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Michalopoulou E, Thymis J, Lampsas S, Pavlidis G, Katogiannis K, Vlachomitros D, Katsanaki E, Kostelli G, Pililis S, Pliouta L, Kountouri A, Papanikolaou IS, Lambadiari V, Ikonomidis I. The Triad of Risk: Linking MASLD, Cardiovascular Disease and Type 2 Diabetes; From Pathophysiology to Treatment. J Clin Med 2025; 14:428. [PMID: 39860434 PMCID: PMC11765821 DOI: 10.3390/jcm14020428] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2024] [Revised: 12/30/2024] [Accepted: 01/08/2025] [Indexed: 01/27/2025] Open
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) is an emerging global health concern, and it is not only the keystone precursor of eventual liver-related morbidity, but it also places patients at considerably higher cardiovascular risk, which is still a leading cause of death in these patients. The most important common underlying pathophysiological mechanisms in these diseases are primarily related to insulin resistance, chronic inflammation and oxidative stress. The presence of MASLD with cardiovascular disease (CVD) and type 2 diabetes mellitus (T2DM) elevates the risk for poor outcomes, thus this review highlights a method to the therapeutic approaches. Given the intertwined nature of MASLD, T2DM, and CVD, there is an urgent need for therapeutic strategies that address all three conditions. Although lifestyle changes are important as treatment, medication plays a crucial role in managing hyperglycemia, enhancing liver function and lowering cardiovascular risk. The onset and progression of MASLD should be addressed through a multifaceted therapeutic approach, targeting inflammatory, immune, metabolic, oxidative stress, hormonal and gutaxis pathways, alongside the treatment strategies for T2DM. In this review, we discuss the effects of antidiabetic drugs with an impact on both liver outcomes and cardiovascular risk in patients affected by MASLD, T2DM and CDV.
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Affiliation(s)
- Eleni Michalopoulou
- 2nd Cardiology Department, Attikon University Hospital, National and Kapodistrian University of Athens, Rimini 1, Chaidari, 12462 Athens, Greece; (E.M.); (J.T.); (G.P.); (K.K.); (D.V.); (E.K.); (G.K.)
| | - John Thymis
- 2nd Cardiology Department, Attikon University Hospital, National and Kapodistrian University of Athens, Rimini 1, Chaidari, 12462 Athens, Greece; (E.M.); (J.T.); (G.P.); (K.K.); (D.V.); (E.K.); (G.K.)
| | - Stamatios Lampsas
- Diabetes Center, 2nd Department of Internal Medicine, Attikon University Hospital, Medical School, National and Kapodistrian University of Athens, Rimini 1, Chaidari, 12462 Athens, Greece; (S.L.); (S.P.); (L.P.); (A.K.); (V.L.)
| | - George Pavlidis
- 2nd Cardiology Department, Attikon University Hospital, National and Kapodistrian University of Athens, Rimini 1, Chaidari, 12462 Athens, Greece; (E.M.); (J.T.); (G.P.); (K.K.); (D.V.); (E.K.); (G.K.)
| | - Konstantinos Katogiannis
- 2nd Cardiology Department, Attikon University Hospital, National and Kapodistrian University of Athens, Rimini 1, Chaidari, 12462 Athens, Greece; (E.M.); (J.T.); (G.P.); (K.K.); (D.V.); (E.K.); (G.K.)
| | - Dimitrios Vlachomitros
- 2nd Cardiology Department, Attikon University Hospital, National and Kapodistrian University of Athens, Rimini 1, Chaidari, 12462 Athens, Greece; (E.M.); (J.T.); (G.P.); (K.K.); (D.V.); (E.K.); (G.K.)
| | - Eleni Katsanaki
- 2nd Cardiology Department, Attikon University Hospital, National and Kapodistrian University of Athens, Rimini 1, Chaidari, 12462 Athens, Greece; (E.M.); (J.T.); (G.P.); (K.K.); (D.V.); (E.K.); (G.K.)
| | - Gavriella Kostelli
- 2nd Cardiology Department, Attikon University Hospital, National and Kapodistrian University of Athens, Rimini 1, Chaidari, 12462 Athens, Greece; (E.M.); (J.T.); (G.P.); (K.K.); (D.V.); (E.K.); (G.K.)
| | - Sotirios Pililis
- Diabetes Center, 2nd Department of Internal Medicine, Attikon University Hospital, Medical School, National and Kapodistrian University of Athens, Rimini 1, Chaidari, 12462 Athens, Greece; (S.L.); (S.P.); (L.P.); (A.K.); (V.L.)
| | - Loukia Pliouta
- Diabetes Center, 2nd Department of Internal Medicine, Attikon University Hospital, Medical School, National and Kapodistrian University of Athens, Rimini 1, Chaidari, 12462 Athens, Greece; (S.L.); (S.P.); (L.P.); (A.K.); (V.L.)
| | - Aikaterini Kountouri
- Diabetes Center, 2nd Department of Internal Medicine, Attikon University Hospital, Medical School, National and Kapodistrian University of Athens, Rimini 1, Chaidari, 12462 Athens, Greece; (S.L.); (S.P.); (L.P.); (A.K.); (V.L.)
| | - Ioannis S. Papanikolaou
- Hepatogastroenterology Unit, Second Department of Internal Medicine-Propaedeutic, Attikon University Hospital, Rimini 1, Chaidari, 12462 Athens, Greece;
| | - Vaia Lambadiari
- Diabetes Center, 2nd Department of Internal Medicine, Attikon University Hospital, Medical School, National and Kapodistrian University of Athens, Rimini 1, Chaidari, 12462 Athens, Greece; (S.L.); (S.P.); (L.P.); (A.K.); (V.L.)
| | - Ignatios Ikonomidis
- 2nd Cardiology Department, Attikon University Hospital, National and Kapodistrian University of Athens, Rimini 1, Chaidari, 12462 Athens, Greece; (E.M.); (J.T.); (G.P.); (K.K.); (D.V.); (E.K.); (G.K.)
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Iwaki M, Yoneda M, Wada N, Otani T, Kobayashi T, Nogami A, Saito S, Nakajima A. Emerging drugs for the treatment of hepatic fibrosis on nonalcoholic steatohepatitis. Expert Opin Emerg Drugs 2024; 29:127-137. [PMID: 38469871 DOI: 10.1080/14728214.2024.2328036] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2023] [Accepted: 03/05/2024] [Indexed: 03/13/2024]
Abstract
INTRODUCTION Approved drug therapies for nonalcoholic steatohepatitis (NASH) are lacking, for which various agents are currently being tested in clinical trials. Effective drugs for liver fibrosis, the factor most associated with prognosis in NASH, are important. AREAS COVERED This study reviewed the treatment of NASH with a focus on the effects of existing drugs and new drugs on liver fibrosis. EXPERT OPINION Considering the complex pathophysiology of fibrosis in NASH, drug therapy may target multiple pathways. The method of assessing fibrosis is important when considering treatment for liver fibrosis in NASH. The Food and Drug Administration considers an important fibrosis endpoint to be histological improvement in at least one fibrosis stage while preventing worsening of fatty hepatitis. To obtain approval as a drug for NASH, efficacy needs to be demonstrated on endpoints such as liver-related events and myocardial infarction. Among the current therapeutic agents for NASH, thiazolidinedione, sodium-glucose co-transporter 2, and selective peroxisome proliferator-activated receptors α modulator have been reported to be effective against fibrosis, although further evidence is required. The effects of pan-peroxisome proliferator-activated receptors, obeticholic acid, and fibroblast growth factor-21 analogs on liver fibrosis in the development stage therapeutics for NASH are of particular interest.
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Affiliation(s)
- Michihiro Iwaki
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Masato Yoneda
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Naohiro Wada
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Tomohiro Otani
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Takashi Kobayashi
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Asako Nogami
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Satoru Saito
- Department of Gastroenterology, Sanno Hospital, Minato-Ku, Tokyo, Japan
| | - Atsushi Nakajima
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
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McGrath MS, Wentworth BJ. The Renin-Angiotensin System in Liver Disease. Int J Mol Sci 2024; 25:5807. [PMID: 38891995 PMCID: PMC11172481 DOI: 10.3390/ijms25115807] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2024] [Revised: 05/23/2024] [Accepted: 05/25/2024] [Indexed: 06/21/2024] Open
Abstract
The renin-angiotensin system (RAS) is a complex homeostatic entity with multiorgan systemic and local effects. Traditionally, RAS works in conjunction with the kidney to control effective arterial circulation, systemic vascular resistance, and electrolyte balance. However, chronic hepatic injury and resulting splanchnic dilation may disrupt this delicate balance. The role of RAS in liver disease, however, is even more extensive, modulating hepatic fibrosis and portal hypertension. Recognition of an alternative RAS pathway in the past few decades has changed our understanding of RAS in liver disease, and the concept of opposing vs. "rebalanced" forces is an ongoing focus of research. Whether RAS inhibition is beneficial in patients with chronic liver disease appears to be context-dependent, but further study is needed to optimize clinical management and reduce organ-specific morbidity and mortality. This review presents the current understanding of RAS in liver disease, acknowledges areas of uncertainty, and describes potential areas of future investigation.
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Affiliation(s)
- Mary S. McGrath
- Department of Medicine, School of Medicine, University of Virginia, Charlottesville, VA 22903, USA;
| | - Brian J. Wentworth
- Division of Gastroenterology & Hepatology, School of Medicine, University of Virginia, Charlottesville, VA 22903, USA
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Chen L, Guo W, Mao C, Shen J, Wan M. Liver fibrosis: pathological features, clinical treatment and application of therapeutic nanoagents. J Mater Chem B 2024; 12:1446-1466. [PMID: 38265305 DOI: 10.1039/d3tb02790b] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2024]
Abstract
Liver fibrosis is a reversible damage-repair response, the pathological features of which mainly include damage to hepatocytes, sinusoid capillarization, hepatic stellate cells activation, excessive accumulation of extracellular matrix and inflammatory response. Although some treatments (including drugs and stem cell therapy) for these pathological features have been shown to be effective, more clinical trials are needed to confirm their effectiveness. In recent years, nanomaterials-based therapies have emerged as an innovative and promising alternative to traditional drugs, being explored for the treatment of liver fibrosis diseases. Natural nanomaterials (including extracellular vesicles) and synthetic nanomaterials (including inorganic nanomaterials and organic nanomaterials) are developed to facilitate drug targeting delivery and combination therapy. In this review, the pathological features of liver fibrosis and the current anti-fibrosis drugs in clinical trials are briefly introduced, followed by a detailed introduction of the therapeutic nanoagents for the precise delivery of anti-fibrosis drugs. Finally, the future development trend in this field is discussed.
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Affiliation(s)
- Lin Chen
- National and Local Joint Engineering Research Center of Biomedical Functional Materials, School of Chemistry and Materials Science, Nanjing Normal University, Nanjing 210023, China.
| | - Wenyan Guo
- National and Local Joint Engineering Research Center of Biomedical Functional Materials, School of Chemistry and Materials Science, Nanjing Normal University, Nanjing 210023, China.
| | - Chun Mao
- National and Local Joint Engineering Research Center of Biomedical Functional Materials, School of Chemistry and Materials Science, Nanjing Normal University, Nanjing 210023, China.
| | - Jian Shen
- National and Local Joint Engineering Research Center of Biomedical Functional Materials, School of Chemistry and Materials Science, Nanjing Normal University, Nanjing 210023, China.
| | - Mimi Wan
- National and Local Joint Engineering Research Center of Biomedical Functional Materials, School of Chemistry and Materials Science, Nanjing Normal University, Nanjing 210023, China.
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Oh JH, Jun DW. Nonalcoholic fatty liver disease–related extrahepatic complications, associated outcomes, and their treatment considerations. METABOLIC STEATOTIC LIVER DISEASE 2024:101-122. [DOI: 10.1016/b978-0-323-99649-5.00007-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Nadolsky K, Cryer DR, Articolo A, Fisher T, Schneider J, Rinella M. Nonalcoholic steatohepatitis diagnosis and treatment from the perspective of patients and primary care physicians: a cross-sectional survey. Ann Med 2023; 55:2211349. [PMID: 37171239 PMCID: PMC10184582 DOI: 10.1080/07853890.2023.2211349] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 05/13/2023] Open
Abstract
BACKGROUND The global prevalence of nonalcoholic steatohepatitis (NASH) is rising. Despite this, NASH is underdiagnosed and does not yet have approved pharmacological treatments. We sought to understand the path to diagnosis, patient interactions with healthcare professionals, treatment regimens, and disease management for patients with NASH. METHODS Cross-sectional online surveys of patients with a self-reported diagnosis of NASH and healthcare professionals treating patients with NASH were conducted from 10th November 2020, to 1st January 2021. This manuscript focuses on responses from 152 patients with NASH and 101 primary care physicians (PCPs). RESULTS Patients (n = 152, mean age = 40, SD = 11) and healthcare professionals (n = 226) were located throughout the US. In the most common patient journey, 72% of patients had initial discussions about symptoms with a PCP but only 30% report receiving their NASH diagnosis from a PCP. Almost half of PCPs (47%) were not aware of any clinical practice guidelines for diagnosis and management of NASH. For ongoing management of NASH, PCPs most frequently prescribed lifestyle changes such as exercise (89%), lifestyle changes focused on diet (79%), and/or metformin (57%). Other healthcare professionals rarely referred patients to PCPs for treatment, but when they did, the primary reasons were patients struggling with lifestyle modifications (58%), needing to lose weight (46%), and needing treatment of comorbidities (42%). CONCLUSIONS PCPs may benefit from greater awareness of NASH and guidelines for its diagnosis and treatment. Given the absence of pharmacological treatments approved for NASH, PCPs can offer support in obesity management, comorbidity management, and risk stratification for liver disease progression.
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Affiliation(s)
- Karl Nadolsky
- MI State University College of Human Medicine, Holland Hospital Endocrinology, Obesity & Diabetes, Holland, MI, USA
| | | | | | | | | | - Mary Rinella
- Department of Medicine, University of Chicago Medicine, Chicago, IL, USA
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Kakouri NS, Thomopoulos CG, Siafi EP, Valatsou AE, Dimitriadis KS, Mani IP, Patsilinakos SP, Tousoulis DM, Tsioufis KP. Overview of the Association between Non-Alcoholic Fatty Liver Disease and Hypertension. CARDIOLOGY DISCOVERY 2023. [DOI: 10.1097/cd9.0000000000000113] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease, and its prevalence is rising. NAFLD is closely associated with metabolic syndrome, with both conditions sharing common clinical characteristics such as obesity, insulin resistance, type 2 diabetes mellitus, hypertension, and hypertriglyceridemia. Several observational studies have evaluated the relationship between NAFLD and hypertension, with the overall evidence suggesting a bidirectional relationship. It is hypothesized that activation of the sympathetic nervous and renin-angiotensin systems, observed in NAFLD with or without insulin resistance promotes the development of hypertension. In patients with hypertension, activation of these systems can lead to hepatic fibrosis and progressive inflammation through increased oxidative stress and activation of hepatic stellate cells and Kupffer cells. The present review examines the pathophysiologic and clinical evidence supporting the bidirectional association between NAFLD and hypertension.
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Affiliation(s)
- Niki S. Kakouri
- First Department of Cardiology, Medical School, National and Kapodistrian University of Athens, Hippokration Hospital, Athens 11527, Greece
| | | | - Eirini P. Siafi
- First Department of Cardiology, Medical School, National and Kapodistrian University of Athens, Hippokration Hospital, Athens 11527, Greece
| | - Angeliki E. Valatsou
- First Department of Cardiology, Medical School, National and Kapodistrian University of Athens, Hippokration Hospital, Athens 11527, Greece
| | - Kyriakos S. Dimitriadis
- First Department of Cardiology, Medical School, National and Kapodistrian University of Athens, Hippokration Hospital, Athens 11527, Greece
| | - Iliana P. Mani
- First Department of Cardiology, Medical School, National and Kapodistrian University of Athens, Hippokration Hospital, Athens 11527, Greece
| | | | - Dimitrios M. Tousoulis
- First Department of Cardiology, Medical School, National and Kapodistrian University of Athens, Hippokration Hospital, Athens 11527, Greece
| | - Konstantinos P. Tsioufis
- First Department of Cardiology, Medical School, National and Kapodistrian University of Athens, Hippokration Hospital, Athens 11527, Greece
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Hirose K, Nakanishi K, Di Tullio MR, Homma S, Sawada N, Yoshida Y, Hirokawa M, Koyama K, Kimura K, Nakao T, Daimon M, Morita H, Kurano M, Komuro I. Association between non-alcoholic fatty liver disease and subclinical left ventricular dysfunction in the general population. EUROPEAN HEART JOURNAL OPEN 2023; 3:oead108. [PMID: 37941727 PMCID: PMC10630098 DOI: 10.1093/ehjopen/oead108] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/29/2023] [Revised: 09/20/2023] [Accepted: 10/12/2023] [Indexed: 11/10/2023]
Abstract
Aims Emerging evidence suggests an association between non-alcoholic fatty liver disease (NAFLD) and heart failure (HF). We investigated the relationship between NAFLD and left ventricular (LV) functional remodelling in a general population sample without overt cardiac and liver disease. Methods and results We included 481 individuals without significant alcohol consumption who voluntarily underwent an extensive cardiovascular health check. The fatty liver index (FLI) was calculated for each participant, and NAFLD was defined as FLI ≥ 60. All participants underwent 2D transthoracic echocardiography; LV global longitudinal strain (LVGLS) was assessed with speckle-tracking analysis. Univariable and multivariable linear regression models were constructed to investigate the possible association between NAFLD and LVGLS. Seventy-one (14.8%) participants were diagnosed with NAFLD. Individuals with NAFLD exhibited larger LV size and LV mass index than those without NAFLD, although left atrial size and E/e' ratio did not differ between groups. Left ventricular global longitudinal strain was significantly reduced in participants with vs. without NAFLD (17.1% ± 2.4% vs. 19.5% ± 3.1%, respectively; P < 0.001). The NAFLD group had a significantly higher frequency of abnormal LVGLS (<16%) than the non-NAFLD group (31.0% vs. 10.7%, respectively; P < 0.001). Multivariable linear regression analysis demonstrated that higher FLI score was significantly associated with impaired LVGLS independent of age, sex, conventional cardiovascular risk factors, and echocardiographic parameters (standardized β -0.11, P = 0.031). Conclusion In the general population without overt cardiac and liver disease, the presence of NAFLD was significantly associated with subclinical LV dysfunction, which may partly explain the elevated risk of HF in individuals with NAFLD.
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Affiliation(s)
- Kazutoshi Hirose
- Department of Cardiovascular Medicine, The University of Tokyo Hospital, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
| | - Koki Nakanishi
- Department of Cardiovascular Medicine, The University of Tokyo Hospital, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
- Department of Clinical Laboratory, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
| | | | - Shunichi Homma
- Department of Medicine, Columbia University, NewYork, NY, USA
| | - Naoko Sawada
- Department of Cardiovascular Medicine, The University of Tokyo Hospital, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
| | - Yuriko Yoshida
- Department of Medicine, Columbia University, NewYork, NY, USA
| | - Megumi Hirokawa
- Department of Cardiovascular Medicine, The University of Tokyo Hospital, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
- Department of Clinical Laboratory, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
| | - Katsuhiro Koyama
- Department of Cardiovascular Medicine, The University of Tokyo Hospital, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
| | - Koichi Kimura
- Department of Cardiovascular Medicine, The University of Tokyo Hospital, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
| | - Tomoko Nakao
- Department of Cardiovascular Medicine, The University of Tokyo Hospital, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
| | - Masao Daimon
- Department of Cardiovascular Medicine, The University of Tokyo Hospital, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
- International University of Health and Welfare, Tokyo, Japan
| | - Hiroyuki Morita
- Department of Cardiovascular Medicine, The University of Tokyo Hospital, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
| | - Makoto Kurano
- Department of Clinical Laboratory, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
| | - Issei Komuro
- Department of Cardiovascular Medicine, The University of Tokyo Hospital, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
- International University of Health and Welfare, Tokyo, Japan
- Department of Frontier Cardiovascular Science, The University of Tokyo Graduate School of Medicine, Tokyo, Japan
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Akter T, Bulbul MRH, Sama-ae I, Azadi MA, Nira KN, Al-Araby SQ, Deen JI, Rafi MKJ, Saha S, Ezaj MMA, Rahman MA. Sour Tamarind Is More Antihypertensive than the Sweeter One, as Evidenced by In Vivo Biochemical Indexes, Ligand-Protein Interactions, Multitarget Interactions, and Molecular Dynamic Simulation. Nutrients 2023; 15:3402. [PMID: 37571339 PMCID: PMC10420995 DOI: 10.3390/nu15153402] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2023] [Revised: 06/23/2023] [Accepted: 06/26/2023] [Indexed: 08/13/2023] Open
Abstract
This research investigated the antihypertensive effects of tamarind products and compared their potentials based on an animal model's data verified by molecular docking, multitarget interactions, and dynamic simulation assays. GC-MS-characterized tamarind products were administered to cholesterol-induced hypertensive albino rat models. The two-week-intervened animals were dissected to collect their serum and organs and respectively subjected to analyses of their hypertension-linked markers and tissue architectures. The lead biometabolites of tamarinds interacted with eight target receptors in the molecular docking and dynamic simulation studies and with multitarget in the network pharmacological analyses. The results show that the serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), C-reactive protein (CRP), troponin I, and lipid profiles were maximally reinstated by the phenolic-enriched ripened sour tamarind extract compared to the sweet one, but the seed extracts had a smaller influence. Among the tamarind's biometabolites, ϒ-sitosterol was found to be the best ligand to interact with the guanylate cyclase receptor, displaying the best drug-likeliness with the highest binding energy, -9.3 Kcal. A multitargeted interaction-based degree algorithm and a phylogenetic tree of pathways showed that the NR3C1, REN, PPARG, and CYP11B1 hub genes were consistently modulated by ϒ-sitosterol to reduce hypertension and related risk factors. The dynamic simulation study showed that the P-RMSD values of ϒ-sitosterol-guanylate cyclase were stable between 75.00 and 100.00 ns at the binding pocket. The findings demonstrate that ripened sour tamarind extract may be a prospective antihypertensive nutraceutical or supplement target affirmed through advanced preclinical and clinical studies.
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Affiliation(s)
- Taslima Akter
- Department of Biochemistry and Molecular Biology, University of Chittagong, Chittagong 4331, Bangladesh; (T.A.); (K.N.N.); (S.Q.A.-A.); (J.I.D.); (M.K.J.R.); (S.S.)
| | | | - Imran Sama-ae
- School of Allied Health Sciences, Walailak University, Nakhon Si Thammarat 80160, Thailand;
| | - M. A. Azadi
- Department of Zoology, University of Chittagong, Chittagong 4331, Bangladesh;
| | - Kamrun Nahar Nira
- Department of Biochemistry and Molecular Biology, University of Chittagong, Chittagong 4331, Bangladesh; (T.A.); (K.N.N.); (S.Q.A.-A.); (J.I.D.); (M.K.J.R.); (S.S.)
| | - Salahuddin Quader Al-Araby
- Department of Biochemistry and Molecular Biology, University of Chittagong, Chittagong 4331, Bangladesh; (T.A.); (K.N.N.); (S.Q.A.-A.); (J.I.D.); (M.K.J.R.); (S.S.)
| | - Jobaier Ibne Deen
- Department of Biochemistry and Molecular Biology, University of Chittagong, Chittagong 4331, Bangladesh; (T.A.); (K.N.N.); (S.Q.A.-A.); (J.I.D.); (M.K.J.R.); (S.S.)
| | - Md. Khalid Juhani Rafi
- Department of Biochemistry and Molecular Biology, University of Chittagong, Chittagong 4331, Bangladesh; (T.A.); (K.N.N.); (S.Q.A.-A.); (J.I.D.); (M.K.J.R.); (S.S.)
| | - Srabonti Saha
- Department of Biochemistry and Molecular Biology, University of Chittagong, Chittagong 4331, Bangladesh; (T.A.); (K.N.N.); (S.Q.A.-A.); (J.I.D.); (M.K.J.R.); (S.S.)
| | - Md. Muzahid Ahmed Ezaj
- Department of Genetic Engineering and Biotechnology, University of Chittagong, Chittagong 4331, Bangladesh;
| | - Md. Atiar Rahman
- Department of Biochemistry and Molecular Biology, University of Chittagong, Chittagong 4331, Bangladesh; (T.A.); (K.N.N.); (S.Q.A.-A.); (J.I.D.); (M.K.J.R.); (S.S.)
- School of Allied Health Sciences, Walailak University, Nakhon Si Thammarat 80160, Thailand;
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Meng C, Song Z, Zhang L, Geng Y, Sun J, Miao G, Liu P. Effects of losartan in patients with NAFLD: A meta-analysis of randomized controlled trial. Open Life Sci 2023; 18:20220583. [PMID: 36970603 PMCID: PMC10031500 DOI: 10.1515/biol-2022-0583] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2022] [Revised: 02/18/2023] [Accepted: 02/19/2023] [Indexed: 03/24/2023] Open
Abstract
Losartan has become a hot spot in the treatment of non-alcoholic fatty liver disease (NAFLD) among angiotensin receptor blocker drugs. We sought to conduct a systematic examination and meta-analysis to examine the effects of losartan on patients with NAFLD. We searched for potentially randomized controlled trials in PubMed, Embase, China National Knowledge Infrastructure, Wanfang, and the Cochrane database up to October 09, 2022. We used the Cochrane risk of bias tool to evaluate the study quality. Analysis of subgroups, sensitivity analysis, and publishing bias were explored. The quality of the included studies was moderate to high. Six trials involving 408 patients were included. The meta-analysis demonstrated that aspartate transaminase was significantly affected by losartan therapy (mean difference [MD] = −5.34, 95% confidence interval [CI] [−6.54, −4.13], Z = 8.70, P < 0.01). The meta-analysis subgroup showed that losartan 50 mg once daily could lower the level of alanine aminotransferase (MD = −18.92, 95% CI [−21.18, −16.66], Z = 16.41, P < 0.01). There was no statistically significant difference in serum total cholesterol, triglyceride, low-density lipoprotein, and high-density lipoprotein.
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Affiliation(s)
- Chang Meng
- Department of Emergency, Emergency General Hospital, XiBaHe South Road 29, Chaoyang District, Beijing, 100028, PR China
| | - Zejun Song
- Department of Gastroenterology, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, No. 168 Litang Road, Changping District, Beijing, 102218, PR China
| | - Lingnan Zhang
- Department of Cardiology, Affiliated Hospital of Hebei University, Hebei University, 212 Yuhua East Road, Lianchi District, Baoding City, 071000, PR China
| | - Yu Geng
- Department of Cardiology, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, NO. 168 Litang Road, Changping District, Beijing102218, P. R. China
| | - Jing Sun
- Department of Critical Care Medicine, Emergency General Hospital, XiBaHe South Road 29, Chaoyang District, Beijing, 100028, PR China
| | - Guobin Miao
- Department of Emergency, Emergency General Hospital, XiBaHe South Road 29, Chaoyang District, Beijing, 100028, PR China
| | - Peng Liu
- Department of Cardiology, Ordos Central Hospital, Ordos School of Clinical Medicine, Inner Mongolia Medical University, 23 Yijinhuoluo West Street, Dongsheng District, Inner Mongolia, 017000, PR China
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11
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Sakboonyarat B, Poovieng J, Lertsakulbunlue S, Jongcherdchootrakul K, Srisawat P, Mungthin M, Rangsin R. Association between raised blood pressure and elevated serum liver enzymes among active-duty Royal Thai Army personnel in Thailand. BMC Cardiovasc Disord 2023; 23:143. [PMID: 36944947 PMCID: PMC10029162 DOI: 10.1186/s12872-023-03181-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2022] [Accepted: 03/11/2023] [Indexed: 03/23/2023] Open
Abstract
BACKGROUND The relationship between hypertension (HT) and serum liver enzymes was reported in a few studies, but the findings were inconsistent. Therefore, the present study aimed to identify the association between elevated serum liver enzymes and raised BP through the use of a large sample of Royal Thai Army (RTA) personnel. METHODS The dataset obtained from the annual health examination database of RTA personnel in Thailand was utilized. A total of 244,281 RTA personnel aged 35-60 were included in the current study. Elevated serum liver enzymes were defined as aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≥ 40 U/L in males and ≥ 35 U/L in females. HT was defined as systolic BP ≥ 140 or diastolic BP ≥ 90 mmHg. A multivariable linear regression model was used to estimate the coefficient and 95% confidence intervals (CI), whereas a multivariable logistic regression model was applied to estimate adjusted odds ratios (AORs) and 95% CI for the association between raised BP and serum liver enzymes. RESULTS Compared to individuals with SBP < 120 and DBP < 80 mmHg, the β coefficients of log-transformed AST and ALT were 0.13 (95% CI: 0.12-0.13) and 0.11 (95% CI: 0.11-0.12) in males with HT. Meanwhile, the β coefficients of log-transformed AST and ALT were 0.03 (95% CI: 0.02-0.04) and 0.07 (95% CI: 0.05-0.08) in females with HT. In males, HT was associated with elevated AST (AOR: 1.92; 95% CI: 1.85-2.01) and elevated ALT (AOR: 1.43; 95% CI: 1.38-1.48). On the other hand, in females, HT was associated with elevated AST (AOR: 1.42; 95% CI: 1.21-1.66) and elevated ALT (AOR: 1.38; 95% CI: 1.21-1.57). CONCLUSION Raised BP was positively correlated with elevated AST and ALT in active-duty RTA personnel. Moreover, HT was independently attributed to higher odds of elevated AST and ALT in comparison to optimal BP in both males and females. Furthermore, the relationship between serum liver enzymes and BP was modified by sex.
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Affiliation(s)
- Boonsub Sakboonyarat
- Department of Military and Community Medicine, Phramongkutklao College of Medicine, Bangkok, 10400, Thailand
| | - Jaturon Poovieng
- Department of Medicine, Phramongkutklao College of Medicine, Bangkok, 10400, Thailand
| | | | - Kanlaya Jongcherdchootrakul
- Department of Military and Community Medicine, Phramongkutklao College of Medicine, Bangkok, 10400, Thailand
| | - Phutsapong Srisawat
- Department of Military and Community Medicine, Phramongkutklao College of Medicine, Bangkok, 10400, Thailand
| | - Mathirut Mungthin
- Department of Parasitology, Phramongkutklao College of Medicine, Bangkok, 10400, Thailand
| | - Ram Rangsin
- Department of Military and Community Medicine, Phramongkutklao College of Medicine, Bangkok, 10400, Thailand.
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12
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Badr AM, Sherif IO, Mahran YF, Attia HA. Role of Renin-Angiotensin System in the Pathogenesis and Progression of Non-alcoholic Fatty Liver. THE RENIN ANGIOTENSIN SYSTEM IN CANCER, LUNG, LIVER AND INFECTIOUS DISEASES 2023:179-197. [DOI: 10.1007/978-3-031-23621-1_10] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/08/2023]
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13
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Chew NW, Muthiah MD, Sanyal AJ. Nonalcoholic fatty liver disease and nonalcoholic steatohepatitis: pathophysiology and implications for cardiovascular disease. CARDIOVASCULAR ENDOCRINOLOGY AND METABOLISM 2023:137-173. [DOI: 10.1016/b978-0-323-99991-5.00003-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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14
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Oura K, Morishita A, Tani J, Masaki T. Antitumor Effects and Mechanisms of Metabolic Syndrome Medications on Hepatocellular Carcinoma. J Hepatocell Carcinoma 2022; 9:1279-1298. [PMID: 36545268 PMCID: PMC9760577 DOI: 10.2147/jhc.s392051] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2022] [Accepted: 12/04/2022] [Indexed: 12/15/2022] Open
Abstract
Liver cancer has a high incidence and mortality rate worldwide, with hepatocellular carcinoma (HCC) being the most common histological type. With the decrease in the number of newly infected patients and the spread of antiviral therapy, hepatitis virus-negative chronic liver diseases including steatohepatitis are increasingly accounting for a large proportion of HCC, and an important clinical characteristic is the high prevalence of metabolic syndrome including hypertension, type 2 diabetes (T2D), dyslipidemia, and obesity. Since patients with steatohepatitis are less likely to undergo surveillance for early detection of HCC, they may be diagnosed at an advanced stage and have worse prognosis. Therefore, treatment strategies for patients with HCC caused by steatohepatitis, especially in advanced stages, become increasingly important. Further, hypertension, T2D, and dyslipidemia may occur as side effects during systemic treatment, and there will be increasing opportunities to prescribe metabolic syndrome medications, not only for originally comorbid diseases, but also for adverse events during HCC treatment. Interestingly, epidemiological studies have shown that patients taking some metabolic syndrome medications are less likely to develop various types of cancers, including HCC. Basic studies have also shown that these drugs have direct antitumor effects on HCC. In particular, angiotensin II receptor blockers (a drug group for treating hypertension), biguanides (a drug group for treating T2D), and statins (a drug group for treating dyslipidemia) have shown to elucidate antitumor effects against HCC. In this review, we focus on the antitumor effects of metabolic syndrome medications on HCC and their mechanisms based on recent literature. New therapeutic agents are also increasingly being reported. Analysis of the antitumor effects of metabolic syndrome medications on HCC and their mechanisms will be doubly beneficial for HCC patients with metabolic syndrome, and the use of these medications may be a potential strategy against HCC.
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Affiliation(s)
- Kyoko Oura
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa, Japan,Correspondence: Kyoko Oura, Department of Gastroenterology and Neurology, Kagawa University, 1750-1 Ikenobe, Miki, Kida, Kagawa, Japan, Tel +81-87-891-2156, Fax +81-87-891-2158, Email
| | - Asahiro Morishita
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa, Japan
| | - Joji Tani
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa, Japan
| | - Tsutomu Masaki
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa, Japan
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15
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Josloff K, Beiriger J, Khan A, Gawel RJ, Kirby RS, Kendrick AD, Rao AK, Wang RX, Schafer MM, Pearce ME, Chauhan K, Shah YB, Marhefka GD, Halegoua-DeMarzio D. Comprehensive Review of Cardiovascular Disease Risk in Nonalcoholic Fatty Liver Disease. J Cardiovasc Dev Dis 2022; 9:419. [PMID: 36547416 PMCID: PMC9786069 DOI: 10.3390/jcdd9120419] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2022] [Revised: 11/16/2022] [Accepted: 11/23/2022] [Indexed: 11/29/2022] Open
Abstract
Nonalcoholic Fatty Liver Disease (NAFLD) is a growing global phenomenon, and its damaging effects in terms of cardiovascular disease (CVD) risk are becoming more apparent. NAFLD is estimated to affect around one quarter of the world population and is often comorbid with other metabolic disorders including diabetes mellitus, hypertension, coronary artery disease, and metabolic syndrome. In this review, we examine the current evidence describing the many ways that NAFLD itself increases CVD risk. We also discuss the emerging and complex biochemical relationship between NAFLD and its common comorbid conditions, and how they coalesce to increase CVD risk. With NAFLD's rising prevalence and deleterious effects on the cardiovascular system, a complete understanding of the disease must be undertaken, as well as effective strategies to prevent and treat its common comorbid conditions.
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Affiliation(s)
- Kevan Josloff
- Sidney Kimmel Medical College, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
| | - Jacob Beiriger
- Sidney Kimmel Medical College, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
| | - Adnan Khan
- Department of Internal Medicine, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
| | - Richard J. Gawel
- Sidney Kimmel Medical College, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
| | - Richard S. Kirby
- Sidney Kimmel Medical College, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
| | - Aaron D. Kendrick
- Sidney Kimmel Medical College, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
| | - Abhinav K. Rao
- Sidney Kimmel Medical College, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
| | - Roy X. Wang
- Sidney Kimmel Medical College, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
| | - Michelle M. Schafer
- Sidney Kimmel Medical College, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
| | - Margaret E. Pearce
- Sidney Kimmel Medical College, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
| | - Kashyap Chauhan
- Department of Internal Medicine, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
| | - Yash B. Shah
- Sidney Kimmel Medical College, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
| | - Gregary D. Marhefka
- Department of Internal Medicine, Division of Cardiology, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
| | - Dina Halegoua-DeMarzio
- Department of Internal Medicine, Division of Gastroenterology & Hepatology, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
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16
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Zhang D, Zhang Y, Sun B. The Molecular Mechanisms of Liver Fibrosis and Its Potential Therapy in Application. Int J Mol Sci 2022; 23:ijms232012572. [PMID: 36293428 PMCID: PMC9604031 DOI: 10.3390/ijms232012572] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2022] [Revised: 09/27/2022] [Accepted: 10/03/2022] [Indexed: 11/16/2022] Open
Abstract
Liver fibrosis results from repeated and persistent liver damage. It can start with hepatocyte injury and advance to inflammation, which recruits and activates additional liver immune cells, leading to the activation of the hepatic stellate cells (HSCs). It is the primary source of myofibroblasts (MFs), which result in collagen synthesis and extracellular matrix protein accumulation. Although there is no FDA and EMA-approved anti-fibrotic drug, antiviral therapy has made remarkable progress in preventing or even reversing the progression of liver fibrosis, but such a strategy remains elusive for patients with viral, alcoholic or nonalcoholic steatosis, genetic or autoimmune liver disease. Due to the complexity of the etiology, combination treatments affecting two or more targets are likely to be required. Here, we review the pathogenic mechanisms of liver fibrosis and signaling pathways involved, as well as various molecular targets for liver fibrosis treatment. The development of efficient drug delivery systems that target different cells in liver fibrosis therapy is also summarized. We highlight promising anti-fibrotic events in clinical trial and preclinical testing, which include small molecules and natural compounds. Last, we discuss the challenges and opportunities in developing anti-fibrotic therapies.
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Affiliation(s)
- Danyan Zhang
- School of Life Science and Technology, Shanghai Tech University, Shanghai 201210, China
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China
| | - Yaguang Zhang
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China
- Correspondence: (Y.Z.); (B.S.); Tel.: +86-21-5492-1375 (Y.Z.); +86-21-5492-1375 (B.S.)
| | - Bing Sun
- School of Life Science and Technology, Shanghai Tech University, Shanghai 201210, China
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China
- Correspondence: (Y.Z.); (B.S.); Tel.: +86-21-5492-1375 (Y.Z.); +86-21-5492-1375 (B.S.)
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17
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Association between arterial hypertension and liver outcomes using polygenic risk scores: a population-based study. Sci Rep 2022; 12:15581. [PMID: 36114231 PMCID: PMC9481629 DOI: 10.1038/s41598-022-20084-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2022] [Accepted: 09/08/2022] [Indexed: 12/03/2022] Open
Abstract
Arterial hypertension (HTA) is associated with liver disease, but causality remains unclear. We investigated whether genetic predisposition to HTA is associated with liver disease in the population, and if antihypertensive medication modifies this association. Participants of the Finnish health-examination surveys, FINRISK 1992–2012 and Health 2000 (n = 33,770), were linked with national electronic healthcare registers for liver-related outcomes (K70-K77, C22.0) and with the drug reimbursement registry for new initiation of antihypertensive medication during follow-up. Genetic predisposition to HTA was defined by polygenic risk scores (PRSs). During a median 12.9-year follow-up (409,268.9 person-years), 441 liver-related outcomes occurred. In the fully-adjusted Cox-regression models, both measured systolic blood pressure and clinically defined HTA were associated with liver-related outcomes. PRSs for systolic and diastolic blood pressure were significantly associated with liver-related outcomes (HR/SD 1.19, 95% CI 1.01–1.24, and 1.12, 95% CI 1.01–1.25, respectively). In the highest quintile of the systolic blood pressure PRS, new initiation of antihypertensive medication was associated with reduced rates of liver-related outcomes (HR 0.55, 95% CI 0.31–0.97). HTA and a genetic predisposition for HTA are associated with liver-related outcomes in the population. New initiation of antihypertensive medication attenuates this association in persons with high genetic risk for HTA.
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18
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Vos MB, Van Natta ML, Blondet NM, Dasarathy S, Fishbein M, Hertel P, Jain AK, Karpen SJ, Lavine JE, Mohammad S, Miriel LA, Molleston JP, Mouzaki M, Sanyal A, Sharkey EP, Schwimmer JB, Tonascia J, Wilson LA, Xanthakos SA. Randomized placebo-controlled trial of losartan for pediatric NAFLD. Hepatology 2022; 76:429-444. [PMID: 35133671 PMCID: PMC9288975 DOI: 10.1002/hep.32403] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2021] [Revised: 11/18/2021] [Accepted: 12/04/2021] [Indexed: 01/28/2023]
Abstract
BACKGROUND AND AIMS To date, no pharmacotherapy exists for pediatric NAFLD. Losartan, an angiotensin II receptor blocker, has been proposed as a treatment due to its antifibrotic effects. APPROACH AND RESULTS The Nonalcoholic Steatohepatitis Clinical Research Network conducted a multicenter, double-masked, placebo-controlled, randomized clinical trial in children with histologically confirmed NAFLD at 10 sites (September 2018 to April 2020). Inclusion criteria were age 8-17 years, histologic NAFLD activity score ≥ 3, and serum alanine aminotransferase (ALT) ≥ 50 U/l. Children received 100 mg of losartan or placebo orally once daily for 24 weeks. The primary outcome was change in ALT levels from baseline to 24 weeks, and the preset sample size was n = 110. Treatment effects were assessed using linear regression of change in treatment group adjusted for baseline value. Eighty-three participants (81% male, 80% Hispanic) were randomized to losartan (n = 43) or placebo (n = 40). During an enrollment pause, necessitated by the 2019 coronavirus pandemic, an unplanned interim analysis showed low probability (7%) of significant group difference. The Data and Safety Monitoring Board recommended early study termination. Baseline characteristics were similar between groups. The 24-week change in ALT did not differ significantly between losartan versus placebo groups (adjusted mean difference: 1.1 U/l; 95% CI = -30.6, 32.7; p = 0.95), although alkaline phosphatase decreased significantly in the losartan group (adjusted mean difference: -23.4 U/l; 95% CI = -41.5, -5.3; p = 0.01). Systolic blood pressure decreased in the losartan group but increased in placebo (adjusted mean difference: -7.5 mm Hg; 95% CI = -12.2, -2.8; p = 0.002). Compliance by pill counts and numbers and types of adverse events did not differ by group. CONCLUSIONS Losartan did not significantly reduce ALT in children with NAFLD when compared with placebo.
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Affiliation(s)
- Miriam B Vos
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Emory University School of Medicine, Children's Healthcare of Atlanta, Atlanta, Georgia, USA
| | - Mark L Van Natta
- Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA
| | - Niviann M Blondet
- Division of Pediatric Gastroenterology and Hepatology, Seattle Children's Hospital, University of Washington, Seattle, Washington, USA
| | - Srinivasan Dasarathy
- Division of Gastroenterology, Hepatology and Nutrition, Cleveland Clinic, Cleveland, Ohio, USA
| | - Mark Fishbein
- Department of Pediatrics, Feinberg Medical School of Northwestern University, Chicago, Illinois, USA
| | - Paula Hertel
- Division of Gastroenterology, Hepatology and Nutrition, Texas Children's Hospital, Baylor College of Medicine, Houston, Texas, USA
| | - Ajay K Jain
- Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, St. Louis University, St. Louis, Missouri, USA
| | - Saul J Karpen
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Emory University School of Medicine, Children's Healthcare of Atlanta, Atlanta, Georgia, USA
| | - Joel E Lavine
- Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Columbia University Vagelos College of Physicians and Surgeons, New York, New York, USA
| | - Saeed Mohammad
- Department of Pediatrics, Feinberg Medical School of Northwestern University, Chicago, Illinois, USA
| | - Laura A Miriel
- Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA
| | - Jean P Molleston
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Indiana University School of Medicine/Riley Hospital for Children, Indianapolis, Indiana, USA
| | - Marialena Mouzaki
- Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
| | - Arun Sanyal
- Department of Internal Medicine, Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA
| | - Emily P Sharkey
- Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA
| | - Jeffrey B Schwimmer
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of California San Diego School of Medicine, La Jolla, California, USA
| | - James Tonascia
- Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA
| | - Laura A Wilson
- Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA
| | - Stavra A Xanthakos
- Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
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Sharma N, Sircar A, Anders HJ, Gaikwad AB. Crosstalk between kidney and liver in non-alcoholic fatty liver disease: mechanisms and therapeutic approaches. Arch Physiol Biochem 2022; 128:1024-1038. [PMID: 32223569 DOI: 10.1080/13813455.2020.1745851] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Liver and kidney are vital organs that maintain homeostasis and injury to either of them triggers pathogenic pathways affecting the other. For example, non-alcoholic fatty liver disease (NAFLD) promotes the progression of chronic kidney disease (CKD), vice versa acute kidney injury (AKI) endorses the induction and progression of liver dysfunction. Progress in clinical and basic research suggest a role of excessive fructose intake, insulin resistance, inflammatory cytokines production, activation of the renin-angiotensin system, redox imbalance, and their impact on epigenetic regulation of gene expression in this context. Recent developments in experimental and clinical research have identified several biochemical and molecular pathways for AKI-liver interaction, including altered liver enzymes profile, metabolic acidosis, oxidative stress, activation of inflammatory and regulated cell death pathways. This review focuses on the current preclinical and clinical findings on kidney-liver crosstalk in NAFLD-CKD and AKI-liver dysfunction settings and highlights potential molecular mechanisms and therapeutic targets.
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Affiliation(s)
- Nisha Sharma
- Laboratory of Molecular Pharmacology, Department of Pharmacy, Birla Institute of Technology and Science, Pilani Campus, Pilani, Rajasthan, India
| | - Anannya Sircar
- Laboratory of Molecular Pharmacology, Department of Pharmacy, Birla Institute of Technology and Science, Pilani Campus, Pilani, Rajasthan, India
| | - Hans-Joachim Anders
- Division of Nephrology, Department of Internal Medicine IV, University Hospital of the Ludwig Maximilians University Munich, Munich, Germany
| | - Anil Bhanudas Gaikwad
- Laboratory of Molecular Pharmacology, Department of Pharmacy, Birla Institute of Technology and Science, Pilani Campus, Pilani, Rajasthan, India
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20
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Combination Therapies for Nonalcoholic Fatty Liver Disease. J Pers Med 2022; 12:jpm12071166. [PMID: 35887662 PMCID: PMC9322793 DOI: 10.3390/jpm12071166] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2022] [Revised: 07/01/2022] [Accepted: 07/13/2022] [Indexed: 11/17/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is considered a highly prevalent disease associated with various co-morbidities that lead to socioeconomic burden. Despite large-scale investigation, no pharmacological treatment has been approved specifically for NAFLD to date. Lifestyle modifications and diet are regarded as highly beneficial for the management of NAFLD, albeit with poor compliance, thus rendering pharmacological treatment highly important. Based on the current failure to discover a “magic bullet” to treat all patients with NAFLD and considering the multifaceted pathophysiology of the disease, combination therapies may be considered to be a rational alternative approach. In this regard, several drug categories have been considered, including, but not limited to, lipid-lowering, anti-hypertensive, glucose-lowering, anti-obesity, anti-oxidant, anti-inflammatory and anti-fibrotic medications. The aim of this review is, in addition to summarizing some of the multiple factors contributing to the pathophysiology of NAFLD, to focus on the efficacy of pharmacological combinations on the management of NAFLD. This may provide evidence for a more personalized treatment of patients with NAFLD in the future.
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21
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Increased Risk of NAFLD in Adults with Glomerular Hyperfiltration: An 8-Year Cohort Study Based on 147,162 Koreans. J Pers Med 2022; 12:jpm12071142. [PMID: 35887639 PMCID: PMC9320347 DOI: 10.3390/jpm12071142] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2022] [Revised: 07/10/2022] [Accepted: 07/13/2022] [Indexed: 11/21/2022] Open
Abstract
This study evaluated whether glomerular hyperfiltration (GHF) could predict nonalcoholic fatty liver disease (NAFLD) and fibrosis. A longitudinal cohort study including 147,479 participants aged 20–65 years without NAFLD and kidney disease at baseline was performed. GHF cutoff values were defined as age- and sex-specific estimated glomerular filtration rate (eGFRs) above the 95th percentile, and eGFR values between the 50th and 65th percentiles were used as reference groups. NAFLD was diagnosed via abdominal ultrasonography, and the fibrosis status was evaluated using the NAFLD fibrosis score and Fibrosis-4. During 598,745 person years of follow-up (median, 4.6 years), subjects with GHF at baseline had the highest hazard ratio (HR) for the development of NAFLD (HR 1.21; 95% CI 1.14–1.29) and fibrosis progression (HR 1.42; 95% CI 1.11–1.82) after adjusting for confounding factors. A higher baseline eGFR percentile maintained a higher risk of NAFLD and fibrosis probability. The persistent GHF group during follow-up had the highest HR for NAFLD compared to the persistent non-GHF group (HR 1.31; 95% CI 1.14–1.51). These results were consistent in all subgroups and statistically more prominent in participants without diabetes. GHF was positively associated with increased risk of NAFLD and probability of liver fibrosis in healthy adults.
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22
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Iwaki M, Kessoku T, Tanaka K, Ozaki A, Kasai Y, Yamamoto A, Takahashi K, Kobayashi T, Nogami A, Honda Y, Ogawa Y, Imajo K, Yoneda M, Kobayashi N, Saito S, Nakajima A. Efficacy and safety of guanabenz acetate treatment for non-alcoholic fatty liver disease: a study protocol for a randomised investigator-initiated phase IIa study. BMJ Open 2022; 12:e060335. [PMID: 35820743 PMCID: PMC9277396 DOI: 10.1136/bmjopen-2021-060335] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/07/2022] Open
Abstract
INTRODUCTION Non-alcoholic fatty liver disease (NAFLD) is a metabolic syndrome phenotype in the liver and thus obviously associated with metabolic abnormalities, including insulin resistance-related to hyperglycaemic and hyperlipidaemia. The prevalence of NAFLD is increasing worldwide. However, currently, there is no consensus regarding the efficacy and safety of drugs used to treat patients with NAFLD/non-alcoholic steatohepatitis (NASH). Guanabenz acetate, a selective α2-adrenoceptor stimulator used in the treatment of hypertension, binds at a high-affinity constant to a nuclear transcriptional coregulator, helicase with zinc finger 2 (Helz2) and inhibits Helz2-medaited steatosis in the liver; chronic oral administration of guanabenz acetate produces a dose-dependent inhibition of lipid accumulation by inhibiting lipogenesis and activating fatty acid Β-oxidation in the liver of obese mice, resulting in improvement of insulin resistance and hyperlipidaemia. Taken all together, guanabenz acetate has a potentially effective in improving the development of NAFLD/NASH and metabolic abnormalities. In this randomised, open label, parallel-group, phase IIa study, we made attempts to conduct a proof-of-concept assessment by evaluating the efficacy and safety of guanabenz acetate treatment in patients with NAFLD/NASH. METHODS AND ANALYSIS A total of 28 adult patients with NAFLD or NASH and hypertension complications meeting the inclusion/exclusion criteria will be enrolled. Patients will be randomised to receive either 4 or 8 mg guanabenz acetate (n=14 per group). Blood tests and MRI will be performed 16 weeks after commencement of treatment. The primary endpoint will be the percentage reduction in hepatic fat content (%) measured using MRI-proton density fat fraction from baseline by at least 3.46% at week 16 after treatment initiation. ETHICS AND DISSEMINATION Ethics approval was obtained from the Ethics Committee of Yokohama City University Hospital before participant enrolment (YCU021001). The results of this study will be submitted for publication in international peer-reviewed journals, and the key findings will be presented at international scientific conferences. Participants wishing to know the results of this study will be contacted directly on data publication. TRIAL REGISTRATION NUMBER This trial is registered with ClinicalTrials.gov (number: NCT05084404). PROTOCOL VERSION V.1.1, 19 August 2021.
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Affiliation(s)
- Michihiro Iwaki
- Department of Gastroenterology and Hepatology, Yokohama City University School of Medicine Graduate School of Medicine, Yokohama, Japan
| | - Takaomi Kessoku
- Department of Gastroenterology and Hepatology, Yokohama City University School of Medicine Graduate School of Medicine, Yokohama, Japan
- Department of Palliative Medicine, Yokohama City University Hospital, Yokohama, Japan
| | - Kosuke Tanaka
- Department of Gastroenterology and Hepatology, Yokohama City University School of Medicine Graduate School of Medicine, Yokohama, Japan
- Department of Palliative Medicine, Yokohama City University Hospital, Yokohama, Japan
| | - Anna Ozaki
- Department of Gastroenterology and Hepatology, Yokohama City University School of Medicine Graduate School of Medicine, Yokohama, Japan
| | - Yuki Kasai
- Department of Gastroenterology and Hepatology, Yokohama City University School of Medicine Graduate School of Medicine, Yokohama, Japan
| | - Atsushi Yamamoto
- Department of Gastroenterology and Hepatology, Yokohama City University School of Medicine Graduate School of Medicine, Yokohama, Japan
| | - Kota Takahashi
- Department of Gastroenterology and Hepatology, Yokohama City University School of Medicine Graduate School of Medicine, Yokohama, Japan
| | - Takashi Kobayashi
- Department of Gastroenterology and Hepatology, Yokohama City University School of Medicine Graduate School of Medicine, Yokohama, Japan
| | - Asako Nogami
- Department of Gastroenterology and Hepatology, Yokohama City University School of Medicine Graduate School of Medicine, Yokohama, Japan
| | - Yasushi Honda
- Department of Gastroenterology and Hepatology, Yokohama City University School of Medicine Graduate School of Medicine, Yokohama, Japan
| | - Yuji Ogawa
- Department of Gastroenterology, National Hospital Organisation Yokohama Medical Center, Yokohama, Japan
| | - Kento Imajo
- Department of Gastroenterology, Shin Yurigaoka General Hospital, Kawasaki, Japan
| | - Masato Yoneda
- Department of Gastroenterology and Hepatology, Yokohama City University School of Medicine Graduate School of Medicine, Yokohama, Japan
| | | | - Satoru Saito
- Department of Gastroenterology and Hepatology, Yokohama City University School of Medicine Graduate School of Medicine, Yokohama, Japan
| | - Atsushi Nakajima
- Department of Gastroenterology and Hepatology, Yokohama City University School of Medicine Graduate School of Medicine, Yokohama, Japan
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Caveolin-1 Alleviates Acetaminophen—Induced Hepatotoxicity in Alcoholic Fatty Liver Disease by Regulating the Ang II/EGFR/ERK Axis. Int J Mol Sci 2022; 23:ijms23147587. [PMID: 35886933 PMCID: PMC9317714 DOI: 10.3390/ijms23147587] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2022] [Revised: 07/02/2022] [Accepted: 07/05/2022] [Indexed: 01/18/2023] Open
Abstract
Acetaminophen (APAP) is a widely used antipyretic analgesic which can lead to acute liver failure after overdoses. Chronic alcoholic fatty liver disease (AFLD) appears to enhance the risk and severity of APAP-induced liver injury, and the level of angiotensin II (Ang II) increased sharply at the same time. However, the underlying mechanisms remain unclear. Caveolin-1 (CAV1) has been proven to have a protective effect on AFLD. This study aimed to examine whether CAV1 can protect the APAP-induced hepatotoxicity of AFLD by affecting Ang II or its related targets. In vivo, the AFLD model was established according to the chronic-plus-binge ethanol model. Liver injury and hepatic lipid accumulation level were determined. The levels of Angiotensin converting enzyme 2 (ACE2), Ang II, CAV1, and other relevant proteins were evaluated by western blotting. In vitro, L02 cells were treated with alcohol and oleic acid mixture and APAP. CAV1 and ACE2 expression was downregulated in APAP-treated AFLD mice compared to APAP-treated mice. The overexpression of CAV1 in mice and L02 cells alleviated APAP-induced hepatotoxicity in AFLD and downregulated Ang II, p-EGFR/EGFR and P-ERK/ERK expression. Immunofluorescence experiments revealed interactions between CAV1, Ang II, and EGFR. The application of losartan (an Ang II receptor antagonist) and PD98059 (an ERK1/2 inhibitor) alleviated APAP-induced hepatotoxicity in AFLD. In conclusion, our findings verified that CAV1 alleviates APAP-aggravated hepatotoxicity in AFLD by downregulating the Ang II /EGFR/ERK axis, which could be a novel therapeutic target for its prevention or treatment.
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Trends in drug prescriptions for type 2 diabetes, hypertension, and dyslipidemia among adults with non-alcoholic fatty liver disease. Ann Hepatol 2022; 27:100699. [PMID: 35278680 DOI: 10.1016/j.aohep.2022.100699] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2022] [Accepted: 02/22/2022] [Indexed: 02/04/2023]
Abstract
INTRODUCTION AND OBJECTIVES Clinical guidelines recommend specific drugs for type 2 diabetes (T2D), hypertension, and dyslipidemia in patients with non-alcoholic fatty liver disease (NAFLD) and/or non-alcoholic steatohepatitis (NASH). We aimed to investigate the differences in prescription trends of antidiabetic, antihypertensive, and lipid-lowering drugs among adult patients according to the presence of comorbid NAFLD and/or NASH. METHODS We conducted a cross-sectional analysis using a large claims database from January 2013 to December 2020. RESULTS Among 7,716,908 people, 47,157 patients with T2D, 180,050 with hypertension, and 191,348 with dyslipidemia were identified. A total of 8,897, 16,451, and 24,762 patients with NAFLD, as well as 435, 523, and 1033 patients with NASH, had T2D, hypertension, and dyslipidemia, respectively. Among antidiabetic drugs, sodium-glucose cotransporter-2 inhibitors (SGLT2is) and thiazolidine were more frequently prescribed to patients with NAFLD than to those without NAFLD (non-NAFLD) (thiazolidine: 1.4% and 2.8% and SGLT2is: 17.8% and 25.9% for non-NAFLD and NAFLD, respectively [2019-2020]). Among antihypertensive drugs, angiotensin II receptor antagonists exhibited a slightly higher prescription ratio in patients with NAFLD (33.6% vs. 39.0%). Regarding lipid-lowering drugs, fibrates were more frequently prescribed to patients with NAFLD (10.3% vs. 18.4%). CONCLUSIONS Specific drugs tended to be prescribed to patients with NAFLD. However, the differences in prescription ratios were not considerable. Further investigation is required to confirm the effects of drugs on the prognosis of patients with NAFLD or NASH.
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25
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Comprehensive Review and Updates on Holistic Approach Towards Non-Alcoholic Fatty Liver Disease Management with Cardiovascular Disease. Curr Atheroscler Rep 2022; 24:515-532. [PMID: 35507280 DOI: 10.1007/s11883-022-01027-5] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/01/2022] [Indexed: 02/06/2023]
Abstract
PURPOSE OF REVIEW The global prevalence of non-alcoholic fatty liver disease (NAFLD) presents an unmet need in treating these, often asymptomatic, individuals. In this review, we summarised NAFLD management and described recent developments in non-alcoholic steatohepatitis (NASH) therapeutics that can shape the future of NAFLD. RECENT FINDINGS A multi-disciplinary effort in promoting sustainable lifestyle measures is paramount, with the goal of either limiting energy surplus alone or in combination with targeting downstream pathways of inflammation and fibrosis. Several antidiabetic medications like PPAR-γ agonist and glucagon-like peptide receptor agonists have beneficial effects on the metabolic profile as well as NASH histology. Vitamin E has shown promise in specific groups of patients with the haptoglobin2 allele protein. Newer drugs have demonstrated promising results in NASH resolution and fibrosis improvement such as obeticholic acid, resmetirom, aramchol, efruxifermin, aldafermin and lanifibranor. Apart from discussing the results of late stage clinical trials and the possible challenges in managing these patients with limited approved therapies, we also discussed the specific management of comorbidities (diabetes, hypertension, hyperlipidaemia, cardiovascular diseases) in NAFLD patients. Treatment strategy needs to target improvements in liver-related outcomes and cardiometabolic profile.
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Progression of Nonalcoholic Fatty Liver Disease-Associated Fibrosis in a Large Cohort of Patients with Type 2 Diabetes. Dig Dis Sci 2022; 67:1379-1388. [PMID: 33779880 DOI: 10.1007/s10620-021-06955-x] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2020] [Accepted: 03/12/2021] [Indexed: 12/25/2022]
Abstract
BACKGROUND Nonalcoholic fatty liver disease (NAFLD) can progress to advanced fibrosis, especially in patients with type 2 diabetes. Small studies have shown that fibrosis can also regress. AIM We aimed to provide large-scale data on progression and regression of fibrosis in diabetics with NAFLD. METHODS Adult diabetic patients with the diagnosis of NAFLD based on ICD-9 codes were identified. We used scores from noninvasive tests to identify patients with advanced fibrosis, calculated at first assessment and last follow-up visit. Cutoff values for advanced fibrosis were AST: ALT ratio > 1.4, AST to platelet ratio index > 1.5, FIB-4 score > 2.67, and NAFLD fibrosis score > 0.676. RESULTS Our cohort included 50,695 diabetics with NAFLD (55.3% female; 71% Caucasian; mean age, 51.2 ± 11.6 y). During median follow-up of 84.4 months, 25.8% transitioned from no advanced fibrosis to advanced fibrosis (progression), 6.4% transitioned from advanced fibrosis to no advanced fibrosis (regression), and the rest remained stable. Factors associated with transition to advanced fibrosis were female sex, older age at first evaluation, African-American race, obesity, chronic kidney disease, or coronary artery disease. Use of insulin increased the risk of progression to advanced fibrosis (odds ratio,1.36; p < .001), whereas use of oral hypoglycemic agents, angiotensin 2 receptor blockers, and fibrates was associated with reduced risk (odds ratios, 0.92, 0.94 and 0.90, respectively; all p < .05). CONCLUSIONS In a large cohort of patients with type 2 diabetes and NAFLD, more than a quarter progressed to advanced fibrosis. These findings indicate the need for early detection and staging of NAFLD in diabetics.
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Von-Hafe M, Borges-Canha M, Vale C, Leite AR, Sérgio Neves J, Carvalho D, Leite-Moreira A. Nonalcoholic Fatty Liver Disease and Endocrine Axes-A Scoping Review. Metabolites 2022; 12:298. [PMID: 35448486 PMCID: PMC9026925 DOI: 10.3390/metabo12040298] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2022] [Revised: 03/20/2022] [Accepted: 03/27/2022] [Indexed: 02/07/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease. NAFLD often occurs associated with endocrinopathies. Evidence suggests that endocrine dysfunction may play an important role in NAFLD development, progression, and severity. Our work aimed to explore and summarize the crosstalk between the liver and different endocrine organs, their hormones, and dysfunctions. For instance, our results show that hyperprolactinemia, hypercortisolemia, and polycystic ovary syndrome seem to worsen NAFLD's pathway. Hypothyroidism and low growth hormone levels also may contribute to NAFLD's progression, and a bidirectional association between hypercortisolism and hypogonadism and the NAFLD pathway looks likely, given the current evidence. Therefore, we concluded that it appears likely that there is a link between several endocrine disorders and NAFLD other than the typically known type 2 diabetes mellitus and metabolic syndrome (MS). Nevertheless, there is controversial and insufficient evidence in this area of knowledge.
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Affiliation(s)
- Madalena Von-Hafe
- Departamento de Cirurgia e Fisiologia, Faculdade de Medicina da Universidade do Porto, 4200-319 Porto, Portugal; (M.V.-H.); (C.V.); (A.R.L.); (J.S.N.); (A.L.-M.)
| | - Marta Borges-Canha
- Departamento de Cirurgia e Fisiologia, Faculdade de Medicina da Universidade do Porto, 4200-319 Porto, Portugal; (M.V.-H.); (C.V.); (A.R.L.); (J.S.N.); (A.L.-M.)
- Serviço de Endocrinologia, Diabetes e Metabolismo do Centro Hospitalar Universitário de São João, Alameda Prof. Hernâni Monteiro, 4200-319 Porto, Portugal;
| | - Catarina Vale
- Departamento de Cirurgia e Fisiologia, Faculdade de Medicina da Universidade do Porto, 4200-319 Porto, Portugal; (M.V.-H.); (C.V.); (A.R.L.); (J.S.N.); (A.L.-M.)
| | - Ana Rita Leite
- Departamento de Cirurgia e Fisiologia, Faculdade de Medicina da Universidade do Porto, 4200-319 Porto, Portugal; (M.V.-H.); (C.V.); (A.R.L.); (J.S.N.); (A.L.-M.)
| | - João Sérgio Neves
- Departamento de Cirurgia e Fisiologia, Faculdade de Medicina da Universidade do Porto, 4200-319 Porto, Portugal; (M.V.-H.); (C.V.); (A.R.L.); (J.S.N.); (A.L.-M.)
- Serviço de Endocrinologia, Diabetes e Metabolismo do Centro Hospitalar Universitário de São João, Alameda Prof. Hernâni Monteiro, 4200-319 Porto, Portugal;
| | - Davide Carvalho
- Serviço de Endocrinologia, Diabetes e Metabolismo do Centro Hospitalar Universitário de São João, Alameda Prof. Hernâni Monteiro, 4200-319 Porto, Portugal;
- Investigação e Inovação em Saúde (i3s), Faculdade de Medicina da Universidade do Porto, 4200-319 Porto, Portugal
| | - Adelino Leite-Moreira
- Departamento de Cirurgia e Fisiologia, Faculdade de Medicina da Universidade do Porto, 4200-319 Porto, Portugal; (M.V.-H.); (C.V.); (A.R.L.); (J.S.N.); (A.L.-M.)
- Serviço de Cirurgia Cardiotorácica do Centro Hospitalar Universitário de São João, 4200-319 Porto, Portugal
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Beneficial Effects of Dietary Nitrite on a Model of Nonalcoholic Steatohepatitis Induced by High-Fat/High-Cholesterol Diets in SHRSP5/Dmcr Rats: A Preliminary Study. Int J Mol Sci 2022; 23:ijms23062931. [PMID: 35328352 PMCID: PMC8951310 DOI: 10.3390/ijms23062931] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2022] [Revised: 03/06/2022] [Accepted: 03/07/2022] [Indexed: 12/10/2022] Open
Abstract
Nonalcoholic steatohepatitis (NASH) is a chronic liver disease that leads to liver cirrhosis and hepatocellular carcinoma. Endothelial dysfunction caused by hepatic lipotoxicity is an underlying NASH pathology observed in the liver and the cardiovascular system. Here, we evaluated the effect of dietary nitrite on a rat NASH model. Stroke-prone, spontaneously hypertensive 5/Dmcr rats were fed a high-fat/high-cholesterol diet to develop the NASH model, with nitrite or captopril (100 mg/L, each) supplementation in drinking water for 8 weeks. The effects of nitrite and captopril were evaluated using immunohistochemical analyses of the liver and heart tissues. Dietary nitrite suppressed liver fibrosis in the rats by reducing oxidative stress, as measured using the protein levels of nicotinamide adenine dinucleotide phosphate oxidase components and inflammatory cell accumulation in the liver. Nitrite lowered the blood pressure in hypertensive NASH rats and suppressed left ventricular chamber enlargement. Similar therapeutic effects were observed in a captopril-treated rat NASH model, suggesting the possibility of a common signaling pathway through which nitrite and captopril improve NASH pathology. In conclusion, dietary nitrite attenuates the development of NASH with cardiovascular involvement in rats and provides an alternative NASH therapeutic strategy.
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Di Pasqua LG, Cagna M, Berardo C, Vairetti M, Ferrigno A. Detailed Molecular Mechanisms Involved in Drug-Induced Non-Alcoholic Fatty Liver Disease and Non-Alcoholic Steatohepatitis: An Update. Biomedicines 2022; 10:194. [PMID: 35052872 PMCID: PMC8774221 DOI: 10.3390/biomedicines10010194] [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: 11/19/2021] [Revised: 01/11/2022] [Accepted: 01/12/2022] [Indexed: 12/12/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are some of the biggest public health challenges due to their spread and increasing incidence around the world. NAFLD is characterized by intrahepatic lipid deposition, accompanied by dyslipidemia, hypertension, and insulin resistance, leading to more serious complications. Among the various causes, drug administration for the treatment of numerous kinds of diseases, such as antiarrhythmic and antihypertensive drugs, promotes the onset and progression of steatosis, causing drug-induced hepatic steatosis (DIHS). Here, we reviewed in detail the major classes of drugs that cause DIHS and the specific molecular mechanisms involved in these processes. Eight classes of drugs, among the most used for the treatment of common pathologies, were considered. The most diffused mechanism whereby drugs can induce NAFLD/NASH is interfering with mitochondrial activity, inhibiting fatty acid oxidation, but other pathways involved in lipid homeostasis are also affected. PubMed research was performed to obtain significant papers published up to November 2021. The key words included the class of drugs, or the specific compound, combined with steatosis, nonalcoholic steatohepatitis, fibrosis, fatty liver and hepatic lipid deposition. Additional information was found in the citations listed in other papers, when they were not displayed in the original search.
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Affiliation(s)
- Laura Giuseppina Di Pasqua
- Unit of Cellular and Molecular Pharmacology and Toxicology, Department of Internal Medicine and Therapeutics, University of Pavia, 27100 Pavia, Italy
| | - Marta Cagna
- Unit of Cellular and Molecular Pharmacology and Toxicology, Department of Internal Medicine and Therapeutics, University of Pavia, 27100 Pavia, Italy
| | - Clarissa Berardo
- Unit of Cellular and Molecular Pharmacology and Toxicology, Department of Internal Medicine and Therapeutics, University of Pavia, 27100 Pavia, Italy
| | - Mariapia Vairetti
- Unit of Cellular and Molecular Pharmacology and Toxicology, Department of Internal Medicine and Therapeutics, University of Pavia, 27100 Pavia, Italy
| | - Andrea Ferrigno
- Unit of Cellular and Molecular Pharmacology and Toxicology, Department of Internal Medicine and Therapeutics, University of Pavia, 27100 Pavia, Italy
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Satiya J, Snyder HS, Singh SP, Satapathy SK. Narrative review of current and emerging pharmacological therapies for nonalcoholic steatohepatitis. Transl Gastroenterol Hepatol 2021; 6:60. [PMID: 34805582 DOI: 10.21037/tgh-20-247] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2020] [Accepted: 09/25/2020] [Indexed: 12/28/2022] Open
Abstract
Nonalcoholic steatohepatitis (NASH) is the most common cause of chronic liver disease today, and it has now emerged as the leading etiology of end-stage liver disease requiring liver transplantation. It is a progressive form of non-alcoholic fatty liver disease which can not only progress to cirrhosis of liver and hepatocellular carcinoma (HCC), but is associated with increased cardiovascular risks too. Despite all the advances in the understanding of the risk factors and the pathogenetic pathways involved in the pathogenesis and progression of NASH, an effective therapy for NASH has not been developed yet. Although lifestyle modifications including dietary modifications and physical activity remain the mainstay of therapy, there is an unmet need to develop a drug or a combination of drugs which can not only reduce the fatty infiltration of the liver, but also arrest the development and progression of fibrosis and advancement to cirrhosis of liver and HCC. The pharmacologic therapies which are being developed target the various components believed to be involved in the pathogenesis of nonalcoholic fatty liver disease (NAFLD)/NASH which includes insulin resistance, lipid metabolism oxidative stress, lipid peroxidation, inflammatory and cell death pathways, and fibrosis. In this review, we summarize the current state of knowledge on pharmacotherapy of NASH, and also highlight the recent developments in the field, for optimizing the management and treatment of NASH.
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Affiliation(s)
- Jinendra Satiya
- Division of Gastroenterology and Hepatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Heather S Snyder
- Department of Pharmacy, Emory University Hospital, Atlanta, GA, USA
| | - Shivaram Prasad Singh
- Department of Gastroenterology, S.C.B. Medical College, Cuttack, India.,Kalinga Gastroenterology Foundation, Beam Diagnostics Centre, Cuttack, India
| | - Sanjaya K Satapathy
- Division of Hepatology, Sandra Atlas Bass Center for Liver Diseases and Transplantation, Northwell Health, Manhasset, NY, USA
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Proteomic analysis of serum samples of paracoccidioidomycosis patients with severe pulmonary sequel. PLoS Negl Trop Dis 2021; 15:e0009714. [PMID: 34424905 PMCID: PMC8425554 DOI: 10.1371/journal.pntd.0009714] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2021] [Revised: 09/08/2021] [Accepted: 08/06/2021] [Indexed: 12/26/2022] Open
Abstract
Background Pulmonary sequelae (PS) in patients with chronic paracoccidioidomycosis (PCM) typically include pulmonary fibrosis and emphysema. Knowledge of the molecular pathways involved in PS of PCM is required for treatment and biomarker identification. Methodology/Principal findings This non-concurrent cohort study included 29 patients with pulmonary PCM that were followed before and after treatment. From this group, 17 patients evolved to mild/ moderate PS and 12 evolved severe PS. Sera from patients were evaluated before treatment and at clinical cure, serological cure, and apparent cure. A nanoACQUITY UPLC-Xevo QT MS system and PLGS software were used to identify serum differentially expressed proteins, data are available via ProteomeXchange with identifier PXD026906. Serum differentially expressed proteins were then categorized using Cytoscape software and the Reactome pathway database. Seventy-two differentially expressed serum proteins were identified in patients with severe PS compared with patients with mild/moderate PS. Most proteins altered in severe PS were involved in wound healing, inflammatory response, and oxygen transport pathways. Before treatment and at clinical cure, signaling proteins participating in wound healing, complement cascade, cholesterol transport and retinoid metabolism pathways were downregulated in patients with severe PS, whereas signaling proteins in gluconeogenesis and gas exchange pathways were upregulated. At serological cure, the pattern of protein expression reversed. At apparent cure pathways related with tissue repair (fibrosis) became downregulated, and pathway related oxygen transport became upregulated. Additionally, we identified 15 proteins as candidate biomarkers for severe PS. Conclusions/Significance Development of severe PS is related to increased expression of proteins involved in glycolytic pathway and oxygen exchange), indicative of the greater cellular activity and replication associated with early dysregulation of wound healing and aberrant tissue repair. Our findings provide new targets to study mechanisms of PS in PCM, as well as potential biomarkers. Pulmonary fibrosis is the main sequel of paracoccidioidomycosis (PCM), a fungal disease that affects mainly men, rural workers. The development of pulmonary fibrosis is complex and involves several mechanisms that culminate in aberrant collagen production and deposition in the lungs making it became stiff and blocking the air passages. These changes lead to difficulty in breathing and in PCM patients dyspnea in response to high or low levels of exertion is common. Therefore, these patients show incapacity to work and the decreased quality of life. With the possibility of identifying some marker, for example, it could help the indication of respiratory physiotherapy, professional rehabilitation, or therapeutic intervention. This is the first study to examine the pulmonary sequelae (PS) in patients with paracoccidioidomycosis using an approach combining proteomics with bioinformatics. Here, we identify the specific proteome pattern found in PCM patients with severe sequelae that distinguishes these patients from that with mild/moderate sequelae. Our results showed that time points immediately before treatment and at clinical cure are key moments at which PS can progress to severe PS due a dysregulation in wound healing with consequent delayed in the healing processes resulting in an aberrant scar. As such, we suggest that the prognoses for severe PS should be considered as soon as possible and as early as diagnosis of PCM. Furthermore, we used proteomics to identify possible serum biomarkers with which to predict the likely development of severe PS, to be validated in future studies.
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Kawaguchi K, Sakai Y, Terashima T, Shimode T, Seki A, Orita N, Takeshita Y, Shimakami T, Takatori H, Arai K, Kitamura K, Yamashita T, Yamashita T, Takamura M, Mizukoshi E, Takamura T, Honda M, Wada T, Kaneko S. Decline in serum albumin concentration is a predictor of serious events in nonalcoholic fatty liver disease. Medicine (Baltimore) 2021; 100:e26835. [PMID: 34397849 PMCID: PMC8341320 DOI: 10.1097/md.0000000000026835] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2020] [Revised: 06/20/2021] [Accepted: 07/19/2021] [Indexed: 02/07/2023] Open
Abstract
ABSTRACT Nonalcoholic fatty liver disease (NAFLD) is associated with metabolic syndrome, which includes diabetes mellitus and hyperlipidemia. A fraction of NAFLD patients develop nonalcoholic steatohepatitis, leading to cirrhosis associated with various serious complications, including hepatocellular carcinoma, gastroesophageal varices, cardiovascular events, and other organ malignancy. Although the incidence of chronic viral hepatitis with associated complications has gradually decreased as highly effective antiviral therapies have been established, the number of patients with steatohepatitis has been increasing.This retrospective study examined data of 229 patients from 22 hospitals in our region. We examined 155 cases of chronological data and assessed the development of liver fibrosis and evaluated hepatic reserve-related markers such as platelet count, FIB-4 index, prothrombin time, and serum albumin concentration. We analyzed the relationship of these chronological changes and the incidence of NAFLD related serious complications.Data related to liver fibrosis progression, albumin, and prothrombin time were significantly associated with the occurrence of serious complications associated with cirrhosis. We compared 22 event and 133 nonevent cases of chronological changes in the data per year and found that serum albumin concentration was significantly lower in the group that developed serious complications (event cases: -0.21 g/dL/year, nonevent cases: -0.04 g/dL/year (P < .001)). This albumin decline was only the associated factor with the event incidence by multivariate analysis (P < .01).Annual decline in serum albumin concentration in patients with NAFLD is associated with serious events from the outcome of multicenter retrospective study. This highlights its potential utility as a surrogate marker to assess the efficacy of prediction of NAFLD related serious events.
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Affiliation(s)
- Kazunori Kawaguchi
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Sciences
| | - Yoshio Sakai
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Sciences
- Department of Laboratory Medicine, Kanazawa University Graduate School of Medical Sciences
| | - Takeshi Terashima
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Sciences
| | - Tetsuhiro Shimode
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Sciences
| | - Akihiro Seki
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Sciences
| | - Noriaki Orita
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Sciences
| | - Yumie Takeshita
- Department of Endocrinology and Metabolism, Kanazawa University Graduate School of Medical Sciences
| | - Tetsuro Shimakami
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Sciences
| | - Hajime Takatori
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Sciences
| | - Kuniaki Arai
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Sciences
| | - Kazuya Kitamura
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Sciences
| | - Taro Yamashita
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Sciences
| | - Tatsuya Yamashita
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Sciences
| | - Masayuki Takamura
- Department of Cardiology, Kanazawa University Graduate School of Medical Sciences
| | - Eishiro Mizukoshi
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Sciences
| | - Toshinari Takamura
- Department of Endocrinology and Metabolism, Kanazawa University Graduate School of Medical Sciences
| | - Masao Honda
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Sciences
| | - Takashi Wada
- Department of Laboratory Medicine, Kanazawa University Graduate School of Medical Sciences
| | - Shuichi Kaneko
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Sciences
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Mantovani A, Valenti L. A call to action for fatty liver disease. Liver Int 2021; 41:1182-1185. [PMID: 34002475 DOI: 10.1111/liv.14907] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Accepted: 04/08/2021] [Indexed: 02/13/2023]
Affiliation(s)
- Alessandro Mantovani
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University Hospital of Verona, Verona, Italy
| | - Luca Valenti
- Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy.,Precision Medicine, Department of Transfusion Medicine and Hematology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
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Diabetic Kidney Disease, Cardiovascular Disease and Non-Alcoholic Fatty Liver Disease: A New Triumvirate? J Clin Med 2021; 10:jcm10092040. [PMID: 34068699 PMCID: PMC8126096 DOI: 10.3390/jcm10092040] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2021] [Revised: 05/03/2021] [Accepted: 05/06/2021] [Indexed: 12/12/2022] Open
Abstract
Non-alcoholic fatty liver disease is a highly prevalent disease worldwide with a renowned relation to cardiovascular disease and chronic kidney disease. These diseases share a common pathophysiology including insulin resistance, oxidative stress, chronic inflammation, dysbiosis and genetic susceptibilities. Non-alcoholic fatty liver disease is especially prevalent and more severe in type 2 diabetes. Patients with non-alcoholic fatty liver disease should have liver fibrosis assessment in order to identify those at the highest risk of adverse outcomes so that appropriate management strategies can be implemented. Early diagnosis and treatment of non-alcoholic fatty liver disease could ameliorate the burden of cardiovascular disease and chronic kidney disease.
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Ramadan MS, Russo V, Nigro G, Durante-Mangoni E, Zampino R. Interplay between Heart Disease and Metabolic Steatosis: A Contemporary Perspective. J Clin Med 2021; 10:jcm10081569. [PMID: 33917867 PMCID: PMC8068259 DOI: 10.3390/jcm10081569] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2021] [Revised: 03/26/2021] [Accepted: 04/03/2021] [Indexed: 12/12/2022] Open
Abstract
The liver-heart axis is a growing field of interest owing to rising evidence of complex bidirectional interplay between the two organs. Recent data suggest non-alcoholic fatty liver disease (NAFLD) has a significant, independent association with a wide spectrum of structural and functional cardiac diseases, and seems to worsen cardiovascular disease (CVD) prognosis. Conversely, the effect of cardiac disease on NAFLD is not well studied and data are mostly limited to cardiogenic liver disease. We believe it is important to further investigate the heart-liver relationship because of the tremendous global health and economic burden the two diseases pose, and the impact of such investigations on clinical decision making and management guidelines for both diseases. In this review, we summarize the current knowledge on NAFLD diagnosis, its systemic manifestations, and associations with CVD. More specifically, we review the pathophysiological mechanisms that govern the interplay between NAFLD and CVD and evaluate the relationship between different CVD treatments and NAFLD progression.
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Affiliation(s)
- Mohammad Said Ramadan
- Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy;
| | - Vincenzo Russo
- Department of Translational Medical Sciences, AORN Ospedali dei Colli-Monaldi Hospital, 80131 Naples, Italy; (V.R.); (G.N.)
- Cardiology Unit, AORN Ospedali dei Colli-Monaldi Hospital, 80131 Naples, Italy
| | - Gerardo Nigro
- Department of Translational Medical Sciences, AORN Ospedali dei Colli-Monaldi Hospital, 80131 Naples, Italy; (V.R.); (G.N.)
- Cardiology Unit, AORN Ospedali dei Colli-Monaldi Hospital, 80131 Naples, Italy
| | - Emanuele Durante-Mangoni
- Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy;
- Infectious and Transplant Medicine Unit, AORN Ospedali dei Colli-Monaldi Hospital, 80131 Naples, Italy;
- Correspondence:
| | - Rosa Zampino
- Infectious and Transplant Medicine Unit, AORN Ospedali dei Colli-Monaldi Hospital, 80131 Naples, Italy;
- Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy
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S-adenosylmethionine upregulates the angiotensin receptor-binding protein ATRAP via the methylation of HuR in NAFLD. Cell Death Dis 2021; 12:306. [PMID: 33753727 PMCID: PMC7985363 DOI: 10.1038/s41419-021-03591-1] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Revised: 03/01/2021] [Accepted: 03/03/2021] [Indexed: 02/06/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) has emerged globally and is associated with inflammatory signaling. The underlying mechanisms remain poorly delineated, although NAFLD has attracted considerable attention and been extensively investigated. Recent publications have determined that angiotensin II (Ang II) plays an important role in stimulating NAFLD progression by causing lipid metabolism disorder and insulin resistance through its main receptor, Ang II type 1 receptor (AT1R). Herein, we explored the effect of supplementary S-adenosylmethionine (SAM), which is the main biological methyl donor in mammalian cells, in regulating AT1R-associated protein (ATRAP), which is the negative regulator of AT1R. We found that SAM was depleted in NAFLD and that SAM supplementation ameliorated steatosis. In addition, in both high-fat diet-fed C57BL/6 rats and L02 cells treated with oleic acid (OA), ATRAP expression was downregulated at lower SAM concentrations. Mechanistically, we found that the subcellular localization of human antigen R (HuR) was determined by the SAM concentration due to protein methylation modification. Moreover, HuR was demonstrated to directly bind ATRAP mRNA and control its nucleocytoplasmic shuttling. Thus, SAM was suggested to upregulate ATRAP protein expression by maintaining the export of its mRNA from the nucleus. Taken together, our findings suggest that SAM can positively regulate ATRAP in NAFLD and may have various potential benefits for the treatment of NAFLD.
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The Tissue Renin-Angiotensin System and Its Role in the Pathogenesis of Major Human Diseases: Quo Vadis? Cells 2021; 10:cells10030650. [PMID: 33804069 PMCID: PMC7999456 DOI: 10.3390/cells10030650] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Revised: 03/09/2021] [Accepted: 03/13/2021] [Indexed: 01/18/2023] Open
Abstract
Evidence has arisen in recent years suggesting that a tissue renin-angiotensin system (tRAS) is involved in the progression of various human diseases. This system contains two regulatory pathways: a pathological pro-inflammatory pathway containing the Angiotensin Converting Enzyme (ACE)/Angiotensin II (AngII)/Angiotensin II receptor type 1 (AGTR1) axis and a protective anti-inflammatory pathway involving the Angiotensin II receptor type 2 (AGTR2)/ACE2/Ang1–7/MasReceptor axis. Numerous studies reported the positive effects of pathologic tRAS pathway inhibition and protective tRAS pathway stimulation on the treatment of cardiovascular, inflammatory, and autoimmune disease and the progression of neuropathic pain. Cell senescence and aging are known to be related to RAS pathways. Further, this system directly interacts with SARS-CoV 2 and seems to be an important target of interest in the COVID-19 pandemic. This review focuses on the involvement of tRAS in the progression of the mentioned diseases from an interdisciplinary clinical perspective and highlights therapeutic strategies that might be of major clinical importance in the future.
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Kisseleva T, Brenner D. Molecular and cellular mechanisms of liver fibrosis and its regression. Nat Rev Gastroenterol Hepatol 2021; 18:151-166. [PMID: 33128017 DOI: 10.1038/s41575-020-00372-7] [Citation(s) in RCA: 1025] [Impact Index Per Article: 256.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/23/2020] [Indexed: 01/18/2023]
Abstract
Chronic liver injury leads to liver inflammation and fibrosis, through which activated myofibroblasts in the liver secrete extracellular matrix proteins that generate the fibrous scar. The primary source of these myofibroblasts are the resident hepatic stellate cells. Clinical and experimental liver fibrosis regresses when the causative agent is removed, which is associated with the elimination of these activated myofibroblasts and resorption of the fibrous scar. Understanding the mechanisms of liver fibrosis regression could identify new therapeutic targets to treat liver fibrosis. This Review summarizes studies of the molecular mechanisms underlying the reversibility of liver fibrosis, including apoptosis and the inactivation of hepatic stellate cells, the crosstalk between the liver and the systems that orchestrate the recruitment of bone marrow-derived macrophages (and other inflammatory cells) driving fibrosis resolution, and the interactions between various cell types that lead to the intracellular signalling that induces fibrosis or its regression. We also discuss strategies to target hepatic myofibroblasts (for example, via apoptosis or inactivation) and the myeloid cells that degrade the matrix (for example, via their recruitment to fibrotic liver) to facilitate fibrosis resolution and liver regeneration.
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Affiliation(s)
- Tatiana Kisseleva
- Department of Surgery, University of California, San Diego, La Jolla, CA, USA.
| | - David Brenner
- Department of Medicine, University of California, San Diego, La Jolla, CA, USA
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Mantovani A, Dalbeni A. Treatments for NAFLD: State of Art. Int J Mol Sci 2021; 22:ijms22052350. [PMID: 33652942 PMCID: PMC7956331 DOI: 10.3390/ijms22052350] [Citation(s) in RCA: 129] [Impact Index Per Article: 32.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2021] [Revised: 02/22/2021] [Accepted: 02/23/2021] [Indexed: 02/06/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is to date the most common chronic liver disease in clinical practice and, consequently, a major health problem worldwide. It affects approximately 30% of adults in the general population and up to 70% of patients with type 2 diabetes (T2DM). Despite the current knowledge of the epidemiology, pathogenesis, and natural history of NAFLD, no specific pharmacological therapies are until now approved for this disease and, consequently, general strategies have been proposed to manage it. They include: (a) lifestyle change in order to promote weight loss by diet and physical activity, (b) control of the main cardiometabolic risk factors, (c) correction of all modifiable risk factors leading the development and progression of advanced forms of NAFLD, and (d) prevention of hepatic and extra-hepatic complications. In the last decade, several potential agents have been widely investigated for the treatment of NAFLD and its advanced forms—shedding some light but casting a few shadows. They include some glucose-lowering drugs (such as pioglitazone, glucagon-like peptide-1 (GLP-1) receptor agonists, sodium-glucose co-transporter-2 (SGLT-2) inhibitors), antioxidants (such as vitamin E), statins or other lipid lowering agents, bile and non-bile acid farnesoid X activated receptor (FXR) agonists, and others. This narrative review discusses in detail the different available approaches with the potential to prevent and treat NAFLD and its advanced forms.
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Affiliation(s)
- Alessandro Mantovani
- Section of Endocrinology, Diabetes and Metabolism, University and Azienda Ospedaliera Universitaria Integrata of Verona, 37126 Verona, Italy
- Correspondence:
| | - Andrea Dalbeni
- Section of General Medicine, Hypertension and Liver Unit, University and Azienda Ospedaliera Universitaria Integrata of Verona, 37134 Verona, Italy;
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40
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ACE2: from protection of liver disease to propagation of COVID-19. Clin Sci (Lond) 2020; 134:3137-3158. [PMID: 33284956 DOI: 10.1042/cs20201268] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2020] [Revised: 11/19/2020] [Accepted: 11/23/2020] [Indexed: 01/08/2023]
Abstract
Twenty years ago, the discovery of angiotensin-converting enzyme 2 (ACE2) was an important breakthrough dramatically enhancing our understanding of the renin-angiotensin system (RAS). The classical RAS is driven by its key enzyme ACE and is pivotal in the regulation of blood pressure and fluid homeostasis. More recently, it has been recognised that the protective RAS regulated by ACE2 counterbalances many of the deleterious effects of the classical RAS. Studies in murine models demonstrated that manipulating the protective RAS can dramatically alter many diseases including liver disease. Liver-specific overexpression of ACE2 in mice with liver fibrosis has proved to be highly effective in antagonising liver injury and fibrosis progression. Importantly, despite its highly protective role in disease pathogenesis, ACE2 is hijacked by SARS-CoV-2 as a cellular receptor to gain entry to alveolar epithelial cells, causing COVID-19, a severe respiratory disease in humans. COVID-19 is frequently life-threatening especially in elderly or people with other medical conditions. As an unprecedented number of COVID-19 patients have been affected globally, there is an urgent need to discover novel therapeutics targeting the interaction between the SARS-CoV-2 spike protein and ACE2. Understanding the role of ACE2 in physiology, pathobiology and as a cellular receptor for SARS-CoV-2 infection provides insight into potential new therapeutic strategies aiming to prevent SARS-CoV-2 infection related tissue injury. This review outlines the role of the RAS with a strong focus on ACE2-driven protective RAS in liver disease and provides therapeutic approaches to develop strategies to prevent SARS-CoV-2 infection in humans.
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41
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Jiang C, Iwaisako K, Cong M, Diggle K, Hassanein T, Brenner DA, Kisseleva T. Traditional Chinese Medicine Fuzheng Huayu Prevents Development of Liver Fibrosis in Mice. ACTA ACUST UNITED AC 2020; 4:561-580. [PMID: 33210080 PMCID: PMC7671588 DOI: 10.26502/acbr.50170125] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Aim: To investigate the therapeutic effect of FZHY on hepatic fibrosis in mice and to determine the mechanism of its action. Methods: Wild type mice were subjected to toxic (carbon tetrachloride, CCl4) or cholestatic (bile duct ligation, BDL). Upon induction of liver fibrosis, mice were treated with FZHY (4.0g/kg, 2w, oral gavage) or vehicle (PBS). Livers were analyzed by Sirius Red staining, immunostaining and RT-PCR for profibrogenic and pro-inflammatory genes. The effect of FZHY on hepatocytes, inflammatory responses, activation of fibrogenic myofibroblasts, and ROS production was assessed. Results: FZHY strongly inhibited the development of CCl4- and BDL-induced liver fibrosis in mice. Liver fibrosis was significantly improved in FZHY-treated mice, as demonstrated by reduced content of hepatic hydroxyproline and Sirius Red positive area. Moreover, the number of SMA +and Desmin+ myofibroblasts was significantly reduced in the livers of FZHY-treated mice, and correlated with downregulation of the mRNA levels of α-SMA, collagen-α1(I), tissue inhibitor of matrix metalloproteinase-1 (TIMP-1), TGF-β1 and its receptor TGF-βRI, and platelet-derived growth factor-β (PDGF-β), suggesting that FZHY inhibits activation of fibrogenic myofibroblasts. Furthermore, administration of FZHY markedly decreased recruitment of F4/80+ inflammatory macrophages to the livers of CCl4- and BDL-injured mice, and this effect was associated with downregulation of monocyte chemoattractant protein-1(MCP-1) and macrophage inflammatory protein-1 (MIP-1) mRNA. In addition, the lipid peroxidation products 4-hydroxynonenal (4-HNE) and malondialdehyde (MDA) were reduced, demonstrating that treatment with FZHY can effectively block ROS production in livers of CCl4- and BDL-injured mice. Conclusions: Traditional Chinese Medicine FZHY has a variety of anti-fibrotic effects, including strong anti-oxidant, anti-inflammatory and anti-fibrotic effects on myeloid cells and hepatocytes. Although FZHY compound does not seem to directly affect HSCs, it regulates HSC activation via inhibition of macrophage recruitment to fibrotic liver.
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Affiliation(s)
- Chunyan Jiang
- Beijing Friendship Hospital, Capital Medical University, Beijing, China
- Department of Medicine, University of California, San Diego, La Jolla, CA, USA
| | - Keiko Iwaisako
- Department of Medical Life Systems, Faculty of Life and Medical Sciences, Doshisha University, Kyotanabe, Japan
- Department of Medicine, University of California, San Diego, La Jolla, CA, USA
| | - Min Cong
- Beijing Friendship Hospital, Capital Medical University, Beijing, China
- Department of Medicine, University of California, San Diego, La Jolla, CA, USA
| | - Karin Diggle
- Department of Medicine, University of California, San Diego, La Jolla, CA, USA
| | | | - David A Brenner
- Department of Medicine, University of California, San Diego, La Jolla, CA, USA
| | - Tatiana Kisseleva
- Department of Surgery, University of California, San Diego, La Jolla, CA, USA
- Corresponding author: Tatiana Kisseleva, MD, Department of Surgery, University of California, San Diego, La Jolla, CA 92093, USA,
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42
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Hanif H, Khan MM, Ali MJ, Shah PA, Satiya J, Lau DT, Aslam A. A New Endemic of Concomitant Nonalcoholic Fatty Liver Disease and Chronic Hepatitis B. Microorganisms 2020; 8:microorganisms8101526. [PMID: 33020450 PMCID: PMC7601829 DOI: 10.3390/microorganisms8101526] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2020] [Revised: 09/28/2020] [Accepted: 09/30/2020] [Indexed: 12/12/2022] Open
Abstract
Hepatitis B virus (HBV) infection remains a global public problem despite the availability of an effective vaccine. In the past decades, nonalcoholic fatty liver disease (NAFLD) has surpassed HBV as the most common cause of chronic liver disease worldwide. The prevalence of concomitant chronic hepatitis B (CHB) and NAFLD thus reaches endemic proportions in geographic regions where both conditions are common. Patients with CHB and NAFLD are at increased risk of liver disease progression to cirrhosis and hepatocellular carcinoma. Due to the complexity of the pathogenesis, accurate diagnosis of NAFLD in CHB patients can be challenging. Liver biopsy is considered the gold standard for diagnosing and determining disease severity, but it is an invasive procedure with potential complications. There is a growing body of literature on the application of novel noninvasive serum biomarkers and advanced radiological modalities to diagnose and evaluate NAFLD, but most have not been adequately validated, especially for patients with CHB. Currently, there is no approved therapy for NAFLD, although many new agents are in different phases of development. This review provides a summary of the epidemiology, clinical features, diagnosis, and management of the NAFLD and highlights the unmet needs in the areas of CHB and NAFLD coexistence.
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Affiliation(s)
- Hira Hanif
- Liver Center, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; (H.H.); (M.M.K.); (M.J.A.); (P.A.S.); (J.S.)
| | - Muzammil M. Khan
- Liver Center, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; (H.H.); (M.M.K.); (M.J.A.); (P.A.S.); (J.S.)
| | - Mukarram J. Ali
- Liver Center, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; (H.H.); (M.M.K.); (M.J.A.); (P.A.S.); (J.S.)
| | - Pir A. Shah
- Liver Center, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; (H.H.); (M.M.K.); (M.J.A.); (P.A.S.); (J.S.)
- Department of Internal Medicine, University of Texas, San Antonio, TX 78229, USA
| | - Jinendra Satiya
- Liver Center, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; (H.H.); (M.M.K.); (M.J.A.); (P.A.S.); (J.S.)
| | - Daryl T.Y. Lau
- Liver Center, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; (H.H.); (M.M.K.); (M.J.A.); (P.A.S.); (J.S.)
- Correspondence: (D.T.Y.L.); (A.A.)
| | - Aysha Aslam
- Department of Medicine, Louis A Weiss Memorial Hospital, Chicago, IL 60640, USA
- Correspondence: (D.T.Y.L.); (A.A.)
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Dawood RM, El-Meguid MA, Salum GM, El Awady MK. Key Players of Hepatic Fibrosis. J Interferon Cytokine Res 2020; 40:472-489. [PMID: 32845785 DOI: 10.1089/jir.2020.0059] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023] Open
Affiliation(s)
- Reham M. Dawood
- Genetic Engineering Division, Department of Microbial Biotechnology, National Research Centre, Giza, Egypt
| | - Mai A. El-Meguid
- Genetic Engineering Division, Department of Microbial Biotechnology, National Research Centre, Giza, Egypt
| | - Ghada Maher Salum
- Genetic Engineering Division, Department of Microbial Biotechnology, National Research Centre, Giza, Egypt
| | - Mostafa K. El Awady
- Genetic Engineering Division, Department of Microbial Biotechnology, National Research Centre, Giza, Egypt
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44
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Guo YC, Lu LG. Antihepatic Fibrosis Drugs in Clinical Trials. J Clin Transl Hepatol 2020; 8:304-312. [PMID: 33083254 PMCID: PMC7562798 DOI: 10.14218/jcth.2020.00023] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2020] [Revised: 05/07/2020] [Accepted: 07/30/2020] [Indexed: 12/12/2022] Open
Abstract
Liver fibrosis is not an independent disease. It refers to the abnormal proliferation of connective tissues in the liver caused by various pathogenic factors. Thus far, liver fibrosis has been considered to be associated with a set of factors, such as viral infection, alcohol abuse, non-alcoholic fatty liver disease, and autoimmune hepatitis, as well as genetic diseases. To date, clinical therapeutics for liver fibrosis still face challenges, as elimination of potential causes and conventional antifibrotic drugs cannot alleviate fibrosis in most patients. Recently, potential therapeutic targets of liver fibrosis, such as metabolism, inflammation, cell death and the extracellular matrix, have been explored through basic and clinical research. Therefore, it is extremely urgent to review the antihepatic fibrosis therapeutics for treatment of liver fibrosis in current clinical trials.
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Affiliation(s)
- Yue-Cheng Guo
- Shanghai Key Laboratory of Pancreatic Diseases, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Lun-Gen Lu
- Shanghai Key Laboratory of Pancreatic Diseases, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Correspondence to: Lun-Gen Lu, Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, No. 650 Songjiang Road, Shanghai 201620, China. Tel: +86-21-63240090, E-mail:
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45
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Differences among patients with and without nonalcoholic fatty liver disease having elevated alanine aminotransferase levels at various stages of metabolic syndrome. PLoS One 2020; 15:e0238388. [PMID: 32866186 PMCID: PMC7458345 DOI: 10.1371/journal.pone.0238388] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2020] [Accepted: 08/14/2020] [Indexed: 12/20/2022] Open
Abstract
Background The prevalence of nonalcoholic fatty liver disease (NAFLD) in the non-obese population has increased and NAFLD is not always recognized in individuals with metabolic syndrome (MS). The risk of cirrhosis is higher in patients having NAFLD with elevated alanine aminotransferase (ALT) levels than in those having NAFLD with normal ALT levels. Objective To measure the differences in clinical factors associated with NAFLD having elevation of ALT among subjects with Non-MS, Pre-MS, and MS, and to measure differences in metabolites between MS subjects with and without NAFLD having elevation of ALT. Methods Among 7,054 persons undergoing health check-ups, we included 3,025 subjects who met the selection criteria. We measured differences in clinical factors for NAFLD having elevation of ALT among subjects with Non-MS, Pre-MS, and MS, and compared metabolites between subjects with and without NAFLD having elevation of ALT in 32 subjects with MS. Results The prevalence of NAFLD and NAFLD having elevation of ALT was significantly progressively greater in subjects with Non-MS, Pre-MS, and MS (p <0.001, respectively). In the Non-MS group, there were significant differences between subjects with and without NAFLD having elevation of ALT with respect to body mass index (BMI), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol, hemoglobin A1c, uric acid, aspartate aminotransferase (AST); In the Pre-MS group, there were significant differences in BMI, hypertension, AST, and gamma-glutamyl transpeptidase (GGT); In the MS group, there were significant differences in HDL-C, impaired glucose tolerance, AST, and GGT. There were significant differences in levels of metabolites of nicotinamide, inosine, and acetyl-L-carnitine between MS subjects with and without NAFLD having elevation of ALT (all p <0.05). Conclusions Although NAFLD having elevation of ALT is important for development of NAFLD, differences in factors associated with NAFLD having elevation of ALT at various stages of MS should be considered. Additionally, several metabolites may play roles in the identification of risk for NAFLD in individuals with MS.
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The Japanese Society of Hypertension Guidelines for the Management of Hypertension (JSH 2019). Hypertens Res 2020; 42:1235-1481. [PMID: 31375757 DOI: 10.1038/s41440-019-0284-9] [Citation(s) in RCA: 1236] [Impact Index Per Article: 247.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
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Common Drug Pipelines for the Treatment of Diabetic Nephropathy and Hepatopathy: Can We Kill Two Birds with One Stone? Int J Mol Sci 2020; 21:ijms21144939. [PMID: 32668632 PMCID: PMC7404115 DOI: 10.3390/ijms21144939] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2020] [Revised: 06/30/2020] [Accepted: 06/30/2020] [Indexed: 12/17/2022] Open
Abstract
Type 2 diabetes (T2D) is associated with diabetic nephropathy as well as nonalcoholic steatohepatitis (NASH), which can be called "diabetic hepatopathy or diabetic liver disease". NASH, a severe form of nonalcoholic fatty disease (NAFLD), can sometimes progress to cirrhosis, hepatocellular carcinoma and hepatic failure. T2D patients are at higher risk for liver-related mortality compared with the nondiabetic population. NAFLD is closely associated with chronic kidney disease (CKD) or diabetic nephropathy according to cross-sectional and longitudinal studies. Simultaneous kidney liver transplantation (SKLT) is dramatically increasing in the United States, because NASH-related cirrhosis often complicates end-stage renal disease. Growing evidence suggests that NAFLD and CKD share common pathogenetic mechanisms and potential therapeutic targets. Glucagon-like peptide 1 (GLP-1) receptor agonists and sodium-glucose cotransporter 2 (SGLT2) inhibitors are expected to ameliorate NASH and diabetic nephropathy/CKD. There are no approved therapies for NASH, but a variety of drug pipelines are now under development. Several agents of them can also ameliorate diabetic nephropathy/CKD, including peroxisome proliferator-activated receptors agonists, apoptosis signaling kinase 1 inhibitor, nuclear factor-erythroid-2-related factor 2 activator, C-C chemokine receptor types 2/5 antagonist and nonsteroidal mineral corticoid receptor antagonist. This review focuses on common drug pipelines in the treatment of diabetic nephropathy and hepatopathy.
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Sumida Y, Yoneda M, Tokushige K, Kawanaka M, Fujii H, Yoneda M, Imajo K, Takahashi H, Eguchi Y, Ono M, Nozaki Y, Hyogo H, Koseki M, Yoshida Y, Kawaguchi T, Kamada Y, Okanoue T, Nakajima A. Antidiabetic Therapy in the Treatment of Nonalcoholic Steatohepatitis. Int J Mol Sci 2020; 21:ijms21061907. [PMID: 32168769 PMCID: PMC7139365 DOI: 10.3390/ijms21061907] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2020] [Revised: 03/04/2020] [Accepted: 03/05/2020] [Indexed: 02/07/2023] Open
Abstract
Liver-related diseases are the third-leading causes (9.3%) of mortality in type 2 diabetes (T2D) in Japan. T2D is closely associated with nonalcoholic fatty liver disease (NAFLD), which is the most prevalent chronic liver disease worldwide. Nonalcoholic steatohepatitis (NASH), a severe form of NAFLD, can lead to hepatocellular carcinoma (HCC) and hepatic failure. No pharmacotherapies are established for NASH patients with T2D. Though vitamin E is established as a first-line agent for NASH without T2D, its efficacy for NASH with T2D recently failed to be proven. The effects of pioglitazone on NASH histology with T2D have extensively been established, but several concerns exist, such as body weight gain, fluid retention, cancer incidence, and bone fracture. Glucagon-like peptide 1 (GLP-1) receptor agonists and sodium-glucose cotransporter 2 (SGLT2) inhibitors are expected to ameliorate NASH and NAFLD (LEAN study, LEAD trial, and E-LIFT study). Among a variety of SGLT2 inhibitors, dapagliflozin has already entered the phase 3 trial (DEAN study). A key clinical need is to determine the kinds of antidiabetic drugs that are the most appropriate for the treatment of NASH to prevent the progression of hepatic fibrosis, resulting in HCC or liver-related mortality without increasing the risk of cardiovascular or renal events. Combination therapies, such as glucagon receptor agonist/GLP-1 or gastrointestinal peptide/GLP-1, are under development. This review focused on antidiabetic agents and future perspectives on the view of the treatment of NAFLD with T2D.
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Affiliation(s)
- Yoshio Sumida
- Division of Hepatology and Pancreatology, Department of Internal Medicine, Aichi Medical University, Nagakute, Aichi 480-1195, Japan;
- Correspondence: ; Tel.: +81-561-62-3311; Fax: +81-561-62-1508
| | - Masashi Yoneda
- Division of Hepatology and Pancreatology, Department of Internal Medicine, Aichi Medical University, Nagakute, Aichi 480-1195, Japan;
| | - Katsutoshi Tokushige
- Department of Internal Medicine, Institute of Gastroenterology, Tokyo Women’s Medical University, Tokyo 162-8666, Japan;
| | - Miwa Kawanaka
- Department of General Internal Medicine2, Kawasaki Medical School, Okayama 700-8505, Japan;
| | - Hideki Fujii
- Department of Hepatology, Graduate School of Medicine, Osaka City University, Osaka 558-8585, Japan;
| | - Masato Yoneda
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan; (M.Y.); (K.I.); (A.N.)
| | - Kento Imajo
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan; (M.Y.); (K.I.); (A.N.)
| | - Hirokazu Takahashi
- Department of Metabolism and Endocrinology, Faculty of Medicine, Saga University, Saga 840-8502, Japan;
| | - Yuichiro Eguchi
- Liver Center, Saga University Hospital, Saga 840-8502, Japan;
| | - Masafumi Ono
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Tokyo Women’s Medical University Medical Center East, Tokyo 116-8567, Japan;
| | - Yuichi Nozaki
- Department of Gastroenterology, National Center for Global Health and Medicine, Tokyo 162-8655, Japan;
| | - Hideyuki Hyogo
- Department of Gastroenterology, JA Hiroshima General Hospital, Hiroshima 738-8503, Japan;
| | - Masahiro Koseki
- Division of Cardiovascular Medicine, Department of Medicine, Osaka University Graduate School of Medicine, Suita Osaka 565-0871, Japan;
| | - Yuichi Yoshida
- Department of Gastroenterology and Hepatology, Suita Municipal Hospital, Osaka 564-8567, Japan
| | - Takumi Kawaguchi
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume 830-0011, Japan;
| | - Yoshihiro Kamada
- Department of Molecular Biochemistry & Clinical Investigation, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan;
| | - Takeshi Okanoue
- Hepatology Center, Saiseikai Suita Hospital, Osaka 564-0013, Japan;
| | - Atsushi Nakajima
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan; (M.Y.); (K.I.); (A.N.)
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Stahl EP, Dhindsa DS, Lee SK, Sandesara PB, Chalasani NP, Sperling LS. Nonalcoholic Fatty Liver Disease and the Heart: JACC State-of-the-Art Review. J Am Coll Cardiol 2020; 73:948-963. [PMID: 30819364 DOI: 10.1016/j.jacc.2018.11.050] [Citation(s) in RCA: 266] [Impact Index Per Article: 53.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2018] [Revised: 11/14/2018] [Accepted: 11/26/2018] [Indexed: 02/07/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) and cardiovascular disease (CVD) are both manifestations of end-organ damage of the metabolic syndrome. Through multiple pathophysiological mechanisms, CVD and NAFLD are associated with each other. Systemic inflammation, endothelial dysfunction, hepatic insulin resistance, oxidative stress, and altered lipid metabolism are some of the mechanisms by which NAFLD increases the risk of CVD. Patients with NAFLD develop increased atherosclerosis, cardiomyopathy, and arrhythmia, which clinically result in cardiovascular morbidity and mortality. Defining the mechanisms linking these 2 diseases offers the opportunity to further develop targeted therapies. The aim of this comprehensive review is to examine the association between CVD and NAFLD and discuss the overlapping management approaches.
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Affiliation(s)
- Eric P Stahl
- Department of Internal Medicine, Emory University School of Medicine, Atlanta, Georgia
| | - Devinder S Dhindsa
- Emory Clinical Cardiovascular Research Institute, Division of Cardiology, Emory University School of Medicine, Atlanta, Georgia
| | - Suegene K Lee
- Department of Internal Medicine, Emory University School of Medicine, Atlanta, Georgia
| | - Pratik B Sandesara
- Emory Clinical Cardiovascular Research Institute, Division of Cardiology, Emory University School of Medicine, Atlanta, Georgia
| | - Naga P Chalasani
- Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, Indiana
| | - Laurence S Sperling
- Emory Clinical Cardiovascular Research Institute, Division of Cardiology, Emory University School of Medicine, Atlanta, Georgia.
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Ganguli S, DeLeeuw P, Satapathy SK. A Review Of Current And Upcoming Treatment Modalities In Non-Alcoholic Fatty Liver Disease And Non-Alcoholic Steatohepatitis. Hepat Med 2019; 11:159-178. [PMID: 31814783 PMCID: PMC6863115 DOI: 10.2147/hmer.s188991] [Citation(s) in RCA: 29] [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: 06/17/2019] [Accepted: 10/03/2019] [Indexed: 12/15/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in the West. Non-alcoholic steatohepatitis (NASH) is the progressive form of NAFLD and can lead to cirrhosis, hepatocellular carcinoma, and is associated with increased cardiovascular risks. Multiple components and risk factors are thought to be involved in the pathogenesis of NAFLD and NASH. Optimal therapy has not yet been found, but many advances have been made with the discovery of potential therapeutic options. In this paper, we aim to provide a comprehensive review of approved, studied, and upcoming treatment options for NAFLD and NASH. Non-pharmacologic therapy (lifestyle modifications and bariatric surgery) and pharmacologic therapy are both reviewed. Pharmacologic therapy target components thought to be involved in the pathogenesis of this disease process including insulin resistance, oxidative stress, inflammation, lipid metabolism, and fibrosis are reviewed in this paper. Results of the emerging treatment targets in phase 2 and 3 clinical trials are also included.
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Affiliation(s)
- Surosree Ganguli
- Division of Internal Medicine, University of Louisville, Louisville, KY 40202, USA
| | - Peter DeLeeuw
- Division of Internal Medicine, University of Tennessee Health Science Center, Memphis, TN 38163, USA
| | - Sanjaya K Satapathy
- Division of Hepatology and Sandra Atlas Bass Center for Liver Diseases, Northwell Health, Manhasset, NY 11030, USA
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