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1
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Jeong S, Shin WY, Oh YH. Immunotherapy for NAFLD and NAFLD-related hepatocellular carcinoma. Front Endocrinol (Lausanne) 2023; 14:1150360. [PMID: 37020584 PMCID: PMC10069645 DOI: 10.3389/fendo.2023.1150360] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2023] [Accepted: 03/06/2023] [Indexed: 04/07/2023] Open
Abstract
The progression of non-alcoholic fatty liver disease (NAFLD), the most common liver disease, leads to non-alcoholic steatohepatitis and hepatocellular carcinoma. Despite the increasing incidence and prevalence of NAFLD, its therapeutic and preventive strategies to lower the disease burden is limited. In recent years, immunotherapy, including anti-programmed cell death 1/programmed cell death 1 ligand 1 treatment, has emerged as a potential approach to reach satisfactory modulation for the progression of NAFLD and treatment of NAFLD-related hepatocellular carcinoma. However, the effectiveness of immunotherapy against NAFLD and NAFLD-related hepatocellular carcinoma is in the early phase and it is yet not advanced. In addition, conflicting results are being reported regarding the prognosis of patients with NAFLD-related hepatocellular carcinoma and high expression of programmed cell death 1/programmed cell death 1 ligand 1. Herein, this review will discuss and elucidate the attempts and underlying mechanisms of immunotherapy against NAFLD and NAFLD-related hepatocellular carcinoma.
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Affiliation(s)
- Seogsong Jeong
- Department of Biomedical Informatics, CHA University School of Medicine, CHA University, Seongnam, Republic of Korea
- Institute for Biomedical Informatics, School of Medicine, CHA University, Seongnam, Republic of Korea
| | - Woo-Young Shin
- Department of Family medicine, Chung-Ang University Gwangmyeong Hospital, Chung-Ang University College of Medicine, Gwangmyeong, Republic of Korea
| | - Yun Hwan Oh
- Department of Family medicine, Chung-Ang University Gwangmyeong Hospital, Chung-Ang University College of Medicine, Gwangmyeong, Republic of Korea
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2
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Ndakotsu A, Vivekanandan G. The Role of Thiazolidinediones in the Amelioration of Nonalcoholic Fatty Liver Disease: A Systematic Review. Cureus 2022; 14:e25380. [PMID: 35765391 PMCID: PMC9233742 DOI: 10.7759/cureus.25380] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2022] [Accepted: 05/27/2022] [Indexed: 11/05/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a broad term encompassing hepatic steatosis and non-alcoholic steatohepatitis (NASH), a form of chronic hepatitis. This may, unfortunately, lead to terminal complications like cirrhosis and hepatocellular carcinoma (HCC). NAFLD is strongly associated with obesity, type 2 diabetes (T2DM), hypertension, and metabolic syndrome. The growing prevalence of NAFLD, its associated conditions, and its complications are alarming. The insulin sensitizer group "thiazolidinediones" has shown some therapeutic benefits in this condition. This systematic review is intended to focus on the clinical efficacy of this group in patients with NAFLD, employing PubMed, Google Scholar, and the Cochrane Library as databases. We discovered 10 randomized control trials (RCTs; nine involving pioglitazone and one involving rosiglitazone) involving 887 participants. All studies varied in duration from 6 to 24 months. Most of the involved trials had a small number of participants, and the intrinsic quality of the studies was mixed. Pioglitazone consistently improved histological parameters and normalized liver transaminases, although evidence supporting the benefits of other drugs in this class was minimal. Thiazolidinediones, particularly pioglitazone, have proven efficacious in patients with NAFLD/NASH. However, more extensive trials need to be carried out to investigate this drug class's benefits further. Unfortunately, this drug has attendant side effects like weight gain and fractures, limiting its widespread use; hence, careful selection for likely candidates is imperative.
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Affiliation(s)
- Andrew Ndakotsu
- Internal Medicine, California Institute of Behavioral Neurosciences and Psychology, Fairfield, USA
| | - Govinathan Vivekanandan
- Internal Medicine, California Institute of Behavioral Neurosciences and Psychology, Fairfield, USA
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3
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Lange NF, Graf V, Caussy C, Dufour JF. PPAR-Targeted Therapies in the Treatment of Non-Alcoholic Fatty Liver Disease in Diabetic Patients. Int J Mol Sci 2022; 23:ijms23084305. [PMID: 35457120 PMCID: PMC9028563 DOI: 10.3390/ijms23084305] [Citation(s) in RCA: 43] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2022] [Revised: 04/06/2022] [Accepted: 04/08/2022] [Indexed: 02/06/2023] Open
Abstract
Peroxisome proliferator-activated receptors (PPAR), ligand-activated transcription factors of the nuclear hormone receptor superfamily, have been identified as key metabolic regulators in the liver, skeletal muscle, and adipose tissue, among others. As a leading cause of liver disease worldwide, non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) cause a significant burden worldwide and therapeutic strategies are needed. This review provides an overview of the evidence on PPAR-targeted treatment of NAFLD and NASH in individuals with type 2 diabetes mellitus. We considered current evidence from clinical trials and observational studies as well as the impact of treatment on comorbid metabolic conditions such as obesity, dyslipidemia, and cardiovascular disease. Future areas of research, such as possible sexually dimorphic effects of PPAR-targeted therapies, are briefly reviewed.
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Affiliation(s)
- Naomi F. Lange
- Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, 3010 Bern, Switzerland
- Graduate School for Health Sciences, University of Bern, 3012 Bern, Switzerland
- Correspondence: (N.F.L.); (J.-F.D.)
| | - Vanessa Graf
- Department of Diabetes, Endocrinology, Clinical Nutrition, and Metabolism, Inselspital, Bern University Hospital, University of Bern, 3010 Bern, Switzerland;
| | - Cyrielle Caussy
- Univ Lyon, CarMen Laboratory, INSERM, INRA, INSA Lyon, Université Claude Bernard Lyon 1, 69495 Pierre-Bénite, France;
- Département Endocrinologie, Diabète et Nutrition, Hôpital Lyon Sud, Hospices Civils de Lyon, 69495 Pierre-Bénite, France
| | - Jean-François Dufour
- Centre des Maladies Digestives, 1003 Lausanne, Switzerland
- Swiss NASH Foundation, 3011 Bern, Switzerland
- Correspondence: (N.F.L.); (J.-F.D.)
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4
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Zhang X, Deng F, Zhang Y, Zhang X, Chen J, Jiang Y. PPARγ attenuates hepatic inflammation and oxidative stress of non‑alcoholic steatohepatitis via modulating the miR‑21‑5p/SFRP5 pathway. Mol Med Rep 2021; 24:823. [PMID: 34558644 PMCID: PMC8485121 DOI: 10.3892/mmr.2021.12463] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2021] [Accepted: 08/12/2021] [Indexed: 12/13/2022] Open
Abstract
Inflammation and oxidative stress are key steps in the progression of non‑alcoholic steatohepatitis (NASH). Intervention in these two processes will therefore benefit NASH treatment. Peroxisome proliferator‑activated receptor γ (PPARγ), as a multiple functional transcription factor, has been reported to be involved in the prevention of NASH progression. However, the mechanism by which PPARγ prevents NASH remains to be elucidated. The present study demonstrated that the level of PPARγ was inversely correlated with that of microRNA (miRNA/miRs)‑21‑5p in both mice and humans with NASH. Activation of PPARγ inhibited lipid droplet accumulation, hepatic inflammation and oxidative stress by downregulating miR‑21‑5p in an in vitro model. Luciferase reporter and chromatin immunoprecipitation assays demonstrated that PPARγ suppressed transcriptional activity of miR‑21‑5p and bound to miR‑21‑5p promoter region. Furthermore, PPARγ downregulated miR‑21‑5p while miR‑21‑5p upregulated secreted frizzled‑related protein 5 (SFRP5) by targeting the 3'‑UTR of its mRNA. In vivo experiments revealed that PPARγ repressed inflammation and oxidative stress and miR‑21‑5p expression while increased SFRP5 level in a NASH mouse model. In summary, PPARγ attenuates inflammation and oxidative stress in NASH by modulating the miR‑21‑5p/SFRP5 pathway, thus holding promise of a new target for NASH treatment.
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Affiliation(s)
- Xiying Zhang
- Department of Endocrinology, Banan People's Hospital of Chongqing, Chongqing 401320, P.R. China
| | - Fang Deng
- Department of Endocrinology, Southwest Hospital, Army Medical University, Chongqing 400038, P.R. China
| | - Yuping Zhang
- Department of Endocrinology, Southwest Hospital, Army Medical University, Chongqing 400038, P.R. China
| | - Xiaohong Zhang
- Department of Endocrinology, Banan People's Hospital of Chongqing, Chongqing 401320, P.R. China
| | - Jianfei Chen
- Department of Cardiology, Banan People's Hospital of Chongqing, Chongqing 401320, P.R. China
| | - Youzhao Jiang
- Department of Endocrinology, Banan People's Hospital of Chongqing, Chongqing 401320, P.R. China
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Ferguson D, Finck BN. Emerging therapeutic approaches for the treatment of NAFLD and type 2 diabetes mellitus. Nat Rev Endocrinol 2021; 17:484-495. [PMID: 34131333 PMCID: PMC8570106 DOI: 10.1038/s41574-021-00507-z] [Citation(s) in RCA: 303] [Impact Index Per Article: 75.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/29/2021] [Indexed: 12/15/2022]
Abstract
Non-alcoholic fatty liver disease (NAFLD) has emerged as the most prevalent liver disease in the world, yet there are still no approved pharmacological therapies to prevent or treat this condition. NAFLD encompasses a spectrum of severity, ranging from simple steatosis to non-alcoholic steatohepatitis (NASH). Although NASH is linked to an increased risk of hepatocellular carcinoma and cirrhosis and has now become the leading cause of liver failure-related transplantation, the majority of patients with NASH will ultimately die as a result of complications of type 2 diabetes mellitus (T2DM) and cardiometabolic diseases. Importantly, NAFLD is closely linked to obesity and tightly interrelated with insulin resistance and T2DM. Thus, targeting these interconnected conditions and taking a holistic attitude to the treatment of metabolic disease could prove to be a very beneficial approach. This Review will explore the latest relevant literature and discuss the ongoing therapeutic options for NAFLD focused on targeting intermediary metabolism, insulin resistance and T2DM to remedy the global health burden of these diseases.
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Affiliation(s)
- Daniel Ferguson
- Division of Geriatrics and Nutritional Sciences, Center for Human Nutrition, Department of Medicine, Washington University School of Medicine, St Louis, MO, USA
| | - Brian N Finck
- Division of Geriatrics and Nutritional Sciences, Center for Human Nutrition, Department of Medicine, Washington University School of Medicine, St Louis, MO, USA.
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Flessa CM, Kyrou I, Nasiri-Ansari N, Kaltsas G, Papavassiliou AG, Kassi E, Randeva HS. Endoplasmic Reticulum Stress and Autophagy in the Pathogenesis of Non-alcoholic Fatty Liver Disease (NAFLD): Current Evidence and Perspectives. Curr Obes Rep 2021; 10:134-161. [PMID: 33751456 DOI: 10.1007/s13679-021-00431-3] [Citation(s) in RCA: 48] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 02/23/2021] [Indexed: 02/06/2023]
Abstract
PURPOSE OF REVIEW Non-alcoholic fatty liver disease (NAFLD) is one of the most common causes of chronic liver disease with rising prevalence worldwide. Herein, we provide a comprehensive overview of the current knowledge supporting the role of ER stress and autophagy processes in NAFLD pathogenesis and progression. We also highlight the interrelation between these two pathways and the impact of ER stress and autophagy modulators on NAFLD treatment. RECENT FINDINGS The pathophysiological mechanisms involved in NAFLD progression are currently under investigation. The endoplasmic reticulum (ER) stress and the concomitant unfolded protein response (UPR) seem to contribute to its pathogenesis mainly due to high ER content in the liver which exerts significant metabolic functions and can be dysregulated. Furthermore, disruption of autophagy processes has also been identified in NAFLD. The crucial role of these two pathways in NAFLD is underlined by the fact that they have recently emerged as promising targets of therapeutic interventions. There is a greater need for finding the natural/chemical compounds and drugs which can modulate the ER stress pathway and autophagy for the treatment of NAFLD. Clarifying the inter-relation between these two pathways and their interaction with inflammatory and apoptotic mechanisms will allow the development of additional therapeutic options which can better target and reprogram the underlying pathophysiological pathways, aiming to attenuate NAFLD progression.
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Affiliation(s)
- Christina-Maria Flessa
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527, Athens, Greece
- Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism (WISDEM), University Hospitals Coventry and Warwickshire NHS Trust, Coventry, CV2 2DX, UK
| | - Ioannis Kyrou
- Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism (WISDEM), University Hospitals Coventry and Warwickshire NHS Trust, Coventry, CV2 2DX, UK
- Aston Medical Research Institute, Aston Medical School, College of Health and Life Sciences, Aston University, B4 7ET, Birmingham, UK
- Division of Translational and Experimental Medicine, Metabolic and Vascular Health, Warwick Medical School, University of Warwick, Coventry, CV4 7AL, UK
| | - Narjes Nasiri-Ansari
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527, Athens, Greece
| | - Gregory Kaltsas
- Endocrine Unit, 1st Department of Propaedeutic and Internal Medicine, Laiko Hospital, National and Kapodistrian University of Athens, 11527, Athens, Greece
| | - Athanasios G Papavassiliou
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527, Athens, Greece
| | - Eva Kassi
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527, Athens, Greece.
- Endocrine Unit, 1st Department of Propaedeutic and Internal Medicine, Laiko Hospital, National and Kapodistrian University of Athens, 11527, Athens, Greece.
| | - Harpal S Randeva
- Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism (WISDEM), University Hospitals Coventry and Warwickshire NHS Trust, Coventry, CV2 2DX, UK.
- Division of Translational and Experimental Medicine, Metabolic and Vascular Health, Warwick Medical School, University of Warwick, Coventry, CV4 7AL, UK.
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Di Ciaula A, Passarella S, Shanmugam H, Noviello M, Bonfrate L, Wang DQH, Portincasa P. Nonalcoholic Fatty Liver Disease (NAFLD). Mitochondria as Players and Targets of Therapies? Int J Mol Sci 2021; 22:5375. [PMID: 34065331 PMCID: PMC8160908 DOI: 10.3390/ijms22105375] [Citation(s) in RCA: 66] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2021] [Revised: 05/14/2021] [Accepted: 05/18/2021] [Indexed: 12/12/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease and represents the hepatic expression of several metabolic abnormalities of high epidemiologic relevance. Fat accumulation in the hepatocytes results in cellular fragility and risk of progression toward necroinflammation, i.e., nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and eventually hepatocellular carcinoma. Several pathways contribute to fat accumulation and damage in the liver and can also involve the mitochondria, whose functional integrity is essential to maintain liver bioenergetics. In NAFLD/NASH, both structural and functional mitochondrial abnormalities occur and can involve mitochondrial electron transport chain, decreased mitochondrial β-oxidation of free fatty acids, excessive generation of reactive oxygen species, and lipid peroxidation. NASH is a major target of therapy, but there is no established single or combined treatment so far. Notably, translational and clinical studies point to mitochondria as future therapeutic targets in NAFLD since the prevention of mitochondrial damage could improve liver bioenergetics.
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Affiliation(s)
- Agostino Di Ciaula
- Department of Biomedical Sciences & Human Oncology, Clinica Medica “A. Murri”, University of Bari Medical School, 70124 Bari, Italy; (A.D.C.); (H.S.); (M.N.); (L.B.)
| | | | - Harshitha Shanmugam
- Department of Biomedical Sciences & Human Oncology, Clinica Medica “A. Murri”, University of Bari Medical School, 70124 Bari, Italy; (A.D.C.); (H.S.); (M.N.); (L.B.)
| | - Marica Noviello
- Department of Biomedical Sciences & Human Oncology, Clinica Medica “A. Murri”, University of Bari Medical School, 70124 Bari, Italy; (A.D.C.); (H.S.); (M.N.); (L.B.)
| | - Leonilde Bonfrate
- Department of Biomedical Sciences & Human Oncology, Clinica Medica “A. Murri”, University of Bari Medical School, 70124 Bari, Italy; (A.D.C.); (H.S.); (M.N.); (L.B.)
| | - David Q.-H. Wang
- Department of Medicine and Genetics, Division of Gastroenterology and Liver Diseases, Marion Bessin Liver Research Center, Einstein-Mount Sinai Diabetes Research Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA;
| | - Piero Portincasa
- Department of Biomedical Sciences & Human Oncology, Clinica Medica “A. Murri”, University of Bari Medical School, 70124 Bari, Italy; (A.D.C.); (H.S.); (M.N.); (L.B.)
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8
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Kamm DR, Pyles KD, Sharpe MC, Healy LN, Colca JR, McCommis KS. Novel insulin sensitizer MSDC-0602K improves insulinemia and fatty liver disease in mice, alone and in combination with liraglutide. J Biol Chem 2021; 296:100807. [PMID: 34022222 PMCID: PMC8192871 DOI: 10.1016/j.jbc.2021.100807] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Revised: 05/14/2021] [Accepted: 05/18/2021] [Indexed: 01/04/2023] Open
Abstract
Insulin sensitizers and incretin mimetics are antidiabetic agents with vastly different mechanisms of action. Thiazolidinedione (TZD) insulin sensitizers are associated with weight gain, whereas glucagon-like peptide-1 receptor agonists can induce weight loss. We hypothesized that combination of a TZD insulin sensitizer and the glucagon-like peptide-1 receptor agonist liraglutide would more significantly improve mouse models of diabetes and nonalcoholic steatohepatitis (NASH). Diabetic db/db and MS-NASH mice were treated with the TZD MSDC-0602K by oral gavage, liraglutide (Lira) by s.c. injection, or combination 0602K+Lira. Lira slightly reduced body weight and modestly improved glycemia in db/db mice. Comparatively, 0602K-treated and 0602K+Lira-treated mice exhibited slight weight gain but completely corrected glycemia and improved glucose tolerance. 0602K reduced plasma insulin, whereas Lira further increased the hyperinsulinemia of db/db mice. Surprisingly, 0602K+Lira treatment reduced plasma insulin and C-peptide to the same extent as mice treated with 0602K alone. 0602K did not reduce glucose-stimulated insulin secretion in vivo, or in isolated islets, indicating the reduced insulinemia was likely compensatory to improved insulin sensitivity. In MS-NASH mice, both 0602K or Lira alone improved plasma alanine aminotransferase and aspartate aminotransferase, as well as liver histology, but more significant improvements were observed with 0602K+Lira treatment. 0602K or 0602K+Lira also increased pancreatic insulin content in both db/db and MS-NASH mice. In conclusion, MSDC-0602K corrected glycemia and reduced insulinemia when given alone, or in combination with Lira. However, 0602K+Lira combination more significantly improved glucose tolerance and liver histology, suggesting that this combination treatment may be an effective therapeutic strategy for diabetes and NASH.
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Affiliation(s)
- Dakota R Kamm
- Biochemistry & Molecular Biology, Saint Louis University School of Medicine, St Louis, Missouri, USA
| | - Kelly D Pyles
- Biochemistry & Molecular Biology, Saint Louis University School of Medicine, St Louis, Missouri, USA
| | - Martin C Sharpe
- Biochemistry & Molecular Biology, Saint Louis University School of Medicine, St Louis, Missouri, USA
| | - Laura N Healy
- LNH Tox Path Consulting LLC, Newbury Park, California, USA
| | - Jerry R Colca
- Cirius Therapeutics, Kalamazoo, Michigan, USA; Cirius Therapeutics, San Diego, California, USA
| | - Kyle S McCommis
- Biochemistry & Molecular Biology, Saint Louis University School of Medicine, St Louis, Missouri, USA.
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Heda R, Yazawa M, Shi M, Bhaskaran M, Aloor FZ, Thuluvath PJ, Satapathy SK. Non-alcoholic fatty liver and chronic kidney disease: Retrospect, introspect, and prospect. World J Gastroenterol 2021; 27:1864-1882. [PMID: 34007127 PMCID: PMC8108029 DOI: 10.3748/wjg.v27.i17.1864] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2021] [Revised: 03/07/2021] [Accepted: 04/07/2021] [Indexed: 02/06/2023] Open
Abstract
With the growing prevalence of obesity and diabetes in the United States and across the world, a rise in the overall incidence and prevalence of non-alcoholic fatty liver disease (NAFLD) is expected. The risk factors for NAFLD are also associated with the development of chronic kidney disease (CKD). We review the epidemiology, risk factors, genetics, implications of gut dysbiosis, and specific pathogenic mechanisms linking NAFLD to CKD. Mechanisms such as ectopic lipid accumulation, cellular signaling abnormalities, and the interplay between fructose consumption and uric acid accumulation have led to the emergence of potential therapeutic implications for this patient population. Transplant evaluation in the setting of both NAFLD and CKD is also reviewed. Potential strategies for surveillance and management include the monitoring of comorbidities, the use of non-invasive fibrosis scoring systems, and the measurement of laboratory markers. Lastly, we discuss the management of patients with NAFLD and CKD, from preventative measures to experimental interventions.
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Affiliation(s)
- Rajiv Heda
- Department of Internal Medicine, Tulane University School of Medicine, New Orleans, LA 70112, United States
| | - Masahiko Yazawa
- Department of Nephrology and Hypertension, St. Marianna University School of Medicine, Kawasaki 216-8511, Japan
| | - Michelle Shi
- Department of Internal Medicine, Donald and Barbara Zucker School of Medicine, Northwell Health, Manhasset, NY 11030, United States
| | - Madhu Bhaskaran
- Department of Nephrology, Northwell Health/Zucker School of Medicine at Hosftra, Manhasset, NY 11030, United States
| | - Fuad Zain Aloor
- Department of Internal Medicine, Baylor College of Medicine, Houston, TX 77030, United States
| | - Paul J Thuluvath
- Institute of Digestive Health & Liver Diseases, Mercy Medical Center, Baltimore, MD 21202, United States
| | - Sanjaya K Satapathy
- Department of Internal Medicine, Donald and Barbara Zucker School of Medicine, Northwell Health, Manhasset, NY 11030, United States
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Wang X, Ma B, Chen J, You H, Sheng C, Yang P, Qu S. Glucagon-like Peptide-1 Improves Fatty Liver and Enhances Thermogenesis in Brown Adipose Tissue via Inhibiting BMP4-Related Signaling Pathway in High-Fat-Diet-Induced Obese Mice. Int J Endocrinol 2021; 2021:6620289. [PMID: 33986800 PMCID: PMC8093078 DOI: 10.1155/2021/6620289] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2020] [Revised: 02/03/2021] [Accepted: 04/04/2021] [Indexed: 12/15/2022] Open
Abstract
OBJECTIVE Glucagon-like peptide-1 (GLP-1) receptor agonist is effective in decreasing blood glucose and body weight. It could improve fatty liver with unclear mechanisms. Hence, we aimed to explore whether GLP-1 could improve fatty liver by regulating the BMP4-related signaling pathway. METHODS Fifteen C57BL/6 mice were randomly assigned to 3 groups. Group A and Group B were fed with a high-fat diet (HFD) to induce fatty liver while Group C was fed with a regular diet (RD) for 24 weeks. Group A and Group B received a subcutaneous injection of exenatide and vehicle (0.9% NaCl), respectively, once daily at doses of 10 nmol/kg during the last 8 weeks. Bodyweight, liver weight, and lipid levels were measured. Histological analyses of liver tissue were performed. The expression of protein and gene measured by western blotting and real-time polymerase chain reaction (RT-PCR) was compared. RESULTS Eight-week exenatide treatment significantly decreased body weight in Group A (from 44.08 ± 2.89 g to 39.22 ± 1.88 g, P = 0.045). Group A had lower body weight and liver weight than Group B at 24 weeks (39.22 ± 1.88 g vs. 47.34 ± 2.43 g, P = 0.001 and 1.70 ± 0.20 g vs. 2.48 ± 0.19 g, P = 0.001, respectively). Moreover, Group A showed significantly less liver steatosis than Group B. Additionally, Group A led to slightly decreased serum triglyceride (TG) and cholesterol (TC) levels compared to Group B. Western blotting showed that exenatide could prevent HFD-induced upregulation of BMP4 levels and downstream activation of Smad1/5/8 and the P38 MAPK signaling pathway in the liver. Furthermore, exenatide treatment could reduce BMP4 and enhance UCP-1 (an important thermogenin) in brown adipose tissue (BAT). CONCLUSION Exenatide could improve HFD-induced hepatic steatosis and enhance thermogenesis in BAT, which may be partly attributed to the inhibition of the BMP4-related signaling pathway.
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Affiliation(s)
- Xingchun Wang
- Thyriod Research Center of Shanghai, Shanghai Tenth People's Hospital of Tongji University, School of Medicine, Tongji University, Shanghai 200072, China
- Department of Endocrinology and Metabolism, Shanghai Tenth People's Hospital of Tongji University, School of Medicine, Tongji University, Shanghai 200072, China
| | - Bingwei Ma
- Department of Endocrinology and Metabolism, Shanghai Tenth People's Hospital of Tongji University, School of Medicine, Tongji University, Shanghai 200072, China
- Department of Gastrointestinal Surgery, Shanghai Tenth People's Hospital of Tongji University, School of Medicine, Tongji University, Shanghai 200072, China
| | - Jiaqi Chen
- Suzhou Municipal Hospital, Suzhou 215000, Jiangsu, China
| | - Hui You
- Department of Endocrinology and Metabolism, Shanghai Tenth People's Hospital of Tongji University, School of Medicine, Tongji University, Shanghai 200072, China
| | - Chunjun Sheng
- Thyriod Research Center of Shanghai, Shanghai Tenth People's Hospital of Tongji University, School of Medicine, Tongji University, Shanghai 200072, China
- Department of Endocrinology and Metabolism, Shanghai Tenth People's Hospital of Tongji University, School of Medicine, Tongji University, Shanghai 200072, China
| | - Peng Yang
- Thyriod Research Center of Shanghai, Shanghai Tenth People's Hospital of Tongji University, School of Medicine, Tongji University, Shanghai 200072, China
- Department of Endocrinology and Metabolism, Shanghai Tenth People's Hospital of Tongji University, School of Medicine, Tongji University, Shanghai 200072, China
| | - Shen Qu
- Thyriod Research Center of Shanghai, Shanghai Tenth People's Hospital of Tongji University, School of Medicine, Tongji University, Shanghai 200072, China
- Department of Endocrinology and Metabolism, Shanghai Tenth People's Hospital of Tongji University, School of Medicine, Tongji University, Shanghai 200072, China
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11
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Grattagliano I, Di Ciaula A, Baj J, Molina-Molina E, Shanmugam H, Garruti G, Wang DQH, Portincasa P. Protocols for Mitochondria as the Target of Pharmacological Therapy in the Context of Nonalcoholic Fatty Liver Disease (NAFLD). Methods Mol Biol 2021; 2310:201-246. [PMID: 34096005 PMCID: PMC8580566 DOI: 10.1007/978-1-0716-1433-4_12] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is one of the most frequent metabolic chronic liver diseases in developed countries and puts the populations at risk of progression to liver necro-inflammation, fibrosis, cirrhosis, and hepatocellular carcinoma. Mitochondrial dysfunction is involved in the onset of NAFLD and contributes to the progression from NAFLD to nonalcoholic steatohepatitis (NASH). Thus, liver mitochondria could become the target for treatments for improving liver function in NAFLD patients. This chapter describes the most important steps used for potential therapeutic interventions in NAFLD patients, discusses current options gathered from both experimental and clinical evidence, and presents some novel options for potentially improving mitochondrial function in NAFLD.
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Affiliation(s)
- Ignazio Grattagliano
- Clinica Medica "A. Murri", Department of Biomedical Sciences and Human Oncology, University of Bari Medical School, Bari, Italy
- Italian College of General Practitioners and Primary Care, Bari, Italy
| | - Agostino Di Ciaula
- Clinica Medica "A. Murri", Department of Biomedical Sciences and Human Oncology, University of Bari Medical School, Bari, Italy
| | - Jacek Baj
- Department of Anatomy, Medical University of Lublin, Lublin, Poland
| | - Emilio Molina-Molina
- Clinica Medica "A. Murri", Department of Biomedical Sciences and Human Oncology, University of Bari Medical School, Bari, Italy
| | - Harshitha Shanmugam
- Clinica Medica "A. Murri", Department of Biomedical Sciences and Human Oncology, University of Bari Medical School, Bari, Italy
| | - Gabriella Garruti
- Section of Endocrinology, Department of Emergency and Organ Transplantations, University of Bari "Aldo Moro" Medical School, Bari, Italy
| | - David Q-H Wang
- Division of Gastroenterology and Liver Diseases, Department of Medicine and Genetics, Marion Bessin Liver Research Center, Einstein-Mount Sinai Diabetes Research Center, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Piero Portincasa
- Clinica Medica "A. Murri", Department of Biomedical Sciences and Human Oncology, University of Bari Medical School, Bari, Italy.
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12
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Fougerat A, Montagner A, Loiseau N, Guillou H, Wahli W. Peroxisome Proliferator-Activated Receptors and Their Novel Ligands as Candidates for the Treatment of Non-Alcoholic Fatty Liver Disease. Cells 2020; 9:E1638. [PMID: 32650421 PMCID: PMC7408116 DOI: 10.3390/cells9071638] [Citation(s) in RCA: 89] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2020] [Revised: 06/26/2020] [Accepted: 07/04/2020] [Indexed: 12/11/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a major health issue worldwide, frequently associated with obesity and type 2 diabetes. Steatosis is the initial stage of the disease, which is characterized by lipid accumulation in hepatocytes, which can progress to non-alcoholic steatohepatitis (NASH) with inflammation and various levels of fibrosis that further increase the risk of developing cirrhosis and hepatocellular carcinoma. The pathogenesis of NAFLD is influenced by interactions between genetic and environmental factors and involves several biological processes in multiple organs. No effective therapy is currently available for the treatment of NAFLD. Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that regulate many functions that are disturbed in NAFLD, including glucose and lipid metabolism, as well as inflammation. Thus, they represent relevant clinical targets for NAFLD. In this review, we describe the determinants and mechanisms underlying the pathogenesis of NAFLD, its progression and complications, as well as the current therapeutic strategies that are employed. We also focus on the complementary and distinct roles of PPAR isotypes in many biological processes and on the effects of first-generation PPAR agonists. Finally, we review novel and safe PPAR agonists with improved efficacy and their potential use in the treatment of NAFLD.
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Affiliation(s)
- Anne Fougerat
- Institut National de la Recherche Agronomique (INRAE), ToxAlim, UMR1331 Toulouse, France; (A.M.); (N.L.); (H.G.)
| | - Alexandra Montagner
- Institut National de la Recherche Agronomique (INRAE), ToxAlim, UMR1331 Toulouse, France; (A.M.); (N.L.); (H.G.)
- Institut National de la Santé et de la Recherche Médicale (Inserm), Institute of Metabolic and Cardiovascular Diseases, UMR1048 Toulouse, France
- Institute of Metabolic and Cardiovascular Diseases, University of Toulouse, UMR1048 Toulouse, France
| | - Nicolas Loiseau
- Institut National de la Recherche Agronomique (INRAE), ToxAlim, UMR1331 Toulouse, France; (A.M.); (N.L.); (H.G.)
| | - Hervé Guillou
- Institut National de la Recherche Agronomique (INRAE), ToxAlim, UMR1331 Toulouse, France; (A.M.); (N.L.); (H.G.)
| | - Walter Wahli
- Institut National de la Recherche Agronomique (INRAE), ToxAlim, UMR1331 Toulouse, France; (A.M.); (N.L.); (H.G.)
- Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, Clinical Sciences Building, 11 Mandalay Road, Singapore 308232, Singapore
- Center for Integrative Genomics, Université de Lausanne, Le Génopode, CH-1015 Lausanne, Switzerland
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13
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Xia Z, Ding L, Zheng J, Xu Y, Jin W, Sheng X, Wu J. Alginate Suppresses Liver Fibrosis Through the Inhibition of Nuclear Factor-κB Signaling. DRUG DESIGN DEVELOPMENT AND THERAPY 2020; 14:1295-1305. [PMID: 32280199 PMCID: PMC7127827 DOI: 10.2147/dddt.s233665] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/07/2019] [Accepted: 01/08/2020] [Indexed: 01/19/2023]
Abstract
Purpose Liver fibrosis (or liver scarring) is a causative factor for hepatitis, cirrhosis and hepatocellular carcinoma (HCC). Alginate (Agn) isolated from brown algae is known to slow the proliferation of fibroblasts, through the mechanisms of these effects remain undefined. This study explored the benefits of Agn on hepatic health and its associated mechanism(s) of action in hepatic stellate cells (HSC-T6s). Materials and Methods To assess the effects of Agn, HSC-T6s were treated with PDGF and cell proliferation, colony formation, cell migration, cell invasiveness and apoptosis were assessed. Rat models of liver fibrosis were produced through 12-week injections of intraperitoneal (IP) carbon tetrachloride (CCl4). Rats were Agn-treated from weeks 8 to 12, and liver damage was assessed through Masson’s and H & E staining. Gene expression profiles were assayed via RT-PCR, Western blot and commercial ELISA kits. Results Agn reduced the proliferation of HSC-T6s and increased apoptotic rates through the downregulation of the Bcl-2:Bax ratio. Agn also inhibited the invasion and migration of HSC-T6s, prevented ECM deposition, and reduced the occurrence of liver fibrosis in rat models. Agn also prevented IκBα and p65 phosphorylation. Conclusion Agn prevents liver fibrosis through its attenuation of HSC activation and division through the suppression of NF-κB in in vitro and animal models. This highlights how the clinical use of Agn can prevent hepatic fibrosis.
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Affiliation(s)
- Ziqiang Xia
- Department of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, People's Republic of China
| | - Li Ding
- Department of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, People's Republic of China
| | - Juzeng Zheng
- Department of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, People's Republic of China
| | - Yilun Xu
- Department of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, People's Republic of China
| | - Wenyi Jin
- Department of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, People's Republic of China
| | - Xiong Sheng
- Department of Infectious Diseases, The First Affiliated Hospital of Jiaxing College, Jiaxing 314000, People's Republic of China.,Department of Infectious Diseases, The First Hospital of Jiaxing, Jiaxing 314000, People's Republic of China
| | - Jinming Wu
- Department of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, People's Republic of China
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14
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Meng X, Guo X, Zhang J, Moriya J, Kobayashi J, Yamaguchi R, Yamada S. Acupuncture on ST36, CV4 and KI1 Suppresses the Progression of Methionine- and Choline-Deficient Diet-Induced Nonalcoholic Fatty Liver Disease in Mice. Metabolites 2019; 9:299. [PMID: 31835339 PMCID: PMC6949943 DOI: 10.3390/metabo9120299] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2019] [Revised: 12/06/2019] [Accepted: 12/06/2019] [Indexed: 02/07/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases worldwide, and its treatment remain a constant challenge. A number of clinical trials have shown that acupuncture treatment has beneficial effects for patients with NAFLD, but the molecular mechanisms underlying its action are still largely unknown. In this study, we established a mouse model of NAFLD by administering a methionine- and choline-deficient (MCD) diet and selected three acupoints (ST36, CV4, and KI1) or nonacupoints (sham) for needling. We then investigated the effects of acupuncture treatment on the progression of NAFLD and the underlying mechanisms. After two weeks of acupuncture treatment, the liver in the needling-nonapcupoint group (NG) mice appeared pale and yellowish in color, while that in the needling-acupoint group (AG) showed a bright red color. Histologically, fewer lipid droplets and inflammatory foci were observed in the AG liver than in the NG liver. Furthermore, the expression of proinflammatory signaling factors was significantly downregulated in the AG liver. A lipid analysis showed that the levels of triglyceride (TG) and free fatty acid (FFA) were lower in the AG liver than in the NG liver, with an altered expression of lipid metabolism-related factors as well. Moreover, the numbers of 8-hydroxy-2'-deoxyguanosine (8-OHdG)-positive hepatocytes and levels of hepatic thiobarbituric acid reactive substances (TBARS) were significantly lower in AG mice than in NG mice. In line with these results, a higher expressions of antioxidant factors was found in the AG liver than in the NG liver. Our results indicate that acupuncture repressed the progression of NAFLD by inhibiting inflammatory reactions, reducing oxidative stress, and promoting lipid metabolism of hepatocytes, suggesting that this approach might be an important complementary treatment for NAFLD.
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Affiliation(s)
- Xiangjin Meng
- Department of Pathology and Laboratory Medicine, Kanazawa Medical University, 1-1 Daigaku, Uchinada, Kahoku, Ishikawa 920-0293, Japan; (X.M.); (J.Z.); (S.Y.)
- Department of General Internal Medicine, Kanazawa Medical University, Ishikawa 920-0293, Japan; (J.M.); (J.K.)
| | - Xin Guo
- Department of Pathology and Laboratory Medicine, Kanazawa Medical University, 1-1 Daigaku, Uchinada, Kahoku, Ishikawa 920-0293, Japan; (X.M.); (J.Z.); (S.Y.)
- Department of Pathology, Kanazawa Medical University Hospital, Ishikawa 920-0293, Japan
| | - Jing Zhang
- Department of Pathology and Laboratory Medicine, Kanazawa Medical University, 1-1 Daigaku, Uchinada, Kahoku, Ishikawa 920-0293, Japan; (X.M.); (J.Z.); (S.Y.)
| | - Junji Moriya
- Department of General Internal Medicine, Kanazawa Medical University, Ishikawa 920-0293, Japan; (J.M.); (J.K.)
| | - Junji Kobayashi
- Department of General Internal Medicine, Kanazawa Medical University, Ishikawa 920-0293, Japan; (J.M.); (J.K.)
| | - Reimon Yamaguchi
- Department of Dermatology, Kanazawa Medical University, Ishikawa 920-0293, Japan;
| | - Sohsuke Yamada
- Department of Pathology and Laboratory Medicine, Kanazawa Medical University, 1-1 Daigaku, Uchinada, Kahoku, Ishikawa 920-0293, Japan; (X.M.); (J.Z.); (S.Y.)
- Department of Pathology, Kanazawa Medical University Hospital, Ishikawa 920-0293, Japan
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15
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Cheng HS, Tan WR, Low ZS, Marvalim C, Lee JYH, Tan NS. Exploration and Development of PPAR Modulators in Health and Disease: An Update of Clinical Evidence. Int J Mol Sci 2019; 20:E5055. [PMID: 31614690 PMCID: PMC6834327 DOI: 10.3390/ijms20205055] [Citation(s) in RCA: 164] [Impact Index Per Article: 27.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2019] [Revised: 10/10/2019] [Accepted: 10/10/2019] [Indexed: 12/20/2022] Open
Abstract
Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that govern the expression of genes responsible for energy metabolism, cellular development, and differentiation. Their crucial biological roles dictate the significance of PPAR-targeting synthetic ligands in medical research and drug discovery. Clinical implications of PPAR agonists span across a wide range of health conditions, including metabolic diseases, chronic inflammatory diseases, infections, autoimmune diseases, neurological and psychiatric disorders, and malignancies. In this review we aim to consolidate existing clinical evidence of PPAR modulators, highlighting their clinical prospects and challenges. Findings from clinical trials revealed that different agonists of the same PPAR subtype could present different safety profiles and clinical outcomes in a disease-dependent manner. Pemafibrate, due to its high selectivity, is likely to replace other PPARα agonists for dyslipidemia and cardiovascular diseases. PPARγ agonist pioglitazone showed tremendous promises in many non-metabolic disorders like chronic kidney disease, depression, inflammation, and autoimmune diseases. The clinical niche of PPARβ/δ agonists is less well-explored. Interestingly, dual- or pan-PPAR agonists, namely chiglitazar, saroglitazar, elafibranor, and lanifibranor, are gaining momentum with their optimistic outcomes in many diseases including type 2 diabetes, dyslipidemia, non-alcoholic fatty liver disease, and primary biliary cholangitis. Notably, the preclinical and clinical development for PPAR antagonists remains unacceptably deficient. We anticipate the future design of better PPAR modulators with minimal off-target effects, high selectivity, superior bioavailability, and pharmacokinetics. This will open new possibilities for PPAR ligands in medicine.
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Affiliation(s)
- Hong Sheng Cheng
- School of Biological Sciences, Nanyang Technological University Singapore, 60 Nanyang Drive, Singapore 637551, Singapore.
| | - Wei Ren Tan
- Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, 11 Mandalay Road, Singapore 308232, Singapore.
| | - Zun Siong Low
- Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, 11 Mandalay Road, Singapore 308232, Singapore.
| | - Charlie Marvalim
- School of Biological Sciences, Nanyang Technological University Singapore, 60 Nanyang Drive, Singapore 637551, Singapore.
| | - Justin Yin Hao Lee
- Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, 11 Mandalay Road, Singapore 308232, Singapore.
| | - Nguan Soon Tan
- School of Biological Sciences, Nanyang Technological University Singapore, 60 Nanyang Drive, Singapore 637551, Singapore.
- Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, 11 Mandalay Road, Singapore 308232, Singapore.
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16
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Liu F, Bayliss G, Zhuang S. Application of nintedanib and other potential anti-fibrotic agents in fibrotic diseases. Clin Sci (Lond) 2019; 133:1309-1320. [PMID: 31217321 PMCID: PMC7480985 DOI: 10.1042/cs20190249] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2019] [Revised: 05/22/2019] [Accepted: 06/03/2019] [Indexed: 12/19/2022]
Abstract
Nintedanib, a Food and Drug Administration-approved drug for the treatment of patients with idiopathic pulmonary fibrosis (IPK), inhibits both tyrosine kinase receptors and non-receptor kinases, and block activation of platelet-derived growth factor receptors, fibroblast growth factor receptor, vascular endothelial growth factor receptors, and Src family kinases. Preclinical and clinical studies have revealed the potent anti-fibrotic effect of nintedanib in IPK in human and animal models. Recent preclinical studies have also demonstrated the inhibitory effect of nintedanib on the development and progression of tissue fibrosis in other organs, including liver, kidney, and skin. The anti-fibrotic actions of nintedanib occur through a number of mechanisms, including blocking differentiation of fibroblasts to myofibroblasts, inhibition of epithelial-mesenchymal transition, and suppression of inflammation and angiogenesis. In this article, we summarize the mechanisms and efficacy of nintedanib in the treatment of fibrotic diseases in animal models and clinical trials, provide an update on recent advances in the development of other novel antifibrotic agents in preclinical and clinical study, and offer our perspective about the possible clinical application of these agents in fibrotic diseases.
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Affiliation(s)
- Feng Liu
- Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - George Bayliss
- Department of Medicine, Rhode Island Hospital, Alpert Medical School, Brown University, Providence, Rhode Island, U.S.A
| | - Shougang Zhuang
- Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
- Department of Medicine, Rhode Island Hospital, Alpert Medical School, Brown University, Providence, Rhode Island, U.S.A
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17
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Concurrent exercise improves insulin resistance and nonalcoholic fatty liver disease by upregulating PPAR-γ and genes involved in the beta-oxidation of fatty acids in ApoE-KO mice fed a high-fat diet. Lipids Health Dis 2019; 18:6. [PMID: 30611282 PMCID: PMC6320624 DOI: 10.1186/s12944-018-0933-z] [Citation(s) in RCA: 90] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2018] [Accepted: 11/27/2018] [Indexed: 12/16/2022] Open
Abstract
Objective To emphasize the mechanism of concurrent exercise effect on lipid disorders in insulin resistance (IR) and nonalcoholic fatty liver disease (NAFLD). Materials and methods Twenty male ApoE knockout mice were randomly divided into two groups: HFD group (n = 10) fed a high fat diet, and HFDE group (n = 10) with high-fat diet intervention for 12 weeks and swimming exercise. Other ten healthy male C57BL/6 J mice were fed a normal diet, and included as control group. Retro-orbital blood samples were collected for biochemical analysis. Oil red O staining of liver tissues was performed to confirm the exercise effect. Western blotting was performed to evaluate the expressions of PPAR-γ, CPT-1, MCAD. Results The levels of TG, TC, LDL, FFA, FIN, FPG and Homa-IRI in the HFD group were significantly higher than ND group, while these were markedly decreased in the HFDE group compared with HFD group. The Oil Red O staining of liver samples further confirmed the exercise effect on the change of lipid deposition in the liver. Western blotting showed increased expressions of PPAR-γ, CPT-1, MCAD induced by high fat diet were significantly downregulated by exercise. Conclusion A concurrent 12-week exercise protocol alleviated the lipid metabolism disorders of IR and NAFLD, probably via PPAR-γ/CPT-1/MCAD signaling.
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18
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Finck BN. Targeting Metabolism, Insulin Resistance, and Diabetes to Treat Nonalcoholic Steatohepatitis. Diabetes 2018; 67:2485-2493. [PMID: 30459251 PMCID: PMC6245219 DOI: 10.2337/dbi18-0024] [Citation(s) in RCA: 76] [Impact Index Per Article: 10.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2018] [Accepted: 09/20/2018] [Indexed: 12/25/2022]
Abstract
Obesity, insulin resistance, and diabetes are strongly linked to the accumulation of excessive lipids in the liver parenchyma, a condition known as nonalcoholic fatty liver disease (NAFLD). Given its association with obesity and related metabolic diseases, it is not surprising that the prevalence of NAFLD has dramatically increased in the past few decades. NAFLD has become the most common liver disease in many areas of the world. The term, NAFLD, encompasses a spectrum of disorders that ranges from simple steatosis to steatosis with inflammatory lesions (nonalcoholic steatohepatitis [NASH]). Although simple steatosis might be relatively benign, epidemiologic studies have linked NASH to greatly increased risk of developing cirrhosis and hepatocellular carcinoma. Yet despite this, there are no approved treatments for the disease, and it remains a significant unmet medical need. This Perspective will review some of the relevant literature on the topic and examine approved and experimental NASH therapeutic concepts that target intermediary metabolism, insulin resistance, and diabetes to treat this emerging public health problem.
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Affiliation(s)
- Brian N Finck
- Center for Human Nutrition, Division of Geriatrics and Nutritional Sciences, John T. Milliken Department of Medicine, Washington University School of Medicine in St. Louis, St. Louis, MO
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19
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Brott DA, Goodman MJ, Hermann RP, Merz M, Calvo R, Poorkhalkali N, Kiazand A. Are laboratory parameter (biomarker) values similar to the healthy volunteer reference range in all patient populations? Drug Des Devel Ther 2018; 12:2757-2773. [PMID: 30233139 PMCID: PMC6132491 DOI: 10.2147/dddt.s173671] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
Background Liver biomarkers alanine aminotransferase (ALT) and bilirubin in patients with hepatitis are above the healthy volunteer reference range (HVRR) at baseline (prior to receiving the clinical trial medication). Discussions continue as how to best distinguish drug-induced liver injury in patients with abnormal baseline values participating in clinical trials. This study investigated if other baseline routine clinical safety biomarkers (lab parameters) are different from the HVRR. Materials and methods Clinical trial data (TransCelerate dataset) from placebo and standard of care treated patients were compared to the HVRR using a 10% threshold above or below the HVRR to classify a lab parameter in a patient population as potentially different from the HVRR at baseline. The TransCelerate dataset, batch 4, contained data from patients with Alzheimer’s, asthma, COPD, cardiovascular disease, diabetes, hidradenitis, hypercholesterolemia, rheumatoid arthritis, schizophrenia, stroke, and ulcerative colitis. A subset of the 200 biomarkers in Trans-Celerate were evaluated in this pilot: glucose, platelet count, neutrophil count, ALT, aspartate aminotransferase (AST), and bilirubin. Results Glucose was potentially higher than the HVRR in patients with diabetes, COPD, cardiovascular disease, hypercholesterolemia, and schizophrenia. At least one or more of the hematology and hepatic biomarkers were different from the HVRR in at least one patient population, except bilirubin. All the patient populations, except Alzheimer’s and asthma, had at least one biomarker that was higher than the HVRR. Summary The routine biomarkers evaluated in this pilot study demonstrated that not all lab parameters in patient populations are similar to the HVRR. Further efforts are needed to determine which biomarkers are different from the HVRR and how to evaluate the biomarkers in patient populations for detecting drug-induced altered lab values in clinical trials.
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Affiliation(s)
- David A Brott
- Patient Safety, Safety Science, AstraZeneca Pharmaceuticals, Gaithersburg, MD, USA,
| | - Michael J Goodman
- Patient Safety, Safety Science, AstraZeneca Pharmaceuticals, Gaithersburg, MD, USA,
| | - Richard P Hermann
- Patient Safety, Safety Science, AstraZeneca Pharmaceuticals, Gaithersburg, MD, USA,
| | - Michael Merz
- Patient Safety, Safety Science, AstraZeneca Pharmaceuticals, Webel, Germany
| | - Roser Calvo
- Patient Safety, Safety Science, AstraZeneca Pharmaceuticals, Gaithersburg, MD, USA,
| | | | - Alexandre Kiazand
- Patient Safety, Safety Science, AstraZeneca Pharmaceuticals, Gaithersburg, MD, USA,
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Abstract
Non-alcoholic fatty liver disease is a leading cause of chronic liver disease that can lead to cirrhosis, hepatocellular cancer, and end-stage liver disease, and it is linked to elevated cardiovascular- and cancer-related morbidity and mortality. Insulin resistance related to metabolic syndrome is the main pathogenic trigger that, in association with adverse genetic, lifestyle, and other factors, precipitates the development of non-alcoholic fatty liver disease. Biochemical markers and radiological imaging, along with liver biopsy in selected cases, help in the disease’s diagnosis and prognostication. Weight loss is the cornerstone treatment of non-alcoholic fatty liver disease; however, it is difficult to achieve and maintain, so pharmacotherapy was developed. The remarkable evolution in understanding disease pathogenesis has led to the development of new medical therapies and even the modification of currently available ones. This review summarizes recent advances in understanding the epidemiology, natural history, pathogenesis, diagnosis, and management of non-alcoholic fatty liver disease.
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Affiliation(s)
- Somaya Albhaisi
- The Division of Internal Medicine, Virginia Commonwealth University, Richmond, USA
| | - Arun Sanyal
- The Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University, Richmond, USA
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21
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Song HM, Li X, Liu YY, Lu WP, Cui ZH, Zhou L, Yao D, Zhang HM. Carnosic acid protects mice from high-fat diet-induced NAFLD by regulating MARCKS. Int J Mol Med 2018; 42:193-207. [PMID: 29620148 PMCID: PMC5979837 DOI: 10.3892/ijmm.2018.3593] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2016] [Accepted: 01/24/2018] [Indexed: 12/22/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) comprises a spectrum of liver damage characterized by abnormal hepatic fat accumulation and inflammatory response. Although the molecular mechanisms responsible for the disease are not yet fully understood, the pathogenesis of NAFLD likely involves multiple signals. The identification of effective therapeutic strategies to target these signals is of utmost importance. Carnosic acid (CA), as a phenolic diterpene with anticancer, anti-bacterial, anti-diabetic and neuroprotective properties, is produced by many species of the Lamiaceae family. Myristoylated alanine-rich C-kinase substrate (MARCKS) is a major protein kinase C (PKC) substrate in many different cell types. In the present study, wild-type C57BL/6 and MARCKS-deficient mice were randomly divided into the normal chow- or high-fat (HF) diet-fed groups. The HF diet increased the fasting glucose and insulin levels, and promoted glucose intolerance in the wild-type mice. MARCKS deficiency further upregulated intolerance, fasting glucose and insulin. The HF diet also promoted hepatic steatosis, serum alanine transaminase (ALT) and aspartate transaminase (AST) activity, inflammation and lipid accumulation in the wild-type mice. These responses were accelerated in the MARCKS-deficient mice. Importantly, increased inflammation and lipid accumulation were associated with phosphoinositide 3-kinase (PI3K)/AKT, NLR family pyrin domain containing 3 (NLRP3)/nuclear factor-κB (NF-κB) and sterol regulatory element binding protein-1c (SREBP-1c) signaling pathway activation. The mice treated with CA exhibited a significantly improved glucose and insulin tolerance. The production of pro-inflammatory cytokines and lipid accumulation were suppressed by CA. Significantly, MARCKS was reduced in mice fed the HF diet. CA treatment upregulated MARCKS expression compared to the HF group. Furthermore, the activation of the PI3K/AKT, NLRP3/NF-κB and SREBP-1c signaling pathways was inhibited by CA. Taken together, our data suggest that CA suppresses inflammation and lipogenesis in mice fed a HF diet through MARCKS regulation. Thus, CA may be prove to be a useful anti-NAFLD agent.
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Affiliation(s)
- Hong-Mao Song
- Department of Otolaryngology-Head and Neck Surgery, Huai'an Hospital Affiliated to Xuzhou Medical University, Huai'an, Jiangsu 223300, P.R. China
| | - Xiang Li
- Department of Clinical Laboratory, Huai'an Hospital Affiliated to Xuzhou Medical University, Huai'an, Jiangsu 223300, P.R. China
| | - Yuan-Yuan Liu
- Department of Endocrinology, Huai'an First People's Hospital, Nanjing Medical University, Huai'an, Jiangsu 223300, P.R. China
| | - Wei-Ping Lu
- Department of Endocrinology, Huai'an First People's Hospital, Nanjing Medical University, Huai'an, Jiangsu 223300, P.R. China
| | - Zhao-Hui Cui
- Department of Endocrinology, Huai'an First People's Hospital, Nanjing Medical University, Huai'an, Jiangsu 223300, P.R. China
| | - Li Zhou
- Department of Endocrinology, Huai'an First People's Hospital, Nanjing Medical University, Huai'an, Jiangsu 223300, P.R. China
| | - Di Yao
- Department of Endocrinology, Huai'an First People's Hospital, Nanjing Medical University, Huai'an, Jiangsu 223300, P.R. China
| | - Hong-Man Zhang
- Department of Endocrinology, Huai'an First People's Hospital, Nanjing Medical University, Huai'an, Jiangsu 223300, P.R. China
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Mills EP, Brown KPD, Smith JD, Vang PW, Trotta K. Treating nonalcoholic fatty liver disease in patients with type 2 diabetes mellitus: a review of efficacy and safety. Ther Adv Endocrinol Metab 2018; 9:15-28. [PMID: 29344336 PMCID: PMC5761952 DOI: 10.1177/2042018817741852] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2017] [Accepted: 10/23/2017] [Indexed: 12/18/2022] Open
Abstract
OBJECTIVE To review current literature for the efficacy and safety of treatment for nonalcoholic fatty liver disease (NAFLD) in patients with type 2 diabetes mellitus (T2DM). DATA SOURCES A PubMed literature search from January 1990 to June 2017 was conducted using the search terms nonalcoholic fatty liver disease, diabetes mellitus, type 2, therapy, treatment, treat, therapeutics, nonalcoholic fatty liver, nonalcoholic hepatosteatosis, NASH, NAFLD, metformin, and statin. Bibliographies of chosen articles were reviewed. STUDY SELECTION AND DATA EXTRACTION Relevant articles on metformin, thiazolidinediones (TZD), glucagon-like peptide-1 receptor agonists (GLP-1 RA), and statins for the treatment of NAFLD which included patients with T2DM were reviewed. A total of 23 relevant studies were found and included randomized controlled, observational, and open-label designs, as well as three meta-analyses. DATA SYNTHESIS Metformin combined with weight loss provides a modest improvement in steatosis and no improvement in fibrosis in patients with NAFLD and T2DM. TZDs showed positive results on fibrosis and resolution of NASH but at least half of patients studied were nonresponders. GLP-1 RAs also showed favorable results on reductions in transaminases and steatosis and improvements in insulin sensitivity and weight loss but lack efficacy data for resolution of NASH or improvement in fibrosis scores. Statins showed favorable results on reductions in transaminases but mixed results for improvement in steatosis and fibrosis scores. CONCLUSION All reviewed treatment options are safe for management of NAFLD in patients with T2DM but long-term histological improvements are minimal. TZDs are efficacious for resolution of NASH and improvements in fibrosis but long-term use is required to maintain these results.
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Affiliation(s)
| | - K. Paige D. Brown
- Campbell University College of Pharmacy & Health Sciences, Pharmacy Practice, Buies Creek, NC, USA
| | - Jennifer D. Smith
- William Jennings Bryan Dorn VA Medical Center, Columbia, SC 29209, USA
| | - Phillip W. Vang
- Campbell University College of Pharmacy & Health Sciences, Pharmacy Practice, Buies Creek, NC, USA
| | - Katie Trotta
- Campbell University College of Pharmacy & Health Sciences, Pharmacy Practice, Buies Creek, NC, USA
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23
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Lakhani HV, Sharma D, Dodrill MW, Nawab A, Sharma N, Cottrill CL, Shapiro JI, Sodhi K. Phenotypic Alteration of Hepatocytes in Non-Alcoholic Fatty Liver Disease. Int J Med Sci 2018; 15:1591-1599. [PMID: 30588181 PMCID: PMC6299410 DOI: 10.7150/ijms.27953] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2018] [Accepted: 08/31/2018] [Indexed: 02/06/2023] Open
Abstract
Non-Alcoholic Fatty Liver Disease (NAFLD) has been recognized as the most common liver disorder in developed countries. NAFLD progresses from fat accumulation in hepatocytes to steatohepatitis to further stages of fibrosis and cirrhosis. Simple steatosis, i.e. fat deposition in the liver, is considered benign and gives way to non-alcoholic steatohepatitis (NASH) with a higher probability of progressing to cirrhosis, and liver-related mortality. Evidence has been found that this progression has been associated with marked alterations in hepatocyte histology and a shift in marker expression of healthy hepatocytes including increased expression of peroxisome proliferator-activated receptor gamma (PPARγ), adipocyte protein (aP2), CD36, interleukin-6 (IL-6), interleukin-18 (IL-18) and adiponectin. This progression shares much in common with the obesity phenotype, which involves a transformation of adipocytes from small, healthy cells to large, dysfunctional ones that contribute to redox imbalance and the progression of metabolic syndrome. Further, activation of Src/ERK signaling via the sodium potassium adenosine triphosphatase (Na/K-ATPase) α-1 subunit in impaired hepatocytes may contribute to redox imbalance, exacerbating the progression of NAFLD. This review hypothesizes that an adipogenic transformation of hepatocytes propagates redox imbalance and that the processes occurring in adipogenesis become activated in fat-laden hepatocytes in liver, thereby driving progression to NAFLD. Further, this review discusses therapeutic interventions to reverse NAFLD including the thiazolidinediones (TZDs) and a variety of antioxidant species. The peptide, pNaKtide, which is an antagonist of Na/K-ATPase signaling, is also proposed as a potential pharmacologic option for reducing reactive oxygen species (ROS) and reversing NAFLD by inhibiting the Na/K-ATPase-modulated ROS amplification loop.
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Affiliation(s)
- Hari Vishal Lakhani
- Department of Internal Medicine, Marshall University Joan C Edwards School of Medicine, Huntington, WV, USA
| | - Dana Sharma
- Department of Internal Medicine, Marshall University Joan C Edwards School of Medicine, Huntington, WV, USA
| | - Michael W Dodrill
- Department of Internal Medicine, Marshall University Joan C Edwards School of Medicine, Huntington, WV, USA
| | - Athar Nawab
- Department of Internal Medicine, Marshall University Joan C Edwards School of Medicine, Huntington, WV, USA
| | - Nitin Sharma
- Department of Internal Medicine, Marshall University Joan C Edwards School of Medicine, Huntington, WV, USA
| | - Cameron Lee Cottrill
- Department of Internal Medicine, Marshall University Joan C Edwards School of Medicine, Huntington, WV, USA
| | - Joseph I Shapiro
- Department of Internal Medicine, Marshall University Joan C Edwards School of Medicine, Huntington, WV, USA
| | - Komal Sodhi
- Department of Surgery, Marshall University Joan C Edwards School of Medicine, Huntington, WV, USA
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24
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Abstract
Fibrosis is a major player in cardiovascular disease, both as a contributor to the development of disease, as well as a post-injury response that drives progression. Despite the identification of many mechanisms responsible for cardiovascular fibrosis, to date no treatments have emerged that have effectively reduced the excess deposition of extracellular matrix associated with fibrotic conditions. Novel treatments have recently been identified that hold promise as potential therapeutic agents for cardiovascular diseases associated with fibrosis, as well as other fibrotic conditions. The purpose of this review is to provide an overview of emerging antifibrotic agents that have shown encouraging results in preclinical or early clinical studies, but have not yet been approved for use in human disease. One of these agents is bone morphogenetic protein-7 (BMP7), which has beneficial effects in multiple models of fibrotic disease. Another approach discussed involves altering the levels of micro-RNA (miR) species, including miR-29 and miR-101, which regulate the expression of fibrosis-related gene targets. Further, the antifibrotic potential of agonists of the peroxisome proliferator-activated receptors will be discussed. Finally, evidence will be reviewed in support of the polypeptide hormone relaxin. Relaxin is long known for its extracellular remodeling properties in pregnancy, and is rapidly emerging as an effective antifibrotic agent in a number of organ systems. Moreover, relaxin has potent vascular and renal effects that make it a particularly attractive approach for the treatment of cardiovascular diseases. In each case, the mechanism of action and the applicability to various fibrotic diseases will be discussed.
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Affiliation(s)
- Benita L McVicker
- Research Service, VA Nebraska-Western Iowa Health Care System, OmahaNE, United States.,Division of Gastroenterology and Hepatology, University of Nebraska Medical Center, OmahaNE, United States
| | - Robert G Bennett
- Research Service, VA Nebraska-Western Iowa Health Care System, OmahaNE, United States.,The Division of Diabetes, Endocrinology, and Metabolism, Department of Internal Medicine, University of Nebraska Medical Center, OmahaNE, United States.,Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, OmahaNE, United States
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25
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Liss KHH, Finck BN. PPARs and nonalcoholic fatty liver disease. Biochimie 2017; 136:65-74. [PMID: 27916647 PMCID: PMC5380579 DOI: 10.1016/j.biochi.2016.11.009] [Citation(s) in RCA: 217] [Impact Index Per Article: 27.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2016] [Revised: 11/23/2016] [Accepted: 11/28/2016] [Indexed: 02/07/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) encompasses a range of liver pathology ranging from simple steatosis to varying degrees of inflammation, hepatocyte injury and fibrosis. Without intervention it can progress to end-stage liver disease and hepatocellular carcinoma. Given its close association with obesity, the prevalence of NAFLD has increased dramatically worldwide. Currently, there are no FDA-approved medications for the treatment of NAFLD and although lifestyle modifications with appropriate diet and exercise have been shown to be beneficial, this has been difficult to achieve and sustain for the majority of patients. As such, the search for effective therapeutic agents is an active area of research. Peroxisome proliferator-activated receptors (PPARs) belong to a class of nuclear receptors. Because of their key role in the transcriptional regulation of mediators of glucose and lipid metabolism, PPAR ligands have been investigated as possible therapeutic agents. Here we review the current evidence from preclinical and clinical studies investigating the therapeutic potential of PPAR ligands for the treatment of NAFLD.
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Affiliation(s)
- Kim H H Liss
- Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, 63110, USA
| | - Brian N Finck
- Department of Medicine, Washington University School of Medicine, St. Louis, MO, 63110, USA.
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26
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Colca JR, McDonald WG, McCommis KS, Finck BN. Treating fatty liver disease by modulating mitochondrial pyruvate metabolism. Hepatol Commun 2017; 1:193-197. [PMID: 29404453 PMCID: PMC5721453 DOI: 10.1002/hep4.1036] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2017] [Revised: 03/15/2017] [Accepted: 03/27/2017] [Indexed: 12/31/2022] Open
Abstract
Modifying the entry of pyruvate into mitochondria may provide a unique approach to treat metabolic disease. The pharmacology of a new class of insulin sensitizers directed against a newly identified mitochondrial target may treat many aspects of nonalcoholic steatohepatitis, including fibrosis. This commentary suggests treating nonalcoholic steatohepatitis through a newly identified mechanism consistent with pathophysiology. (Hepatology Communications 2017;1:193‐197)
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Affiliation(s)
- Jerry R Colca
- Metabolic Solutions Development Company Kalamazoo MI
| | | | - Kyle S McCommis
- Department of Medicine Washington University School of Medicine St. Louis MO
| | - Brian N Finck
- Department of Medicine Washington University School of Medicine St. Louis MO
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27
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Massart J, Begriche K, Moreau C, Fromenty B. Role of nonalcoholic fatty liver disease as risk factor for drug-induced hepatotoxicity. J Clin Transl Res 2017; 3:212-232. [PMID: 28691103 PMCID: PMC5500243 DOI: 10.18053/jctres.03.2017s1.006] [Citation(s) in RCA: 50] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Obesity is often associated with nonalcoholic fatty liver disease (NAFLD), which refers to a large spectrum of hepatic lesions including fatty liver, nonalcoholic steatohepatitis (NASH) and cirrhosis. Different investigations showed or suggested that obesity and NAFLD are able to increase the risk of hepatotoxicity of different drugs. Some of these drugs could induce more frequently an acute hepatitis in obese individuals whereas others could worsen pre-existing NAFLD. AIM The main objective of the present review was to collect the available information regarding the role of NAFLD as risk factor for drug-induced hepatotoxicity. For this purpose, we performed a data-mining analysis using different queries including drug-induced liver injury (or DILI), drug-induced hepatotoxicity, fatty liver, nonalcoholic fatty liver disease (or NAFLD), steatosis and obesity. The main data from the collected articles are reported in this review and when available, some pathophysiological hypotheses are put forward. RELEVANCE FOR PATIENTS Drugs that could pose a potential risk in obese patients include compounds belonging to different pharmacological classes such as acetaminophen, halothane, methotrexate, rosiglitazone, stavudine and tamoxifen. For some of these drugs, experimental investigations in obese rodents confirmed the clinical observations and unveiled different pathophysiological mechanisms which could explain why these pharmaceuticals are particularly hepatotoxic in obesity and NAFLD. Other drugs such as pentoxifylline, phenobarbital and omeprazole might also pose a risk but more investigations are required to determine whether this risk is significant or not. Because obese people often take several drugs for the treatment of different obesity-related diseases such as type 2 diabetes, hyperlipidemia and coronary heart disease, it is urgent to identify the main pharmaceuticals that can cause acute hepatitis on a fatty liver background or induce NAFLD worsening.
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Affiliation(s)
- Julie Massart
- Department of Molecular Medicine and Surgery, Karolinska University Hospital, Karolinska Institutet, SE-171 77 Stockholm, Sweden
| | | | - Caroline Moreau
- INSERM, U991, Université de Rennes 1, Rennes, France.,Service de Biochimie et Toxicologie, CHU Pontchaillou, Rennes, France
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28
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He L, Liu X, Wang L, Yang Z. Thiazolidinediones for nonalcoholic steatohepatitis: A meta-analysis of randomized clinical trials. Medicine (Baltimore) 2016; 95:e4947. [PMID: 27759627 PMCID: PMC5079311 DOI: 10.1097/md.0000000000004947] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
The findings regarding the effects of thiazolidinediones (TZDs) in nonalcoholic steatohepatitis (NASH) patients have been inconsistent, and the assessment of different clinical variables for evaluating the effects of TZDs confound a direct comparison of the results of different randomized clinical trials (RCTs), especially with regard to lifestyle changes. In this paper, we performed a meta-analysis of randomized controlled trials to clarify the effects of TZD treatment with and without lifestyle changes on histological markers of NASH and clinical variables related to insulin resistance (IR), hyperlipidemia, and obesity. We searched the literature using the following MeSH terms: "nonalcoholic steatohepatitis," "non-alcoholic steatohepatitis," "thiazolidinedione," "pioglitazone," "rosiglitazone," "randomized," and "clinical trial." Five eligible RCTs were selected, in which patients were treated with either pioglitazone or rosiglitazone, with or without lifestyle changes. We compared the effects of TZD treatment on hepatic fibrosis, lobular inflammation, IR improvement, fasting serum insulin, adiposity, and dyslipidemia between the various studies using fixed and random effects models, and heterogeneity in clinical outcomes was assessed. Significant improvement in hepatic fibrosis did not occur among the patients treated with TZDs alone or in those who underwent both lifestyle changes and TZD therapy. Lobular inflammation decreased in NASH patients who received TZD treatment and in those who underwent both TZD therapy and lifestyle changes. Although TZD treatment resulted in no significant improvement in IR, NASH patients who underwent both lifestyle changes and TZD therapy experienced a significantly greater reduction in their fasting insulin level than that observed in the control patients, whereas patients treated with TZDs alone did not. Although TZD-treated patients experienced significantly greater weight gain than the control patients, TZD treatment had no significant impact on body-mass index, percentage of body fat, or serum levels of cholesterol and triglyceride. Our findings indicate that additional variables should be assessed to obtain a more comprehensive evaluation of the effects of TZD treatment on IR and comorbidity risk factors in NASH patients, and suggest that including lifestyle changes and additional insulin-sensitizing agents in TZD regimens might improve the benefits of TZD therapy for NASH.
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Affiliation(s)
- Lingling He
- The Department of Traditional Chinese Medicine, Beijing Ditan Hospital
| | - Xiaoli Liu
- The Department of Traditional Chinese Medicine, Beijing Ditan Hospital
| | - Lijia Wang
- The Department of Traditional Chinese Medicine, Beijing Ditan Hospital
| | - Zhiyun Yang
- The Department of Traditional Chinese Medicine, Beijing Ditan Hospital
- Collabrorative Innovation Center of Infectious Diseases (ZY), Capital Medical University, Chaoyang, Beijing, China
- Correspondence: Zhiyun Yang, Department of Traditional Chinese Medicine, Beijing Ditan Hospital, Capital Medical University, No. 8 Jingshun Dong Road, Chaoyang, Beijing 100015, P.R. China (e-mail: )
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29
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Mulder P, Morrison MC, Verschuren L, Liang W, van Bockel JH, Kooistra T, Wielinga PY, Kleemann R. Reduction of obesity-associated white adipose tissue inflammation by rosiglitazone is associated with reduced non-alcoholic fatty liver disease in LDLr-deficient mice. Sci Rep 2016; 6:31542. [PMID: 27545964 PMCID: PMC4992869 DOI: 10.1038/srep31542] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2016] [Accepted: 07/18/2016] [Indexed: 12/14/2022] Open
Abstract
Obesity is associated with chronic low-grade inflammation that drives the development of metabolic diseases, including non-alcoholic fatty liver disease (NAFLD). We recently showed that white adipose tissue (WAT) constitutes an important source of inflammatory factors. Hence, interventions that attenuate WAT inflammation may reduce NAFLD development. Male LDLr-/- mice were fed a high-fat diet (HFD) for 9 weeks followed by 7 weeks of HFD with or without rosiglitazone. Effects on WAT inflammation and NAFLD development were analyzed using biochemical and (immuno)histochemical techniques, combined with gene expression analyses. Nine weeks of HFD feeding induced obesity and WAT inflammation, which progressed gradually until the end of the study. Rosiglitazone fully blocked progression of WAT inflammation and activated PPARγ significantly in WAT. Rosiglitazone intervention did not activate PPARγ in liver, but improved liver histology and counteracted the expression of genes associated with severe NAFLD in humans. Rosiglitazone reduced expression of pro-inflammatory factors in WAT (TNF-α, leptin) and increased expression of adiponectin, which was reflected in plasma. Furthermore, rosiglitazone lowered circulating levels of pro-inflammatory saturated fatty acids. Together, these observations provide a rationale for the observed indirect hepatoprotective effects and suggest that WAT represents a promising therapeutic target for the treatment of obesity-associated NAFLD.
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Affiliation(s)
- Petra Mulder
- Department of Metabolic Health Research, Netherlands Organization for Applied Scientific Research (TNO), Zernikedreef 9, 2333 CK Leiden, The Netherlands.,Department of Vascular Surgery, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands
| | - Martine C Morrison
- Department of Metabolic Health Research, Netherlands Organization for Applied Scientific Research (TNO), Zernikedreef 9, 2333 CK Leiden, The Netherlands
| | - Lars Verschuren
- Department of Microbiology and Systems Biology, Netherlands Organization for Applied Scientific Research (TNO), 3704 HE, Zeist, The Netherlands
| | - Wen Liang
- Department of Metabolic Health Research, Netherlands Organization for Applied Scientific Research (TNO), Zernikedreef 9, 2333 CK Leiden, The Netherlands
| | - J Hajo van Bockel
- Department of Vascular Surgery, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands
| | - Teake Kooistra
- Department of Metabolic Health Research, Netherlands Organization for Applied Scientific Research (TNO), Zernikedreef 9, 2333 CK Leiden, The Netherlands
| | - Peter Y Wielinga
- Department of Metabolic Health Research, Netherlands Organization for Applied Scientific Research (TNO), Zernikedreef 9, 2333 CK Leiden, The Netherlands
| | - Robert Kleemann
- Department of Metabolic Health Research, Netherlands Organization for Applied Scientific Research (TNO), Zernikedreef 9, 2333 CK Leiden, The Netherlands.,Department of Vascular Surgery, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands
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30
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Morita S, Neto DDS, Morita FHA, Morita NK, Lobo SMA. Prevalence of Non-alcoholic Fatty Liver Disease and Steatohepatitis Risk Factors in Patients Undergoing Bariatric Surgery. Obes Surg 2016; 25:2335-43. [PMID: 25920616 DOI: 10.1007/s11695-015-1696-5] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
BACKGROUND Non-alcoholic fatty liver disease (NAFLD) associated with obesity comprises pathological changes ranging from steatosis to steatohepatitis; these can evolve to cirrhosis and hepatocellular carcinoma. OBJECTIVES The objectives of this study are to assess the prevalence of and predictive markers for steatohepatitis in obese patients undergoing bariatric surgery. METHODS A prospective study of 184 morbidly obese patients undergoing bariatric surgery formed the study cohort. Patients taking potentially hepatotoxic medications and those with viral diseases and a history of excessive alcohol consumption were excluded. Liver biopsies were performed during surgery with a "Trucut" needle. Patients were classified into the following groups according to the histopathological findings: normal, steatosis, mild steatohepatitis, and moderate-severe steatohepatitis. Factors associated with steatohepatitis were evaluated using logistic regression. p values <0.05 were considered significant. RESULTS The prevalence of NAFLD was 84 % (steatosis, 22.0 %; mild steatohepatitis, 30.8 %; moderate-severe steatohepatitis, 32.0 %). Independent predictive factors for steatohepatitis were age (odds ratio (OR), 1.05; 95 % confidence interval (CI), 1.01-1.09; p = 0.011), waist circumference (OR, 1.03; 95 % CI, 1.00-1.06; p = 0.021), serum alanine aminotransferase (ALT) levels (OR, 1.04; 95 % CI, 1.01-1.08; p = 0.005), and serum triglyceride levels (OR, 1.01; 95 % CI, 1.00-1.01; p = 0.042). Score values for each predictor were derived from regression coefficients and odds ratio, and a total (risk) score was obtained from the sum of the points to evaluate the probability of having steatohepatitis. CONCLUSION Age, waist circumference, serum ALT levels, and serum triglyceride levels are efficient and non-invasive predictive markers for the diagnosis and management of steatohepatitis in morbidly obese patients.
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Affiliation(s)
- Shinhiti Morita
- Surgery Department, Bariatric and Metabolic Surgery Services, Hospital de Base, Faculdade de Medicina de São José do Rio Preto (FAMERP), São José do Rio Preto, São Paulo, Brazil.
- , Rua Las Vegas 444, Bairro Debora Cristina, 15093-010, São José do Rio Preto, SP, Brazil.
| | - Dalísio De Santi Neto
- Pathology Department, Faculdade de Medicina de São José do Rio Preto (FAMERP), São José do Rio Preto, São Paulo, Brazil.
| | - Flávio Hiroshi Ananias Morita
- Surgery Department, Bariatric and Metabolic Surgery Services, Hospital de Base, Faculdade de Medicina de São José do Rio Preto (FAMERP), São José do Rio Preto, São Paulo, Brazil.
| | - Nina Kimie Morita
- Surgery Department, Bariatric and Metabolic Surgery Services, Hospital de Base, Faculdade de Medicina de São José do Rio Preto (FAMERP), São José do Rio Preto, São Paulo, Brazil.
| | - Suzana Margareth Ajeje Lobo
- Division of Intensive Care, Internal Medicine Department, Hospital de Base, Faculdade de Medicina de São José do Rio Preto (FAMERP), São José do Rio Preto, São Paulo, Brazil.
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31
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Kho MC, Lee YJ, Park JH, Cha JD, Choi KM, Kang DG, Lee HS. Combination with Red ginseng and Polygoni Multiflori ameliorates highfructose diet induced metabolic syndrome. BMC COMPLEMENTARY AND ALTERNATIVE MEDICINE 2016; 16:98. [PMID: 26961224 PMCID: PMC4784406 DOI: 10.1186/s12906-016-1063-7] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/11/2015] [Accepted: 02/19/2016] [Indexed: 11/13/2022]
Abstract
BACKGROUND Metabolic syndrome such as dyslipidemia, hypertension, obesity, impaired glucose tolerance and fatty liver, can be caused by modification of diet by means of overconsumption of high fructose diet. This study was designed to investigate whether combination with Red ginseng and Polygoni Multiflori Radix (RGPM), widely used traditional herbal medicine, ameliorates on highfructose (HF) diet-induced metabolic syndrome. METHODS SD rats were fed the 60% HF diet with/without rosiglitazone, and RGPM 100, 300 mg/kg/day, respectively. All groups received regular diet or HF diet, respectively, for 8 weeks. The last three groups treatment of rosiglitazone and RPGM orally for a period of 6 weeks. RESULTS Chronic treatment with RGPM significantly decreased body weight, fat weight and adipocyte size. RGPM significantly prevented the development of the metabolic disturbances such as hypertension, hyperlipidemia and impaired glucose tolerance. RGPM also led to increase in high density lipoprotein level in the HF group. RGPM suppressed high-fructose diet induced vascular inflammation marker expression such as adhesion molecules and ET-1 in aorta as well as increasing of C-reactive protein (CRP) levels in plasma. Similarly, RGPM attenuated hepatic lipid accumulation by inhibition of monocyte chemoattractant protein-1 (MCP-1) expression. CONCLUSION An administration of RGPM may be a beneficial therapy for the treatment of metabolic syndrome through the improvement of hypertension, obesity, hyperlipidemia, vascular inflammation and insulin resistance.
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Affiliation(s)
- Min Chul Kho
- College of Oriental Medicine and Professional Graduate School of Oriental Medicine, Wonkwang University, Shinyong-dong, Iksan, Jeonbuk, 570-749, Korea
- Hanbang Body-fluid Research Center, Wonkwang University, Shinyong-dong, Iksan, Jeonbuk, 570-749, Korea
| | - Yun Jung Lee
- College of Oriental Medicine and Professional Graduate School of Oriental Medicine, Wonkwang University, Shinyong-dong, Iksan, Jeonbuk, 570-749, Korea
- Hanbang Body-fluid Research Center, Wonkwang University, Shinyong-dong, Iksan, Jeonbuk, 570-749, Korea
| | - Ji Hun Park
- Hanbang Body-fluid Research Center, Wonkwang University, Shinyong-dong, Iksan, Jeonbuk, 570-749, Korea
| | - Jeong Dan Cha
- Department of Research Development, Institute of Jinan Red Ginseng, Jinan, Korea
| | - Kyung Min Choi
- Department of Research Development, Institute of Jinan Red Ginseng, Jinan, Korea
| | - Dae Gill Kang
- College of Oriental Medicine and Professional Graduate School of Oriental Medicine, Wonkwang University, Shinyong-dong, Iksan, Jeonbuk, 570-749, Korea.
- Hanbang Body-fluid Research Center, Wonkwang University, Shinyong-dong, Iksan, Jeonbuk, 570-749, Korea.
- Brain Korea (BK)21 plus team, Professional Graduate School of Oriental Medicine, Wonkwang University, Iksan, Jeonbuk, 540-749, Republic of Korea.
| | - Ho Sub Lee
- College of Oriental Medicine and Professional Graduate School of Oriental Medicine, Wonkwang University, Shinyong-dong, Iksan, Jeonbuk, 570-749, Korea.
- Hanbang Body-fluid Research Center, Wonkwang University, Shinyong-dong, Iksan, Jeonbuk, 570-749, Korea.
- Brain Korea (BK)21 plus team, Professional Graduate School of Oriental Medicine, Wonkwang University, Iksan, Jeonbuk, 540-749, Republic of Korea.
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32
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Kapravelou G, Martínez R, Andrade AM, Nebot E, Camiletti-Moirón D, Aparicio VA, Lopez-Jurado M, Aranda P, Arrebola F, Fernandez-Segura E, Bermano G, Goua M, Galisteo M, Porres JM. Aerobic interval exercise improves parameters of nonalcoholic fatty liver disease (NAFLD) and other alterations of metabolic syndrome in obese Zucker rats. Appl Physiol Nutr Metab 2015; 40:1242-52. [PMID: 26509584 DOI: 10.1139/apnm-2015-0141] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Metabolic syndrome (MS) is a group of metabolic alterations that increase the susceptibility to cardiovascular disease and type 2 diabetes. Nonalcoholic fatty liver disease has been described as the liver manifestation of MS. We aimed to test the beneficial effects of an aerobic interval training (AIT) protocol on different biochemical, microscopic, and functional liver alterations related to the MS in the experimental model of obese Zucker rat. Two groups of lean and obese animals (6 weeks old) followed a protocol of AIT (4 min at 65%-80% of maximal oxygen uptake, followed by 3 min at 50%-65% of maximal oxygen uptake for 45-60 min, 5 days/week, 8 weeks of experimental period), whereas 2 control groups remained sedentary. Obese rats had higher food intake and body weight (P < 0.0001) and suffered significant alterations in plasma lipid profile, area under the curve after oral glucose overload (P < 0.0001), liver histology and functionality, and antioxidant status. The AIT protocol reduced the severity of alterations related to glucose and lipid metabolism and increased the liver protein expression of PPARγ, as well as the gene expression of glutathione peroxidase 4 (P < 0.001). The training protocol also showed significant effects on the activity of hepatic antioxidant enzymes, although this action was greatly influenced by rat phenotype. The present data suggest that AIT protocol is a feasible strategy to improve some of the plasma and liver alterations featured by the MS.
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Affiliation(s)
- Garyfallia Kapravelou
- a Department of Physiology, Institute of Nutrition and Food Technology, Doctoral Program in Nutrition and Food Sciences, University of Granada, Campus Universitario de Cartuja s/n, Granada 18071, Spain
| | - Rosario Martínez
- a Department of Physiology, Institute of Nutrition and Food Technology, Doctoral Program in Nutrition and Food Sciences, University of Granada, Campus Universitario de Cartuja s/n, Granada 18071, Spain
| | - Ana M Andrade
- a Department of Physiology, Institute of Nutrition and Food Technology, Doctoral Program in Nutrition and Food Sciences, University of Granada, Campus Universitario de Cartuja s/n, Granada 18071, Spain
| | - Elena Nebot
- a Department of Physiology, Institute of Nutrition and Food Technology, Doctoral Program in Nutrition and Food Sciences, University of Granada, Campus Universitario de Cartuja s/n, Granada 18071, Spain
| | - Daniel Camiletti-Moirón
- a Department of Physiology, Institute of Nutrition and Food Technology, Doctoral Program in Nutrition and Food Sciences, University of Granada, Campus Universitario de Cartuja s/n, Granada 18071, Spain
| | - Virginia A Aparicio
- a Department of Physiology, Institute of Nutrition and Food Technology, Doctoral Program in Nutrition and Food Sciences, University of Granada, Campus Universitario de Cartuja s/n, Granada 18071, Spain
| | - Maria Lopez-Jurado
- a Department of Physiology, Institute of Nutrition and Food Technology, Doctoral Program in Nutrition and Food Sciences, University of Granada, Campus Universitario de Cartuja s/n, Granada 18071, Spain
| | - Pilar Aranda
- a Department of Physiology, Institute of Nutrition and Food Technology, Doctoral Program in Nutrition and Food Sciences, University of Granada, Campus Universitario de Cartuja s/n, Granada 18071, Spain
| | - Francisco Arrebola
- b Department of Histology, Institute of Neurosciences, University of Granada, Avenida de Madrid s/n, Granada 18071, Spain
| | - Eduardo Fernandez-Segura
- b Department of Histology, Institute of Neurosciences, University of Granada, Avenida de Madrid s/n, Granada 18071, Spain
| | - Giovanna Bermano
- c Institute for Health and Wellbeing Research, Robert Gordon University, Aberdeen AB10 7GJ, UK
| | - Marie Goua
- c Institute for Health and Wellbeing Research, Robert Gordon University, Aberdeen AB10 7GJ, UK
| | - Milagros Galisteo
- d Department of Pharmacology, School of Pharmacy, University of Granada, Campus Universitario de Cartuja s/n, Granada 18071, Spain
| | - Jesus M Porres
- a Department of Physiology, Institute of Nutrition and Food Technology, Doctoral Program in Nutrition and Food Sciences, University of Granada, Campus Universitario de Cartuja s/n, Granada 18071, Spain
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Abstract
Lifestyle modifications and optimization of the management of cardiometabolic comorbidities are currently the mainstay of treatment for patients with nonalcoholic fatty liver disease. Pharmacotherapy to halt or reverse hepatic histological injury and prevent the development of end-stage liver disease is specifically offered to patients with nonalcoholic steatohepatitis (NASH) and those with advanced fibrosis. In this review, the authors discuss the state of the art of various pharmacological agents for NASH. The efficacy of vitamin E and pioglitazone is reasonably well established in a selected group of patients with NASH. Current data do not offer convincing evidence for efficacy of pentoxifylline, long-chain polyunsaturated fatty acids, angiotensin receptor blockers, metformin, or ursodeoxycholic acid. They also discuss the state of several emerging agents for treating NASH including the farsenoid X receptor ligand, obeticholic acid.
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Affiliation(s)
- Samer Gawrieh
- Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, Indiana
| | - Naga Chalasani
- Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, Indiana
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Fabbrini E, Magkos F. Hepatic Steatosis as a Marker of Metabolic Dysfunction. Nutrients 2015; 7:4995-5019. [PMID: 26102213 PMCID: PMC4488828 DOI: 10.3390/nu7064995] [Citation(s) in RCA: 132] [Impact Index Per Article: 13.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2015] [Revised: 06/05/2015] [Accepted: 06/15/2015] [Indexed: 02/06/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the liver manifestation of the complex metabolic derangements associated with obesity. NAFLD is characterized by excessive deposition of fat in the liver (steatosis) and develops when hepatic fatty acid availability from plasma and de novo synthesis exceeds hepatic fatty acid disposal by oxidation and triglyceride export. Hepatic steatosis is therefore the biochemical result of an imbalance between complex pathways of lipid metabolism, and is associated with an array of adverse changes in glucose, fatty acid, and lipoprotein metabolism across all tissues of the body. Intrahepatic triglyceride (IHTG) content is therefore a very good marker (and in some cases may be the cause) of the presence and the degree of multiple-organ metabolic dysfunction. These metabolic abnormalities are likely responsible for many cardiometabolic risk factors associated with NAFLD, such as insulin resistance, type 2 diabetes mellitus, and dyslipidemia. Understanding the factors involved in the pathogenesis and pathophysiology of NAFLD will lead to a better understanding of the mechanisms responsible for the metabolic complications of obesity, and hopefully to the discovery of novel effective treatments for their reversal.
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Affiliation(s)
- Elisa Fabbrini
- Center for Human Nutrition and Atkins Center of Excellence in Obesity Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
| | - Faidon Magkos
- Center for Human Nutrition and Atkins Center of Excellence in Obesity Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
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35
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Tseng HT, Park YJ, Lee YK, Moore DD. The orphan nuclear receptor small heterodimer partner is required for thiazolidinedione effects in leptin-deficient mice. J Biomed Sci 2015; 22:30. [PMID: 25951943 PMCID: PMC4489392 DOI: 10.1186/s12929-015-0133-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2015] [Accepted: 03/30/2015] [Indexed: 01/09/2023] Open
Abstract
BACKGROUND Small heterodimer partner (SHP, NR0B2) is involved in diverse metabolic pathways, including hepatic bile acid, lipid and glucose homeostasis, and has been implicated in effects on the peroxisome proliferator-activated receptor γ (PPARγ), a master regulator of adipogenesis and the receptor for antidiabetic drugs thiazolidinediones (TZDs). In this study, we aim to investigate the role of SHP in TZD response by comparing TZD-treated leptin-deficient (ob/ob) and leptin-, SHP-deficient (ob/ob;Shp(-/-)) double mutant mice. RESULTS Both ob/ob and double mutant ob/ob;Shp(-/-) mice developed hyperglycemia, insulin resistance, and hyperlipidemia, but hepatic fat accumulation was decreased in the double mutant ob/ob;Shp(-/-) mice. PPARγ2 mRNA levels were markedly lower in ob/ob;Shp(-/-) liver and decreased to a lesser extent in adipose tissue. The TZD troglitazone did not reduce glucose or circulating triglyceride levels in ob/ob;Shp(-/-) mice. Expression of the adipocytokines, such as adiponectin and resistin, was not stimulated by troglitazone treatment. Expression of hepatic lipogenic genes was also reduced in ob/ob;Shp(-/-) mice. Moreover, overexpression of SHP by adenovirus infection increased PPARγ2 mRNA levels in mouse primary hepatocytes. CONCLUSIONS Our results suggest that SHP is required for both antidiabetic and hypolipidemic effects of TZDs in ob/ob mice through regulation of PPARγ expression.
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Affiliation(s)
- Hsiu-Ting Tseng
- Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas, USA.
| | - Young Joo Park
- 300 Gumi-dong, Bundang-gu, Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam-si, Kyeonggi-do, South Korea.
| | - Yoon Kwang Lee
- Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, OH, USA.
| | - David D Moore
- Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas, USA.
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Liu J, Wang G, Jia Y, Xu Y. GLP-1 receptor agonists: effects on the progression of non-alcoholic fatty liver disease. Diabetes Metab Res Rev 2015; 31:329-35. [PMID: 25066109 DOI: 10.1002/dmrr.2580] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/17/2014] [Revised: 06/15/2014] [Accepted: 07/06/2014] [Indexed: 12/21/2022]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is one of the most common liver diseases, and its incidence has been increasing recently. In addition to hepatic complications, NAFLD is also recognized as an independent risk factor for cardiovascular disease. Unfortunately, the current therapies for NAFLD display variable efficacy; a novel and effective drug is urgently needed. Glucagon-like peptide-1 (GLP-1), a receptor agonist is a new drug approved for treating type 2 diabetes. Recently, these types of agents have shown a novel therapeutic effect on NAFLD. However, the mechanisms of GLP-1 receptor agonists on the treatment of NAFLD have not yet been explained precisely. Recent studies have demonstrated that GLP-1 reverses the progression of NAFLD not only indirectly through an incretin effect that improves key parameters involved in NAFLD, but also a direct effect on lipid metabolism of hepatocytes and inflammation in liver. In this review, we provided an overview of the role and mechanisms of GLP-1 in the therapy of NAFLD.
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Affiliation(s)
- Jia Liu
- Department of Endocrinology, Beijing Chaoyang Hospital Affiliated to Capital Medical University, Beijing, 100020, People's Republic of China
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Yoon HJ, Cha BS. Pathogenesis and therapeutic approaches for non-alcoholic fatty liver disease. World J Hepatol 2014; 6:800-811. [PMID: 25429318 PMCID: PMC4243154 DOI: 10.4254/wjh.v6.i11.800] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2014] [Revised: 08/27/2014] [Accepted: 10/16/2014] [Indexed: 02/06/2023] Open
Abstract
Non-alcoholic fatty liver disease affects approximately one-third of the population worldwide, and its incidence continues to increase with the increasing prevalence of other metabolic disorders such as type 2 diabetes. As non-alcoholic fatty liver disease can progress to liver cirrhosis, its treatment is attracting greater attention. The pathogenesis of non-alcoholic fatty liver disease is closely associated with insulin resistance and dyslipidemia, especially hypertriglyceridemia. Increased serum levels of free fatty acid and glucose can cause oxidative stress in the liver and peripheral tissue, leading to ectopic fat accumulation, especially in the liver. In this review, we summarize the mechanism underlying the progression of hepatic steatosis to steatohepatitis and cirrhosis. We also discuss established drugs that are already being used to treat non-alcoholic fatty liver disease, in addition to newly discovered agents, with respect to their mechanisms of drug action, focusing mainly on hepatic insulin resistance. As well, we review clinical data that demonstrate the efficacy of these drugs, together with improvements in biochemical or histological parameters.
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Xu H, Xu J, Wang Y, Hu S, Wang Y, Wang J, Xue C. Fucoidan isolated from the sea cucumber Acaudina molpadioides improves insulin resistance in adipocytes via activating PKB/GLUT4 pathway. Eur Food Res Technol 2014. [DOI: 10.1007/s00217-014-2380-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
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Mitchel EB, Lavine JE. Review article: the management of paediatric nonalcoholic fatty liver disease. Aliment Pharmacol Ther 2014; 40:1155-70. [PMID: 25267322 DOI: 10.1111/apt.12972] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2014] [Revised: 06/16/2014] [Accepted: 09/09/2014] [Indexed: 02/07/2023]
Abstract
BACKGROUND Paediatric nonalcoholic fatty liver disease (NAFLD) is a major public health concern given the recent increase in its prevalence and link to obesity and other metabolic comorbidities. Current treatment strategies involve lifestyle changes. Other surgical and pharmacologic interventions have been proposed; however, limited randomised controlled trials (RCTs) in the paediatric population restrict their use. AIM To review the current management of paediatric NAFLD, including lifestyle and pharmacologic interventions, and to formulate recommendations for study design for future studies. METHODS A MEDLINE, Pubmed and Cochrane Review database search used a combination of keywords, including NAFLD, nonalcoholic steatohepatitis (NASH), paediatric, treatments, lifestyle changes, bariatric surgery, orlistat, metformin, thiazolidinediones, vitamin E, cysteamine bitartrate, ursodeoxycholic acid (UDCA), probiotics, omega-3 fatty acids, pentoxyfylline, farnesoid X receptor agonist and toll-like receptor modifiers. The articles were selected based on their relevance to the review. RESULTS Lifestyle interventions involving diet and exercise remain first-line treatment for paediatric NAFLD. Bariatric surgery, orlistat, insulin sensitisers and UDCA have been evaluated but are not recommended as first or second-line therapy. Medications such as cysteamine bitartrate, probiotics, polyunsaturated fats and pentoxyfilline share beneficial effects in trials, however, there is a paucity of adequately powered RCTs in which liver histology is evaluated. Vitamin E has been shown to be effective and safe in improving NASH histology in children. CONCLUSIONS Lifestyle intervention should be first-line treatment for paediatric NAFLD. Vitamin E should be considered for those with biopsy-proven NASH or borderline NASH failing first-line therapy. Other therapeutics show promising results but require larger RCTs with convincing endpoints. Improved screening techniques, objective validated inclusion criteria and outcome measures as well as rigour in study design are necessary for propelling therapeutic discovery.
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Affiliation(s)
- E B Mitchel
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, Columbia University, New York, NY, USA
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40
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Baran B, Akyüz F. Non-alcoholic fatty liver disease: What has changed in the treatment since the beginning? World J Gastroenterol 2014; 20:14219-14229. [PMID: 25339808 PMCID: PMC4202350 DOI: 10.3748/wjg.v20.i39.14219] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2014] [Revised: 04/22/2014] [Accepted: 05/26/2014] [Indexed: 02/06/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is an umbrella term to describe the entire spectrum of this common liver disease. In patients with NAFLD, especially those with non-alcoholic steatohepatitis (NASH), most often have one or more components of the metabolic syndrome, but this is not universal. Although most patients with NAFLD share many clinical features, only a subset of patients develops significant liver inflammation and progressive fibrosis. On the other hand, not all patients with NASH exhibit insulin resistance. NASH can be seen in patients who are lean and have no identifiable risk factors. Many clinical studies have tried numerous drugs and alternative medicine, however, investigators have failed to identify a safe and effective therapy for patients with NASH. As summarized, the heterogeneity of pathogenic pathways in individual patients with NASH may warrant the development of an individualized treatment according to the underlying pathogenic pathway. The differentiation of pathogenetic targets may require the development of diagnostic and prognostic biomarkers, and the identification of genetic susceptibilities. At present, evidence-based medicine provides only a few options including life-style modifications targeting weight loss, pioglitazone and vitamin E in non-diabetic patients with biopsy-proven NASH.
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Nonalcoholic Fatty liver disease: pathogenesis and therapeutics from a mitochondria-centric perspective. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2014; 2014:637027. [PMID: 25371775 PMCID: PMC4211163 DOI: 10.1155/2014/637027] [Citation(s) in RCA: 107] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/14/2014] [Revised: 07/31/2014] [Accepted: 07/31/2014] [Indexed: 12/12/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) describes a spectrum of disorders characterized by the accumulation of triglycerides within the liver. The global prevalence of NAFLD has been increasing as the obesity epidemic shows no sign of relenting. Mitochondria play a central role in hepatic lipid metabolism and also are affected by upstream signaling pathways involved in hepatic metabolism. This review will focus on the role of mitochondria in the pathophysiology of NAFLD and touch on some of the therapeutic approaches targeting mitochondria as well as metabolically important signaling pathways. Mitochondria are able to adapt to lipid accumulation in hepatocytes by increasing rates of beta-oxidation; however increased substrate delivery to the mitochondrial electron transport chain (ETC) leads to increased reactive oxygen species (ROS) production and eventually ETC dysfunction. Decreased ETC function combined with increased rates of fatty acid beta-oxidation leads to the accumulation of incomplete products of beta-oxidation, which combined with increased levels of ROS contribute to insulin resistance. Several related signaling pathways, nuclear receptors, and transcription factors also regulate hepatic lipid metabolism, many of which are redox sensitive and regulated by ROS.
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Steatosis and steatohepatitis: complex disorders. Int J Mol Sci 2014; 15:9924-44. [PMID: 24897026 PMCID: PMC4100130 DOI: 10.3390/ijms15069924] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2014] [Revised: 05/01/2014] [Accepted: 05/20/2014] [Indexed: 12/20/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) which includes steatosis and steatohepatitis, in particular non-alcoholic steatohepatitis (NASH), is a rising health problem world-wide and should be separated from alcoholic steatohepatitis (ASH). NAFLD is regarded as hepatic manifestation of the metabolic syndrome (MetSy), being tightly linked to obesity and type 2 diabetes mellitus (T2DM). Development of steatosis, liver fibrosis and cirrhosis often progresses towards hepatocellular carcinogenesis and frequently results in the indication for liver transplantation, underlining the clinical significance of this disease complex. Work on different murine models and several human patients studies led to the identification of different molecular key players as well as epigenetic factors like miRNAs and SNPs, which have a promoting or protecting function in AFLD/ASH or NAFLD/NASH. To which extent they might be translated into human biology and pathogenesis is still questionable and needs further investigation regarding diagnostic parameters, drug development and a better understanding of the genetic impact. In this review we give an overview about the currently available knowledge and recent findings regarding the development and progression of this disease.
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Stefan N, Ramsauer M, Jordan P, Nowotny B, Kantartzis K, Machann J, Hwang JH, Nowotny P, Kahl S, Harreiter J, Hornemann S, Sanyal AJ, Stewart PM, Pfeiffer AF, Kautzky-Willer A, Roden M, Häring HU, Fürst-Recktenwald S. Inhibition of 11β-HSD1 with RO5093151 for non-alcoholic fatty liver disease: a multicentre, randomised, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinol 2014; 2:406-16. [PMID: 24795254 DOI: 10.1016/s2213-8587(13)70170-0] [Citation(s) in RCA: 81] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
BACKGROUND The prevalence of non-alcoholic fatty liver disease is increasing worldwide and an effective and safe pharmacological treatment is needed. We investigated whether inhibition of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1, also known as HSD11B1) by RO5093151 could safely and effectively decrease liver-fat content in patients with this disorder. METHODS We did this phase 1b trial at four centres in Germany and Austria. Participants with non-alcoholic fatty liver disease (defined as (1)H magnetic resonance spectroscopy liver-fat content >5·56%), insulin resistance (homoeostatic model assessment of insulin resistance [HOMA-IR] of at least 2·0 mmol/L·mU/L), BMI greater than 27 kg/m(2), and aged 35-65 years were randomly assigned by interactive voice response system in a 1:1 ratio, stratified for triglyceride concentration (<1·7 mmol/L or ≥1·7 mmol/L), to oral RO5093151 (200 mg twice daily) or matching placebo for 12 weeks. The main exclusion criteria were other liver diseases, aspartate aminotransferase or alanine aminotransferase concentrations of more than two and a half times the upper limit of normal, history of diabetes or bariatric surgery, and use of weight lowering drugs. Participants and investigators were masked to assignment throughout the study. The primary endpoint was change in liver-fat content from baseline to week 12. Efficacy analysis was by modified intention to treat, including all patients who received at least one dose of study drug and had a baseline and follow-up measurement of liver-fat content. Safety analyses included all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT01277094. FINDINGS We did this trial between Jan 13, 2011, and March 28, 2012. 41 patients were randomly assigned to RO5093151 and 41 to placebo. 35 patients in the RO5093151 group and 39 in the placebo group were included in the efficacy analysis. Mean liver-fat content decreased in the RO5093151 group (from 16·75% [SD 8·67] to 14·28% [8·89]), but not in the placebo group (from 18·53% [10·00] to 18·46% [10·78], p=0·02 for between group difference). 26 participants (65%) in the RO5093151 group had adverse events, compared with 21 (53%) in the placebo group. The most common adverse events were gastrointestinal disorders (12 patients [30%] in the RO5093151 group vs seven [18%] in the placebo group), and infections and infestations (eight [20%] vs nine [23%]). Nervous system disorders occurred in significantly more patients in the RO5093151 group than in the placebo group (nine [23%] vs two [5%]; p=0·02); all other differences in adverse events were non-significant. One participant (3%) in the placebo group and three participants (8%) in the RO5093151 group had serious adverse events. All serious adverse events were deemed unrelated to study treatment. INTERPRETATION Inhibition of 11β-HSD1 by RO5093151 was effective and safe in reducing liver-fat content, suggesting that targeting of 11β-HSD1 might be a promising approach for the treatment of non-alcoholic fatty liver disease. FUNDING F Hoffmann-La Roche.
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Affiliation(s)
- Norbert Stefan
- Department of Internal Medicine, Division of Endocrinology, Diabetology, Vascular Medicine, Nephrology and Clinical Chemistry, University Hospital Tübingen, Tübingen, Germany; Institute of Diabetes Research and Metabolic Diseases, University of Tübingen, Tübingen, Germany; German Center for Diabetes Research, Neuherberg, Germany.
| | | | | | - Bettina Nowotny
- German Center for Diabetes Research, Neuherberg, Germany; Institute for Clinical Diabetology, German Diabetes Center at Heinrich-Heine University Düsseldorf, Düsseldorf, Germany
| | - Konstantinos Kantartzis
- Department of Internal Medicine, Division of Endocrinology, Diabetology, Vascular Medicine, Nephrology and Clinical Chemistry, University Hospital Tübingen, Tübingen, Germany; Institute of Diabetes Research and Metabolic Diseases, University of Tübingen, Tübingen, Germany; German Center for Diabetes Research, Neuherberg, Germany
| | - Jürgen Machann
- Institute of Diabetes Research and Metabolic Diseases, University of Tübingen, Tübingen, Germany; Section on Experimental Radiology, University of Tübingen, Tübingen, Germany; German Center for Diabetes Research, Neuherberg, Germany
| | - Jong-Hee Hwang
- German Center for Diabetes Research, Neuherberg, Germany; Institute for Clinical Diabetology, German Diabetes Center at Heinrich-Heine University Düsseldorf, Düsseldorf, Germany
| | - Peter Nowotny
- German Center for Diabetes Research, Neuherberg, Germany; Institute for Clinical Diabetology, German Diabetes Center at Heinrich-Heine University Düsseldorf, Düsseldorf, Germany
| | - Sabine Kahl
- German Center for Diabetes Research, Neuherberg, Germany; Institute for Clinical Diabetology, German Diabetes Center at Heinrich-Heine University Düsseldorf, Düsseldorf, Germany
| | - Jürgen Harreiter
- Internal Medicine III, Endocrinology and Metabolism, Gender Medicine Unit, Medical University of Vienna, Vienna, Austria
| | - Silke Hornemann
- German Center for Diabetes Research, Neuherberg, Germany; Department of Clinical Nutrition, German Institute of Human Nutrition Potsdam, Nuthetal, Germany
| | - Arun J Sanyal
- Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine Virginia Commonwealth University School of Medicine, Richmond, VA, USA
| | | | - Andreas F Pfeiffer
- German Center for Diabetes Research, Neuherberg, Germany; Department of Clinical Nutrition, German Institute of Human Nutrition Potsdam, Nuthetal, Germany
| | - Alexandra Kautzky-Willer
- Internal Medicine III, Endocrinology and Metabolism, Gender Medicine Unit, Medical University of Vienna, Vienna, Austria
| | - Michael Roden
- German Center for Diabetes Research, Neuherberg, Germany; Institute for Clinical Diabetology, German Diabetes Center at Heinrich-Heine University Düsseldorf, Düsseldorf, Germany; Department of Endocrinology and Diabetology, University Clinical Düsseldorf, Düsseldorf, Germany
| | - Hans-Ulrich Häring
- Department of Internal Medicine, Division of Endocrinology, Diabetology, Vascular Medicine, Nephrology and Clinical Chemistry, University Hospital Tübingen, Tübingen, Germany; Institute of Diabetes Research and Metabolic Diseases, University of Tübingen, Tübingen, Germany; German Center for Diabetes Research, Neuherberg, Germany
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Ozturk ZA, Kadayifci A. Insulin sensitizers for the treatment of non-alcoholic fatty liver disease. World J Hepatol 2014; 6:199-206. [PMID: 24799988 PMCID: PMC4009475 DOI: 10.4254/wjh.v6.i4.199] [Citation(s) in RCA: 56] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2013] [Revised: 01/08/2014] [Accepted: 03/12/2014] [Indexed: 02/06/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the leading cause of liver disease in the Western world and is closely associated with metabolic syndrome, which includes hypertension, central obesity, dyslipidemia and insulin resistance. NAFLD includes a wide spectrum of liver alterations, ranging from simple hepatic steatosis to variable degrees of fibrosis, cirrhosis and even hepatocellular carcinoma. Although the etiology and progression of the disorder remain poorly understood, insulin resistance is considered to play a pivotal role in the pathogenesis. Insulin sensitizers such as biguanides, thiazolidinediones (TZDs), glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase 4 inhibitors have been studied as therapeutic approaches for NAFLD in recent years. Metformin improves insulin sensitivity and serum alanine transaminase and aspartate transaminase (ALT/AST) levels in the majority of subjects; however, it has no significant effect on liver histology. TZDs improve insulin sensitivity, serum ALT/AST levels and histology in some cases, but there are some concerns about the safety of long-term therapy. Selection of appropriate patients for avoiding side effects and the treatment of underlying disease are the main points. These drugs are the best choice for the treatment of NAFLD in patients with type 2 DM who are also candidates for treatment with an insulin sensitizer. The present review provides an overview of insulin sensitizers in the treatment of NAFLD.
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Yakaryilmaz F, Guliter S, Ozenirler S, Erdem O, Akyol G. Vitamin E treatment in patients with nonalcoholic steatohepatitis: A six-month, open-label study of sixteen patients. Curr Ther Res Clin Exp 2014; 65:266-77. [PMID: 24672082 DOI: 10.1016/s0011-393x(04)80077-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/01/2004] [Indexed: 01/07/2023] Open
Abstract
BACKGROUND Free radicals have a pivotal role in the pathogenesis of nonalcoholic steatohepatitis (NASH). Decreasing oxidative stress might have beneficial effects on the biochemical and histologic progression of this disease. OBJECTIVE We aimed to determine the therapeutic effect of vitamin E, a potent antioxidant, on liver enzymes and histology in NASH. METHODS This 6-month, open-label study was conducted at the Departments of Gastroenterology and Pathology, Gazi University School of Medicine (Ankara, Turkey). Patients aged 18 to 70 years with biopsy-proven NASH were included in the study. All patients received vitamin E 800 U/d in 2 divided doses, orally (capsules) for 6 months. Patients were not advised to change their exercise or dietary habits. Body mass index (BMI) was calculated at months 0 (baseline) and 6. Histologic scoring of steatosis, necroinflammatory grade, and fibrosis stage was performed at 0 and 6 months. Liver enzyme activities (alanine aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase [ALP], and gamma-glutamyltransferase [GGT]) were monitored monthly. Control biopsy specimens were obtained at the end of the treatment. All of the liver biopsies were read by a single pathologist (G.A.) who was blinded to the clinical, laboratory, and histopathologic data, as well as the sequence of liver biopsies. Assessments of compliance and tolerability of treatment were performed using a pill count and patient interview, respectively, at the end of each month. RESULTS Sixteen patients (12 men, 4 women; mean [SD] age, 45.5 [6.9] years [range, 37-60 years]) were enrolled. All patients completed 6 months of treatment. Mean BMI did not change significantly from baseline. Significant improvements in mean (SD) serum liver enzyme activities were observed at 6 months compared with baseline (ALT: 38.6 [16.3] U/L vs 84.8 [22.1] U/L, respectively, P = 0.001; AST: 29.8 [15.4] U/L vs 46.0 [16.0] U/L, respectively, P = 0.001; ALP: 154.6 [64.1] U/L vs 211.5 [70.4] U/L, respectively, P= 0.011; and GGT: 49.8 [38.5] U/L vs 64.7 [54.4] U/L, respectively, P = 0.002), as well as in total cholesterol level (176.2 [42.0] mg/dL vs 199.6 [60.6] mg/dL; P = 0.02). Posttreatment liver biopsy was available in 13 patients (81%). Significant improvements in the mean (SD) scores of steatosis (1.46 [0.66] vs 2.43 [0.62]; P = 0.002) and necroinflammatory grade (0.84 [0.24] vs 1.31 [0.51]; P= 0.006) were observed at 6 months compared with baseline, respectively. However, no significant change was noted in the mean (SD) score of fibrosis stage (0.77 [0.33] vs 1.12 [0.59], respectively). None of the patients reported any adverse effects. CONCLUSION In this small, 6-month, open-label study, vitamin E treatment was safe and well tolerated and led to potential biochemical and histologic improvements (except in fibrosis) in patients with NASH.
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Affiliation(s)
- Fahri Yakaryilmaz
- Departments of Gastroenterology, Gazi University School of Medicine, Ankara, Turkey
| | - Sefa Guliter
- Departments of Gastroenterology, Gazi University School of Medicine, Ankara, Turkey
| | - Seren Ozenirler
- Departments of Gastroenterology, Gazi University School of Medicine, Ankara, Turkey
| | - Ozlem Erdem
- Pathology, Gazi University School of Medicine, Ankara, Turkey
| | - Gulen Akyol
- Pathology, Gazi University School of Medicine, Ankara, Turkey
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Younossi ZM, Reyes MJ, Mishra A, Mehta R, Henry L. Systematic review with meta-analysis: non-alcoholic steatohepatitis - a case for personalised treatment based on pathogenic targets. Aliment Pharmacol Ther 2014; 39:3-14. [PMID: 24206433 DOI: 10.1111/apt.12543] [Citation(s) in RCA: 66] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/16/2013] [Revised: 08/06/2013] [Accepted: 10/11/2013] [Indexed: 02/06/2023]
Abstract
BACKGROUND Non-alcoholic fatty liver disease (NAFLD) is an umbrella term, which encompasses simple steatosis and non-alcoholic steatohepatitis (NASH). The entire spectrum of NAFLD has been associated with metabolic syndrome. NASH is associated with increased mortality compared with that of the general population. Many therapeutic options for NASH have been studied. However, there is very little evidence supporting the efficacy of most regimens for the treatment of NASH. AIM To provide a review focusing on the current therapeutic options available for patients with NASH as well as to briefly introduce possible future interventions. METHODS A MEDLINE, Pubmed and Cochrane Review database search using a combination of keywords, which included non-alcoholic fatty liver disease, non-alcoholic hepatic steatosis, NAFLD, NASH, treatment, therapeutics, vitamin E, orlistat and bariatric surgery. An overall summary of the articles was developed for each section of discussion in this review. RESULTS NASH associated with metabolic syndrome can progress advanced fibrosis and cirrhosis. Weight loss and lifestyle modification have been shown to improve NASH. Other medications used for weight loss and metabolic syndrome have been evaluated, such as orlistat, metformin and thiazolidinediones. Alternative regimens using ursodeoxycholic acid, statins and probiotics as well as bariatric surgery have been evaluated, but have not been recommended as first-line treatment for NASH. Vitamin E for NASH patients without diabetes seems to be promising. The lack of effective treatment for NASH suggests the heterogeneity of patients presenting with the NASH phenotype. The best treatment strategy for these patients may be to identify their pathogenic target and develop personalised treatment protocols. CONCLUSIONS Currently, there are few options available for the management of NASH. Future targeted treatment strategies based on the pathogenic pathways may be needed to develop effective treatment for patients with NASH.
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Affiliation(s)
- Z M Younossi
- Department of Medicine, Center for Liver Diseases, Inova Fairfax Hospital, Falls Church, VA, USA; Betty and Guy Beatty Center for Integrated Research, Inova Health System, Falls Church, VA, USA
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Corrado RL, Torres DM, Harrison SA. Review of treatment options for nonalcoholic fatty liver disease. Med Clin North Am 2014; 98:55-72. [PMID: 24266914 DOI: 10.1016/j.mcna.2013.09.001] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Although the future of NAFLD and NASH treatment has many promising agents, clinicians are currently faced with limited options with an emphasis on lifestyle modification. Figs. 1 and 2 summarize current practices for the diagnosis and treatment of NAFLD with the understanding that each patient's treatment must be customized to their comorbidities, exercise tolerance, and willingness to comply with therapy.
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Affiliation(s)
- Richele L Corrado
- Department of Medicine, Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Bethesda, MD 20889-5600, USA
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KASL clinical practice guidelines: management of nonalcoholic fatty liver disease. Clin Mol Hepatol 2013; 19:325-48. [PMID: 24459637 PMCID: PMC3894432 DOI: 10.3350/cmh.2013.19.4.325] [Citation(s) in RCA: 93] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2013] [Accepted: 11/07/2013] [Indexed: 02/06/2023] Open
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Gao X, Fan JG. Diagnosis and management of non-alcoholic fatty liver disease and related metabolic disorders: consensus statement from the Study Group of Liver and Metabolism, Chinese Society of Endocrinology. J Diabetes 2013; 5:406-415. [PMID: 23560695 PMCID: PMC3933762 DOI: 10.1111/1753-0407.12056] [Citation(s) in RCA: 92] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2012] [Revised: 03/17/2013] [Accepted: 04/03/2013] [Indexed: 12/12/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease in Western countries, affecting 20%-33% of the general population. Large population-based surveys in China indicate a prevalence of approximately 15%-30%. Worldwide, including in China, the prevalence of NAFLD has increased rapidly in parallel with regional trends of obesity, type 2 diabetes and metabolic syndrome. In addition, NAFLD has contributed significantly to increased overall, as well as cardiovascular and liver-related, mortality in the general population. In view of rapid advances in research into NAFLD in recent years, this consensus statement provides a brief update on the progress in the field and suggests preferred approaches for the comprehensive management of NAFLD and its related metabolic diseases.
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Affiliation(s)
- Xin Gao
- Department of Endocrinology and Metabolism Zhongshan Hospital, Fudan UniversityShanghai, China
| | - Jian-Gao Fan
- Department of Gastroenterology, Xinhua HospitalShanghai, China
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Gallego-Durán R, Ampuero J, Funuyet J, Romero-Gómez M. [Alcoholic and non-alcoholic steatohepatitis: who is affected and what can we do for them?]. GASTROENTEROLOGIA Y HEPATOLOGIA 2013; 36:587-96. [PMID: 24011648 DOI: 10.1016/j.gastrohep.2013.06.005] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/15/2013] [Accepted: 06/18/2013] [Indexed: 12/21/2022]
Abstract
The most common causes of steatohepatitis are alcohol intake and metabolic disorders. Several methods based on biochemical determinations (carbohydrate deficient transferrin) and questionnaires (AUDIT, CAGE, MALE) are useful for detecting surreptitious alcohol intake. Although new non-invasive methods are under development, based both on lipidomics (Owl-Liver(®)) and on biochemical determinations and anthropometric parameters (NAFLD Fibrosis score) or imaging methods (DeMILI NASH-MRi(®)), none has been proposed as definitive and the gold standard continues to be liver biopsy. The pathogenesis of alcoholic and non-alcoholic steatohepatitis shares some elements such as insulin resistance, cytochrome CYP2E1-mediated oxidative stress, adiponutrin and its PNPLA3 gene, and the microbiota. The first-line treatment consists of lifestyle changes, including giving up alcohol, diet and exercise.
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Affiliation(s)
- Rocío Gallego-Durán
- Unidad Médico-Quirúrgica de Enfermedades Digestivas y CIBERehd, Hospital Universitario de Valme, Universidad de Sevilla, Sevilla, España
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