Xerencia de Xestión Integrada de Santiago de Compostela, Santiago de Compostela, La Coruña, España
| | - Ramón Bataller
- Liver Unit, University of Pittsburg Medical Center, Pittsburg, Pennsylvania, Estados Unidos
| | - Manuel Romero-Gómez
- UGC Aparato Digestivo, CIBERehd, Instituto de Biomedicina de Sevilla. Hospital Universitario Virgen del Rocío, Universidad de Sevilla, Sevilla, España.
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Krstic J, Galhuber M, Schulz TJ, Schupp M, Prokesch A. p53 as a Dichotomous Regulator of Liver Disease: The Dose Makes the Medicine. Int J Mol Sci 2018; 19:E921. [PMID: 29558460 PMCID: PMC5877782 DOI: 10.3390/ijms19030921] [Citation(s) in RCA: 43] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2018] [Revised: 03/16/2018] [Accepted: 03/17/2018] [Indexed: 02/07/2023] Open
Abstract
Lifestyle-related disorders, such as the metabolic syndrome, have become a primary risk factor for the development of liver pathologies that can progress from hepatic steatosis, hepatic insulin resistance, steatohepatitis, fibrosis and cirrhosis, to the most severe condition of hepatocellular carcinoma (HCC). While the prevalence of liver pathologies is steadily increasing in modern societies, there are currently no approved drugs other than chemotherapeutic intervention in late stage HCC. Hence, there is a pressing need to identify and investigate causative molecular pathways that can yield new therapeutic avenues. The transcription factor p53 is well established as a tumor suppressor and has recently been described as a central metabolic player both in physiological and pathological settings. Given that liver is a dynamic tissue with direct exposition to ingested nutrients, hepatic p53, by integrating cellular stress response, metabolism and cell cycle regulation, has emerged as an important regulator of liver homeostasis and dysfunction. The underlying evidence is reviewed herein, with a focus on clinical data and animal studies that highlight a direct influence of p53 activity on different stages of liver diseases. Based on current literature showing that activation of p53 signaling can either attenuate or fuel liver disease, we herein discuss the hypothesis that, while hyper-activation or loss of function can cause disease, moderate induction of hepatic p53 within physiological margins could be beneficial in the prevention and treatment of liver pathologies. Hence, stimuli that lead to a moderate and temporary p53 activation could present new therapeutic approaches through several entry points in the cascade from hepatic steatosis to HCC.
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Affiliation(s)
- Jelena Krstic
- Gottfried Schatz Research Center for Cell Signaling, Metabolism & Aging, Medical University of Graz, 8010 Graz, Austria.
| | - Markus Galhuber
- Gottfried Schatz Research Center for Cell Signaling, Metabolism & Aging, Medical University of Graz, 8010 Graz, Austria.
| | - Tim J Schulz
- Department of Adipocyte Development and Nutrition, German Institute of Human Nutrition, Potsdam-Rehhbrücke, 14558 Nuthetal, Germany.
- German Center for Diabetes Research (DZD), 85764 München-Neuherberg, Germany.
- Institute of Nutritional Science, University of Potsdam, 14558 Nuthetal, Germany.
| | - Michael Schupp
- Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institute of Pharmacology, Center for Cardiovascular Research, 10117 Berlin, Germany.
| | - Andreas Prokesch
- Gottfried Schatz Research Center for Cell Signaling, Metabolism & Aging, Medical University of Graz, 8010 Graz, Austria.
- BioTechMed-Graz, 8010 Graz, Austria.
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Gong Z, Tas E, Yakar S, Muzumdar R. Hepatic lipid metabolism and non-alcoholic fatty liver disease in aging. Mol Cell Endocrinol 2017; 455:115-130. [PMID: 28017785 DOI: 10.1016/j.mce.2016.12.022] [Citation(s) in RCA: 95] [Impact Index Per Article: 11.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2016] [Revised: 09/23/2016] [Accepted: 12/16/2016] [Indexed: 02/06/2023]
Abstract
Aging is associated with dysregulation of glucose and lipid metabolism. Various factors that contribute to the dysregulation include both modifiable (e.g. obesity, insulin resistance) and non-modifiable risk factors (age-associated physiologic changes). Although there is no linear relationship between aging and prevalence of non-alcoholic fatty liver disease, current data strongly suggests that advanced age leads to more severe histological changes and poorer clinical outcomes. Hepatic lipid accumulation could lead to significant hepatic and systemic consequences including steatohepatitis, cirrhosis, impairment of systemic glucose metabolism and metabolic syndrome, thereby contributing to age-related diseases. Insulin, leptin and adiponectin are key regulators of the various physiologic processes that regulate hepatic lipid metabolism. Recent advances have expanded our understanding in this field, highlighting the role of novel mediators such as FGF 21, and mitochondria derived peptides. In this review, we will summarize the mediators of hepatic lipid metabolism and how they are altered in aging.
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Affiliation(s)
- Zhenwei Gong
- Department of Pediatrics, University of Pittsburgh School of Medicine, One Children's Hospital Drive, 4401 Penn Avenue, Pittsburgh, PA 15224, USA; Children's Hospital of Pittsburgh of UPMC, One Children's Hospital Drive, 4401 Penn Avenue, Pittsburgh, PA 15224, USA
| | - Emir Tas
- Children's Hospital of Pittsburgh of UPMC, One Children's Hospital Drive, 4401 Penn Avenue, Pittsburgh, PA 15224, USA
| | - Shoshana Yakar
- David B. Kriser Dental Center, Department of Basic Science and Craniofacial Biology, New York University College of Dentistry, New York, NY 10010, USA
| | - Radhika Muzumdar
- Department of Pediatrics, University of Pittsburgh School of Medicine, One Children's Hospital Drive, 4401 Penn Avenue, Pittsburgh, PA 15224, USA; Children's Hospital of Pittsburgh of UPMC, One Children's Hospital Drive, 4401 Penn Avenue, Pittsburgh, PA 15224, USA; Department of Cell Biology, University of Pittsburgh School of Medicine, 3500 Terrace Street, 5362 Biomedical Sciences Tower, Pittsburgh, PA 15261, USA.
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Sharma DL, Lakhani HV, Klug RL, Snoad B, El-Hamdani R, Shapiro JI, Sodhi K. Investigating Molecular Connections of Non-alcoholic Fatty Liver Disease with Associated Pathological Conditions in West Virginia for Biomarker Analysis. ACTA ACUST UNITED AC 2017; 8. [PMID: 29177105 PMCID: PMC5701750 DOI: 10.4172/2155-9899.1000523] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a disease characterized by a steatosis of the liver that may progress to more serious pathological conditions including: nonalcoholic steatohepatitis (NASH), fibrosis, and cirrhosis. As the prevalence of NAFLD has increased worldwide in recent years, pathophysiology and risk factors associated with disease progression of NAFLD are at the focus of many studies. NAFLD is related to and shares common serum biomarkers with cardiovascular disease (CVD), type 2 diabetes mellitus (T2DM), obesity, and metabolic syndrome (MetS). West Virginia (WV) is a state with some of the highest rates of CVD, obesity and diabetes mellitus. As NAFLD is closely related to these diseases, it is of particular interest in WV. Currently there is no cost-effective, standardized method used clinically to detect NAFLD prior to the onset of reversible complications. At this time, the diagnosis of NAFLD is made with costly radiologic studies and invasive biopsy. These studies are only diagnostic once changes to hepatic tissue have occurred. The diagnosis of NAFLD by traditional methods may not allow for successful intervention and may not be readily available in areas with already sparse medical resources. In this literature review, we identify a list of biomarkers common among CVD, T2DM, obesity, MetS and NAFLD. From this research we propose the following biomarkers are good candidates for inclusion in a panel of biomarkers for the early detection of NAFLD: adiponectin, AST, ALT, apo-B, CK18, CPS1, CRP, FABP-1, ferritin, GGT, GRP78, HDL-C, IGF-1, IL-1β, 6, 8, 10, IRS-2PAI-1, leptin, lumican, MDA SREBP-1c and TNF-α. Creating and implementing a biomarker panel for the early detection and attenuation of NAFLD, prior to the onset of irreversible complication would provide maximum benefit and decrease the disease burden on the patients and healthcare system of WV.
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Affiliation(s)
- Dana L Sharma
- Department of Internal Medicine, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV, USA
| | - Hari Vishal Lakhani
- Department of Internal Medicine, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV, USA
| | - Rebecca L Klug
- Department of Surgery, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV, USA
| | - Brian Snoad
- Department of Internal Medicine, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV, USA
| | - Rawan El-Hamdani
- Department of Internal Medicine, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV, USA
| | - Joseph I Shapiro
- Department of Internal Medicine, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV, USA
| | - Komal Sodhi
- Department of Surgery, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV, USA
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von Loeffelholz C, Lieske S, Neuschäfer-Rube F, Willmes DM, Raschzok N, Sauer IM, König J, Fromm M, Horn P, Chatzigeorgiou A, Pathe-Neuschäfer-Rube A, Jordan J, Pfeiffer AFH, Mingrone G, Bornstein SR, Stroehle P, Harms C, Wunderlich FT, Helfand SL, Bernier M, de Cabo R, Shulman GI, Chavakis T, Püschel GP, Birkenfeld AL. The human longevity gene homolog INDY and interleukin-6 interact in hepatic lipid metabolism. Hepatology 2017; 66:616-630. [PMID: 28133767 PMCID: PMC5519435 DOI: 10.1002/hep.29089] [Citation(s) in RCA: 53] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/11/2016] [Revised: 12/15/2016] [Accepted: 01/19/2017] [Indexed: 12/17/2022]
Abstract
UNLABELLED Reduced expression of the Indy ("I am Not Dead, Yet") gene in lower organisms promotes longevity in a manner akin to caloric restriction. Deletion of the mammalian homolog of Indy (mIndy, Slc13a5) encoding for a plasma membrane-associated citrate transporter expressed highly in the liver, protects mice from high-fat diet-induced and aging-induced obesity and hepatic fat accumulation through a mechanism resembling caloric restriction. We studied a possible role of mIndy in human hepatic fat metabolism. In obese, insulin-resistant patients with nonalcoholic fatty liver disease, hepatic mIndy expression was increased and mIndy expression was also independently associated with hepatic steatosis. In nonhuman primates, a 2-year high-fat, high-sucrose diet increased hepatic mIndy expression. Liver microarray analysis showed that high mIndy expression was associated with pathways involved in hepatic lipid metabolism and immunological processes. Interleukin-6 (IL-6) was identified as a regulator of mIndy by binding to its cognate receptor. Studies in human primary hepatocytes confirmed that IL-6 markedly induced mIndy transcription through the IL-6 receptor and activation of the transcription factor signal transducer and activator of transcription 3, and a putative start site of the human mIndy promoter was determined. Activation of the IL-6-signal transducer and activator of transcription 3 pathway stimulated mIndy expression, enhanced cytoplasmic citrate influx, and augmented hepatic lipogenesis in vivo. In contrast, deletion of mIndy completely prevented the stimulating effect of IL-6 on citrate uptake and reduced hepatic lipogenesis. These data show that mIndy is increased in liver of obese humans and nonhuman primates with NALFD. Moreover, our data identify mIndy as a target gene of IL-6 and determine novel functions of IL-6 through mINDY. CONCLUSION Targeting human mINDY may have therapeutic potential in obese patients with nonalcoholic fatty liver disease. German Clinical Trials Register: DRKS00005450. (Hepatology 2017;66:616-630).
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Affiliation(s)
- Christian von Loeffelholz
- Integrated Research and Treatment Center, Center for Sepsis Control and Care (CSCC), Friedrich Schiller University, and Department of Anesthesiology and Intensive Care, Jena University Hospital, Jena, 01774, Germany
| | - Stefanie Lieske
- Section of Metabolic Vascular Medicine, Medical Clinic III, Dresden University School of Medicine, Paul Langerhans Institute Dresden (PLID), TU Dresden,01307 Germany,Lehrstuhl für Biochemie der Ernährung, Universität Potsdam, Potsdam, 14558, Germany
| | | | - Diana M. Willmes
- Section of Metabolic Vascular Medicine, Medical Clinic III, Dresden University School of Medicine, Paul Langerhans Institute Dresden (PLID), TU Dresden,01307 Germany
| | - Nathanael Raschzok
- General, Visceral, and Transplantation Surgery, Charité – University School of Medicine, Berlin, 10117, Germany
| | - Igor M. Sauer
- General, Visceral, and Transplantation Surgery, Charité – University School of Medicine, Berlin, 10117, Germany
| | - Jörg König
- Institute of Experimental and Clinical Pharmacology and Toxicology, Friedrich-Alexander-Universität, Erlangen-Nürnberg, 91054, Germany
| | - Martin Fromm
- Institute of Experimental and Clinical Pharmacology and Toxicology, Friedrich-Alexander-Universität, Erlangen-Nürnberg, 91054, Germany
| | - Paul Horn
- Integrated Research and Treatment Center, Center for Sepsis Control and Care (CSCC), Friedrich Schiller University, and Department of Anesthesiology and Intensive Care, Jena University Hospital, Jena, 01774, Germany
| | - Antonis Chatzigeorgiou
- Department of Clinical Pathobiochemistry and Institute for Clinical Chemistry and Laboratory Medicine, University Clinic Dresden, TUD, Germany
| | | | - Jens Jordan
- Institute for Clinical Pharmacology, Hannover Medical School, 30625 Hannover, Germany
| | - Andreas F. H. Pfeiffer
- Department of Endocrinology, Diabetes and Nutrition, Charité – University School of Medicine, Berlin, 10117, Germany,German Centre for Diabetes Research (DZD e.V.), Neuherberg, Germany
| | - Geltrude Mingrone
- Division of Diabetes & Nutritional Sciences, Faculty of Life Sciences & Medicine, King’s College London, London SE1 8WA, UK,Catholic University of Rome, Department of Internal Medicine, Rome, Italy
| | - Stefan R. Bornstein
- Section of Metabolic Vascular Medicine, Medical Clinic III, Dresden University School of Medicine, Paul Langerhans Institute Dresden (PLID), TU Dresden,01307 Germany,Division of Diabetes & Nutritional Sciences, Faculty of Life Sciences & Medicine, King’s College London, London SE1 8WA, UK,German Centre for Diabetes Research (DZD e.V.), Neuherberg, Germany
| | - Peter Stroehle
- Max Planck Institute for Metabolism Research, Excellence cluster on cellular stress responses in aging associated diseases (CECAD), Cologne, 5093, Germany
| | - Christoph Harms
- Charité-Universitätsmedizin Berlin, Center for Stroke Research, Department of Experimental Neurology, Charitéplatz 1, 10117 Berlin, Germany
| | - F. Thomas Wunderlich
- Max Planck Institute for Metabolism Research, Excellence cluster on cellular stress responses in aging associated diseases (CECAD), Cologne, 5093, Germany
| | - Stephen. L. Helfand
- Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, RI 02912, USA
| | - Michel Bernier
- Translational Gerontology Branch, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA
| | - Rafael de Cabo
- Translational Gerontology Branch, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA
| | - Gerald I. Shulman
- Department of Internal Medicine, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06520, USA
| | - Triantafyllos Chavakis
- Department of Clinical Pathobiochemistry and Institute for Clinical Chemistry and Laboratory Medicine, University Clinic Dresden, TUD, Germany
| | - Gerhard. P. Püschel
- Lehrstuhl für Biochemie der Ernährung, Universität Potsdam, Potsdam, 14558, Germany
| | - Andreas. L. Birkenfeld
- Section of Metabolic Vascular Medicine, Medical Clinic III, Dresden University School of Medicine, Paul Langerhans Institute Dresden (PLID), TU Dresden,01307 Germany,Division of Diabetes & Nutritional Sciences, Faculty of Life Sciences & Medicine, King’s College London, London SE1 8WA, UK,German Centre for Diabetes Research (DZD e.V.), Neuherberg, Germany,Competence Center for Metabolic Vascular Medicine, GWT-TU Dresden, Germany,Contact Information: Andreas L. Birkenfeld, M.D., Section of Metabolic Vascular Medicine, Dresden University School of Medicine Germany, TU Dresden, Tel: +49 15119188884.
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Kammoun HL, Allen TL, Henstridge DC, Kraakman MJ, Peijs L, Rose-John S, Febbraio MA. Over-expressing the soluble gp130-Fc does not ameliorate methionine and choline deficient diet-induced non alcoholic steatohepatitis in mice. PLoS One 2017. [PMID: 28632778 PMCID: PMC5478123 DOI: 10.1371/journal.pone.0179099] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Non-alcoholic steatohepatitis (NASH) is a liver disease with the potential to lead to cirrhosis and hepatocellular carcinoma. Interleukin-6 (IL-6) has been implicated in the pathogenesis of NASH, with the so-called IL-6 ‘trans-signaling’ cascade being responsible for the pro-inflammatory actions of this cytokine. We aimed to block IL-6 ‘trans-signaling’, using a transgenic mouse that overexpresses human soluble glycoprotein130 (sgp130Fc Tg mice) fed a commonly used dietary model of inducing NASH (methionine and choline deficient-diet; MCD diet) and hypothesized that markers of NASH would be ameliorated in such mice. Sgp130Fc Tg and littermate control mice were fed a MCD or control diet for 4 weeks. The MCD diet induced many hallmarks of NASH including hepatomegaly, steatosis, and liver inflammation. However, in contrast with other mouse models and, indeed, human NASH, the MCD diet model did not increase the mRNA or protein expression of IL-6. Not surprisingly, therefore, markers of MCD diet-induced NASH were unaffected by sgp130Fc transgenic expression. While the MCD diet model induces many pathophysiological markers of NASH, it does not induce increased IL-6 expression in the liver, a key hallmark of human NASH. We, therefore, caution the use of the MCD diet as a viable mouse model of NASH.
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Affiliation(s)
- Helene L. Kammoun
- Cellular and Molecular Metabolism Laboratory, Baker Heart & Diabetes Institute, Melbourne, Australia
- Immunology department, Monash University, Melbourne, Australia
- * E-mail:
| | - Tamara Louise Allen
- Cellular and Molecular Metabolism Laboratory, Baker Heart & Diabetes Institute, Melbourne, Australia
| | - Darren Colin Henstridge
- Cellular and Molecular Metabolism Laboratory, Baker Heart & Diabetes Institute, Melbourne, Australia
| | - Michael James Kraakman
- Cellular and Molecular Metabolism Laboratory, Baker Heart & Diabetes Institute, Melbourne, Australia
| | - Lone Peijs
- Cellular and Molecular Metabolism Laboratory, Baker Heart & Diabetes Institute, Melbourne, Australia
| | - Stefan Rose-John
- Department of Biochemistry, Christian-Albrechts-Universität zu Kiel, Kiel, Germany
| | - Mark Anthony Febbraio
- Cellular and Molecular Metabolism Laboratory, Baker Heart & Diabetes Institute, Melbourne, Australia
- Cellular and Molecular Metabolism, Garvan Institute, Sydney, Australia
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Liang S, Cheng X, Hu Y, Song R, Li G. Insulin-like growth factor 1 and metabolic parameters are associated with nonalcoholic fatty liver disease in obese children and adolescents. Acta Paediatr 2017; 106:298-303. [PMID: 27889912 DOI: 10.1111/apa.13685] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2016] [Revised: 10/08/2016] [Accepted: 11/23/2016] [Indexed: 12/18/2022]
Abstract
AIM Few studies have investigated the relationship between paediatric nonalcoholic fatty liver disease (NAFLD) and insulin-like growth factor 1 (IGF-1). This study, carried out from July 2013 to September 2015, aimed to fill the gap and added metabolic parameters to the analysis. METHODS This was a cross-sectional study of 168 obese children and adolescents (84% male), divided into two groups based on the presence (n = 90) or absence (n = 78) of NAFLD. All participants underwent clinical examinations, anthropometric and laboratory examinations and liver ultrasonography. RESULTS Nonalcoholic fatty liver disease patients had significantly lower IGF-1 standard deviation score (IGF-1 SDS) and higher body mass index (BMI), homeostasis model assessment of insulin resistance (HOMA-IR) and uric acid levels than the control group. The prevalence rate of NAFLD was negatively correlated with the IGF-1 SDS. IGF-1 SDS was negatively associated with NAFLD, while BMI, HOMA-IR and uric acid were positively associated with NAFLD. The combined analysis of the area under the receiver operating characteristic curve for multiple variables, including IGF-1 SDS, BMI, HOMA-IR and uric acid, was 0.812, with a sensitivity of 78.89% and specificity of 74.36%. CONCLUSION IGF-1, BMI, HOMA-IR and uric acid were useful markers of NAFLD in obese children and adolescents.
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Affiliation(s)
- Shuang Liang
- Department of Pediatrics Shandong Provincial Hospital Affiliated to Shandong University Shandong China
| | - Xiangdeng Cheng
- Department of Pediatrics Shandong Provincial Hospital Affiliated to Shandong University Shandong China
| | - Yanyan Hu
- Department of Pediatrics Shandong Provincial Hospital Affiliated to Shandong University Shandong China
| | - Ruxin Song
- Department of Ultrasound Shandong Provincial Hospital Affiliated to Shandong University Shandong China
| | - Guimei Li
- Department of Pediatrics Shandong Provincial Hospital Affiliated to Shandong University Shandong China
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The Association Between IGF-1 Levels and the Histologic Severity of Nonalcoholic Fatty Liver Disease. Clin Transl Gastroenterol 2017; 8:e217. [PMID: 28125073 PMCID: PMC5288606 DOI: 10.1038/ctg.2016.72] [Citation(s) in RCA: 68] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2016] [Accepted: 12/07/2016] [Indexed: 12/13/2022] Open
Abstract
Objectives: The mechanisms responsible for the development of nonalcoholic fatty liver disease (NAFLD) and progression to nonalcoholic steatohepatitis (NASH) are incompletely understood. Growing evidence suggests that growth hormone (GH) and insulin-like growth factor-1 (IGF-1) may have roles in the development and progression of NAFLD. We hypothesized that lower serum IGF-1 levels would be associated with increased liver fat accumulation, inflammation, and fibrosis in a group of meticulously phenotyped obese subjects with liver biopsies. Methods: A retrospective, cross-sectional study was performed at Massachusetts General Hospital, Boston, MA, USA and St. Mary's Hospital, Richmond, VA, USA. Liver biopsies were performed in 142 subjects during NAFLD work-up or bariatric surgery and were graded by a single, blinded pathologist. Main outcome measures included liver histology and serum IGF-1. Results: Mean age was 52±10 years and body mass index (BMI) was 43±9 kg/m2. Mean serum IGF-1 was lower in subjects with lobular inflammation (112±47 vs. 136±57 ng/ml, P=0.01), hepatocyte ballooning (115±48 vs. 135±57 ng/ml, P=0.05), higher fibrosis stage (stage 2–4 vs. 0–1; 96±40 vs. 125±51 ng/ml, P=0.005), and NASH (109±45 vs. 136±57 ng/ml, P=0.002). All results remained significant after controlling for age, BMI, and a diagnosis of diabetes, and all but hepatocyte ballooning (trend, P=0.06) remained significant after excluding individuals with cirrhosis. Steatosis was not significantly associated with mean serum IGF-1 levels. Conclusions: Low serum IGF-1 levels are associated with increased histologic severity of NAFLD when rigorously controlled for age, BMI, the presence of diabetes, and after the exclusion of subjects with cirrhosis. Further investigation is warranted to determine the differential effects of GH and IGF-1 on the development and progression of NAFLD, which could further elucidate pathophysiology and identify therapeutic targets.
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Validation of a Modified Child-Turcotte-Pugh Classification System Utilizing Insulin-Like Growth Factor-1 for Patients with Hepatocellular Carcinoma in an HBV Endemic Area. PLoS One 2017; 12:e0170394. [PMID: 28107416 PMCID: PMC5249174 DOI: 10.1371/journal.pone.0170394] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2016] [Accepted: 01/04/2017] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND Recently, a modified insulin-like growth factor-1 (IGF)-Child-Turcotte-Pugh (CTP) classification was proposed to improve the original CTP classification. This study aimed to validate the new IGF-CTP classification system as a prognostic maker for patients with hepatocellular carcinoma (HCC) in a hepatitis B virus endemic area. METHODS We conducted a post-hoc analysis of a prospective cohort study. We used Harrell's C-index and U-statistics to compare the prognostic performance of both IGF-CTP and CTP classifications for overall survival. We evaluated the relationship between HCC stage and the four components of the IGF-CTP classification (serum levels of IGF-1, albumin, and total bilirubin and prothrombin time [PT]) using nonparametric trend analysis. RESULTS We included a total of 393 patients in this study. In all, 55 patients died during the median follow-up of 59.1 months. There was a difference between IGF-CTP class and CTP class in 14% of patients. Overall, the IGF-CTP classification system had a higher prognostic value (C-index = 0.604, 95% confidence interval [CI] = 0.539-0.668) than the CTP system (C-index = 0.558, 95% CI = 0.501-0.614), but the difference was not statistically significant (P = .07 by U-statistics). A lower serum level of IGF-1 was related to a more advanced cancer stage (P < .01). The remaining components of the IGF-CTP classification were not significantly related to tumor stage (P = .11 for total bilirubin; P = .33 for albumin; and P = .39 for PT). CONCLUSIONS The IGF-CTP classification was slightly better than the original CTP classification for predicting survival of patients with HCC in a chronic hepatitis B endemic area. This is most likely due to the fact that serum IGF-1 levels reflect underlying HCC status.
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A Series of microRNA in the Chromosome 14q32.2 Maternally Imprinted Region Related to Progression of Non-Alcoholic Fatty Liver Disease in a Mouse Model. PLoS One 2016; 11:e0154676. [PMID: 27135827 PMCID: PMC4852931 DOI: 10.1371/journal.pone.0154676] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2015] [Accepted: 04/18/2016] [Indexed: 12/25/2022] Open
Abstract
Background & Aims Simple steatosis (SS) and non-alcoholic steatohepatitis (NASH) are subtypes of non-alcoholic fatty liver disease (NAFLD), and the pathogenic differences between SS and NASH remain unclear. MicroRNAs (miRNAs) are endogenous, non-coding, short RNAs that regulate gene expression. The aim of this study was to use animal models and human samples to examine the relationship between miRNA expression profiles and each type of NAFLD (SS and NASH). Methods DD Shionogi, Fatty Liver Shionogi (FLS) and FLS ob/ob mice were used as models for normal control, SS and NASH, respectively. Microarray analysis and real-time PCR were used to identify candidate NAFLD-related miRNAs. Human serum samples were used to examine the expression profiles of these candidate miRNAs in control subjects and patients with SS or NASH. Results Fourteen miRNAs showed clear expression differences among liver tissues from SS, NASH, and control mice with good reproducibility. Among these NAFLD candidate miRNAs, seven showed similar expression patterns and were upregulated in both SS and NASH tissues; these seven candidate miRNAs mapped to an miRNA cluster in the 14q32.2 maternally imprinted region delineated by delta-like homolog 1 and type III iodothyronine deiodinase (Dlk1-Dio3 mat). Software-based predictions indicated that the transforming growth factor-β pathway, insulin like growth factor-1 and 5' adenosine monophosphate activated protein kinase were potential targets of theses Dlk1-Dio3 mat NAFLD candidate miRNAs. In addition, serum samples from patients with SS or NASH differed markedly with regard to expression of the putative Dlk1-Dio3 mat miRNAs, and these differences accurately corresponded with NAFLD diagnosis. Conclusion The expression profiles of seven miRNAs in 14q32.2 mat have high potential as biomarkers for NAFLD and for improving future research on the pathogenesis and treatment of NASH.
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Kineman RD, Majumdar N, Subbaiah PV, Cordoba-Chacon J. Hepatic PPARγ Is Not Essential for the Rapid Development of Steatosis After Loss of Hepatic GH Signaling, in Adult Male Mice. Endocrinology 2016; 157:1728-35. [PMID: 26950202 PMCID: PMC4870866 DOI: 10.1210/en.2015-2077] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
Our group has previously reported de novo lipogenesis (DNL) and hepatic triglyceride content increases in chow-fed male mice within 7 days of hepatocyte-specific GH receptor knockdown (aLivGHRkd). Here, we report that these changes are associated with an increase in hepatic expression of peroxisome proliferator-activated receptor γ (PPARγ), consistent with previous reports showing steatosis is associated with an increase in PPARγ expression in mice with congenital loss of hepatic GH signaling. PPARγ is thought to be an important driver of steatosis by enhancing DNL, as well as increasing the uptake and esterification of extrahepatic fatty acids (FAs). In order to determine whether hepatic PPARγ is critical for the rapid development of steatosis in the aLivGHRkd mouse model, we have generated aLivGHRkd mice, with or without PPARγ (ie, adult-onset, hepatocyte-specific double knockout of GHR and PPARγ). Hepatic PPARγ was not required for the rapid increase in liver triglyceride content or FA indexes of DNL (16:0/18:2 and 16:1/16:0). However, loss of hepatic PPARγ blunted the rise in fatty acid translocase/CD36 and monoacylglycerol acyltransferase 1 expression induced by aLivGHRkd, and this was associated with a reduction in the hepatic content of 18:2. These results suggest that the major role of PPARγ is to enhance pathways critical in uptake and reesterification of extrahepatic FA. Because FAs have been reported to directly increase PPARγ expression, we speculate that in the aLivGHRkd mouse, the FA produced by DNL enhances the expression of PPARγ, which in turn increases extrahepatic FA uptake, thereby further enhancing PPARγ activity and exacerbating steatosis overtime.
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Affiliation(s)
- Rhonda D Kineman
- Research and Development Division (R.D.K., N.M., P.V.S., J.C.-C.), Jesse Brown Veterans Affairs Medical Center; and Department of Medicine (R.D.K., N.M., P.V.S., J.C.-C.), Section of Endocrinology, Diabetes, and Metabolism, University of Illinois at Chicago, Chicago, Illinois 60612
| | - Neena Majumdar
- Research and Development Division (R.D.K., N.M., P.V.S., J.C.-C.), Jesse Brown Veterans Affairs Medical Center; and Department of Medicine (R.D.K., N.M., P.V.S., J.C.-C.), Section of Endocrinology, Diabetes, and Metabolism, University of Illinois at Chicago, Chicago, Illinois 60612
| | - Papasani V Subbaiah
- Research and Development Division (R.D.K., N.M., P.V.S., J.C.-C.), Jesse Brown Veterans Affairs Medical Center; and Department of Medicine (R.D.K., N.M., P.V.S., J.C.-C.), Section of Endocrinology, Diabetes, and Metabolism, University of Illinois at Chicago, Chicago, Illinois 60612
| | - Jose Cordoba-Chacon
- Research and Development Division (R.D.K., N.M., P.V.S., J.C.-C.), Jesse Brown Veterans Affairs Medical Center; and Department of Medicine (R.D.K., N.M., P.V.S., J.C.-C.), Section of Endocrinology, Diabetes, and Metabolism, University of Illinois at Chicago, Chicago, Illinois 60612
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Guo NJ, Li J, Zhu YF, Guo LR, Chen QF, Huang B. Exenatide inhibits fatty acid induced hepatocyte steatosis and inflammation through activating AMPK. Shijie Huaren Xiaohua Zazhi 2016; 24:1649-1657. [DOI: 10.11569/wcjd.v24.i11.1649] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To detect the effect of glucagon-like peptide-1 (GLP-1) agonist exenatide (EXE) on fat deposition in liver cells and explore the underlying mechanism.
METHODS: A HepG2 cell deposition model was induced with palmitic acid (PA). After cells were incubated with different doses of EXE (25-100 nmoL/L) and PA (500 μmoL/L) for 24 h, fatty deposition was assessed by oil red O staining and the level of intracellular triglyceride (TG). Real-time quantitative PCR (qRT-PCR) was used to detect the expression of lipid metabolism related genes, including fatty acid synthase (FAS), tumor necrosis factor α (TNF-α), and interleukin 6 (IL-6). The expression of p-AMPK and AMPK protein was tested by Western blot. An AMPK inhibitor was used to explore the role of AMPK in fat deposition and inflammation.
RESULTS: Compared with the control group, PA significantly elevated TG and oil red O content, as well as the expression of FAS in HepG2 cells (P < 0.05). EXE significantly inhibited PA induced elevation of TG and oil red O content, as well as FAS gene expression in a dose dependent manner (P < 0.05). The expression of TNF-α and IL-6 significantly increased in the PA treated group (P < 0.05). EXE significantly inhibited the expression of TNF-α and IL-6 in PA treated HepG2 cells (P < 0.05). Co-treatment with AMPK inhibitor significantly reduced the effect of EXE on AMPK, and reduced the inhibitory effect of EXE on fatty deposition and PA induced FAS activation (P < 0.05). AMPK inhibitor significantly diminished the inhibitory effect of EXE on TNF-α and IL-6 activation induced by PA (P < 0.05).
CONCLUSION: EXE reduces fatty acid induced fatty deposition and inflammatory response in liver cells through activation of AMPK.
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Prognostic significance of serum insulin-like growth factor-1 in patients with hepatocellular carcinoma following transarterial chemoembolization. Exp Ther Med 2015; 11:607-612. [PMID: 26893654 DOI: 10.3892/etm.2015.2949] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2014] [Accepted: 09/18/2015] [Indexed: 12/23/2022] Open
Abstract
Insulin-like growth factor-1 (IGF-1) is an effective survival factor that is involved in the development and progression of various tumors. The aim of the present study was to investigate whether baseline serum IGF-1 levels are associated with time to progression (TTP) and overall survival (OS) in patients with hepatocellular carcinoma (HCC) who have undergone transarterial chemoembolization (TACE). A total of 145 patients with HCC who underwent TACE as an initial treatment were enrolled in the study. Baseline serum IGF-1 levels were detected using enzyme-linked immunosorbent assay (ELISA) kits. The patients were followed up for a median follow-up period of 47 months (range, 10.6-69.3 months). During the follow-up, 98 patients (76.6%) experienced disease progression and 59 patients (46.1%) succumbed. The serum IGF-1 level was found to be significantly associated with hepatitis infection status, Child-Pugh class, bilirubin level, tumor size and nodularity, vascular invasion and the Barcelona Clinic Liver Cancer (BCLC) stage. Multivariate analysis was conducted, which indicated that BCLC stage, vascular invasion and serum IGF-1 were independent risk factors for disease progression. When clinical factors were examined as potential independent risk factors for OS, only advanced BCLC stage and low serum IGF-1 levels were found to be significantly associated with poorer OS. These results suggest that serum IGF-1 may serve as a predictor of the prognosis of patients with HCC undergoing TACE.
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Macaluso FS, Maida M, Petta S. Genetic background in nonalcoholic fatty liver disease: A comprehensive review. World J Gastroenterol 2015; 21:11088-11111. [PMID: 26494964 PMCID: PMC4607907 DOI: 10.3748/wjg.v21.i39.11088] [Citation(s) in RCA: 59] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/23/2015] [Revised: 06/11/2015] [Accepted: 09/02/2015] [Indexed: 02/06/2023] Open
Abstract
In the Western world, nonalcoholic fatty liver disease (NAFLD) is considered as one of the most significant liver diseases of the twenty-first century. Its development is certainly driven by environmental factors, but it is also regulated by genetic background. The role of heritability has been widely demonstrated by several epidemiological, familial, and twin studies and case series, and likely reflects the wide inter-individual and inter-ethnic genetic variability in systemic metabolism and wound healing response processes. Consistent with this idea, genome-wide association studies have clearly identified Patatin-like phosholipase domain-containing 3 gene variant I148M as a major player in the development and progression of NAFLD. More recently, the transmembrane 6 superfamily member 2 E167K variant emerged as a relevant contributor in both NAFLD pathogenesis and cardiovascular outcomes. Furthermore, numerous case-control studies have been performed to elucidate the potential role of candidate genes in the pathogenesis and progression of fatty liver, although findings are sometimes contradictory. Accordingly, we performed a comprehensive literature search and review on the role of genetics in NAFLD. We emphasize the strengths and weaknesses of the available literature and outline the putative role of each genetic variant in influencing susceptibility and/or progression of the disease.
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Cordoba-Chacon J, Majumdar N, List EO, Diaz-Ruiz A, Frank SJ, Manzano A, Bartrons R, Puchowicz M, Kopchick JJ, Kineman RD. Growth Hormone Inhibits Hepatic De Novo Lipogenesis in Adult Mice. Diabetes 2015; 64:3093-103. [PMID: 26015548 PMCID: PMC4542445 DOI: 10.2337/db15-0370] [Citation(s) in RCA: 74] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2015] [Accepted: 05/20/2015] [Indexed: 02/07/2023]
Abstract
Patients with nonalcoholic fatty liver disease (NAFLD) are reported to have low growth hormone (GH) production and/or hepatic GH resistance. GH replacement can resolve the fatty liver condition in diet-induced obese rodents and in GH-deficient patients. However, it remains to be determined whether this inhibitory action of GH is due to direct regulation of hepatic lipid metabolism. Therefore, an adult-onset, hepatocyte-specific, GH receptor (GHR) knockdown (aLivGHRkd) mouse was developed to model hepatic GH resistance in humans that may occur after sexual maturation. Just 7 days after aLivGHRkd, hepatic de novo lipogenesis (DNL) was increased in male and female chow-fed mice, compared with GHR-intact littermate controls. However, hepatosteatosis developed only in male and ovariectomized female aLivGHRkd mice. The increase in DNL observed in aLivGHRkd mice was not associated with hyperactivation of the pathway by which insulin is classically considered to regulate DNL. However, glucokinase mRNA and protein levels as well as fructose-2,6-bisphosphate levels were increased in aLivGHRkd mice, suggesting that enhanced glycolysis drives DNL in the GH-resistant liver. These results demonstrate that hepatic GH actions normally serve to inhibit DNL, where loss of this inhibitory signal may explain, in part, the inappropriate increase in hepatic DNL observed in NAFLD patients.
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Affiliation(s)
- Jose Cordoba-Chacon
- Research and Development Division, Jesse Brown VA Medical Center, Chicago, IL Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, College of Medicine, University of Illinois at Chicago, Chicago, IL
| | - Neena Majumdar
- Research and Development Division, Jesse Brown VA Medical Center, Chicago, IL Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, College of Medicine, University of Illinois at Chicago, Chicago, IL
| | - Edward O List
- Edison Biotechnology Institute, Ohio University, Athens, OH Department of Specialty Medicine, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH
| | - Alberto Diaz-Ruiz
- Experimental Gerontology Section, Translational Gerontology Branch, National Institute on Aging, National Institutes of Health, Baltimore, MD
| | - Stuart J Frank
- Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, School of Medicine, University of Alabama at Birmingham, Birmingham, AL Endocrinology Section Medical Service, Birmingham VA Medical Center, Birmingham, AL
| | - Anna Manzano
- Department of Physiological Sciences, University of Barcelona, L'Hospitalet, Barcelona, Spain
| | - Ramon Bartrons
- Department of Physiological Sciences, University of Barcelona, L'Hospitalet, Barcelona, Spain
| | - Michelle Puchowicz
- Department of Nutrition, Case Western Reserve University School of Medicine, Cleveland, OH
| | - John J Kopchick
- Edison Biotechnology Institute, Ohio University, Athens, OH Department of Biomedical Sciences, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH
| | - Rhonda D Kineman
- Research and Development Division, Jesse Brown VA Medical Center, Chicago, IL Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, College of Medicine, University of Illinois at Chicago, Chicago, IL
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Sumida Y, Yonei Y, Tanaka S, Mori K, Kanemasa K, Imai S, Taketani H, Hara T, Seko Y, Ishiba H, Okajima A, Yamaguchi K, Moriguchi M, Mitsuyoshi H, Yasui K, Minami M, Itoh Y. Lower levels of insulin-like growth factor-1 standard deviation score are associated with histological severity of non-alcoholic fatty liver disease. Hepatol Res 2015; 45:771-81. [PMID: 25163357 DOI: 10.1111/hepr.12408] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2014] [Revised: 08/12/2014] [Accepted: 08/20/2014] [Indexed: 02/08/2023]
Abstract
AIM Growth hormone (GH) deficiency may be associated with histological progression of non-alcoholic fatty liver disease (NAFLD) which includes non-alcoholic fatty liver (NAFL) and non-alcoholic steatohepatitis (NASH). Insulin-like growth factor 1 (IGF-1) is mainly produced by hepatocytes and its secretion is stimulated by GH. Our aim was to determine whether more histologically advanced NAFLD is associated with low circulating levels of IGF-1 in Japanese patients. METHODS Serum samples were obtained in 199 Japanese patients with biopsy-proven NAFLD and in 2911 sex- and age-matched healthy people undergoing health checkups. The serum levels of IGF-1 were measured using a commercially available immunoradiometric assay. The standard deviation scores (SDS) of IGF-1 according to age and sex were also calculated in NAFLD patients. RESULTS The serum IGF-1 levels in NAFLD patients were significantly lower (median, 112 ng/mL) compared with the control population (median, 121 ng/mL, P < 0.0001). IGF-1 SDS less than -2.0 SD from median were found in 11.6% of 199 patients. NASH patients exhibited significantly lower levels of IGF-1 SDS (n = 130; median, -0.7) compared with NAFL patients (n = 69; median, -0.3; P = 0.026). The IGF-1 SDS values decreased significantly with increasing lobular inflammation (P < 0.001) and fibrosis (P < 0.001). In multiple regressions, the association between the IGF-1 SDS values and the severity of NAFLD persisted after adjusting for age, sex and insulin resistance. CONCLUSION Low levels of circulating IGF-1 may have a role in the development of advanced NAFLD, independent of insulin resistance. Supplementation with GH/IGF-1 may be a candidate for the treatment of NASH.
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Affiliation(s)
- Yoshio Sumida
- Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Yoshikazu Yonei
- Anti-Aging Medical Research Center, Faculty of Life and Medical Sciences, Doshisha University, Kyotanabe, Japan
| | - Saiyu Tanaka
- Center for Digestive and Liver Diseases, Nara City Hospital, Nara, Japan
| | - Kojiroh Mori
- Center for Digestive and Liver Diseases, Nara City Hospital, Nara, Japan
| | - Kazuyuki Kanemasa
- Center for Digestive and Liver Diseases, Nara City Hospital, Nara, Japan
| | - Shunsuke Imai
- Department of Pathology, Nara City Hospital, Nara, Japan
| | - Hiroyoshi Taketani
- Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Tasuku Hara
- Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Yuya Seko
- Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Hiroshi Ishiba
- Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Akira Okajima
- Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Kanji Yamaguchi
- Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Michihisa Moriguchi
- Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Hironori Mitsuyoshi
- Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Kohichiroh Yasui
- Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Masahito Minami
- Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Yoshito Itoh
- Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto, Japan
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